id
stringlengths 11
16
| query
stringlengths 279
826k
| answer
stringlengths 174
4.34k
|
|---|---|---|
PubmedSumm4800 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: early detection and eradication of malignant tumors at an early stage before metastasize and spread to neighboring areas , can be prevented from threats and problems later . during 20032007
almost 0.0% , 0.9% , 6.0% , 15.0% , 20.8% , 19.7% , 22.6% and 15.1% of mortality has occurred in the following order , 20 yr , 2034 , 3544 , 4554 , 5564 , 6574 , 7584 and above 85 yr(1 ) .
report submitted shows that 0% detection has been possible in those under the age of 20 . while 1.9% , 10.2% , 22.6% , 24.4% , 19.7% , 15.5% and 5.6% of diagnosis has been possible in the inside groups ranging , 3444 , 4554 , 5564 , 6574 , 7584 and above 85 yr ( 1 ) .
early detection of breast cancer is one of the most important issues that researchers have always sought .
pathological mechanism of breast cancer is formed in this manner while cancerous cells produce nitric oxide ( no ) in the proliferative phase ( proliferative ) .
the chemicals cause difficulties in neural control , and thus lead to regional artery dilatation in the early stages of cancer cells growth .
this angiogenesis causes increment in the local temperature even a few years earlier than tumor formation .
deep lesions can cause changes in skin temperature ( 3 , 4 ) . based on the features listed above
, this concept means that , some features used in the diagnosis of breast cancer , entail geometric size , location , shape , topology as well as the thermal features . because , doctors are interested in the thermal imaging after a long time , which comprise the following : 1 ) progress done in the technology of infrared cameras ; 2 ) creation of standard rules for thermal imaging ; 3 ) accurate calibration of the camera .
breast thermography is a potential technique with useful protocol ( 5 ) , which has advantages such as noninvasive , non - radiation , passive , quick , painless , inexpensive , and non - contact camera ( 611 ) .
breast thermography is suitable for women of all ages , including pregnant and nursing women and women with dense tissue in their breast ( 12 ) .
thermogram of a patient provides the distribution of heat in the body . due to the high metabolic rate and progression of vascular angiogenesis ,
thus , cancer cells in infrared images can be indicated in the form of critical focus .
thermography is better than the method of mammography in predicting breast cancer in its early stages , even when the tumor is at the initial stage of formation .
medical thermography could not progress for a long time because of the dependency on hardware and software fields and limitations concerning existing .
recently hardware limitations have declined with the improvements made in the field of photo detectors and pcs .
all the items listed , indicate the success related to the use of thermal images in medicine ( 5 ) .
recently , case studies have been implemented on breast cancer detection in large - scale by thermal imaging , mostly indicate average sensitivity and specificity of 90% ( 7 ) .
thermal imaging is employed in diverse medical applications such as breast cancer detection ( 14 ) , pain management ( 15 ) , and diabetes ( 16 ) .
methods are proposed for the analysis of image processing algorithms such as abnormal statistical methods , thermal asymmetric methods and descriptive matching ( 1719 ) .
although the image processing techniques are important for the analysis of medical thermography , many of these methods are not sensitive enough or delicate algorithms are not applied extensively for independent detection by using of computer .
the purpose of this paper is to provide a diagnostic tool by using computer based on thermal model ( 7 ) .
one of the primary problems for the clustering and detecting breast cancer in thermal imaging is that both of breast areas must first be segmented so that the image processing be performed on it ( 20 ) . since thermal images have diverse formats ( small or large , condensation , etc . )
, separating special area whit high accuracy is very difficult . on the other hand ,
some papers ( 21 ) have used asymmetry of the two regions and moments . in the proposed method ,
the problem has been fixed and there is no requirement to separate the breast from the beginning .
identification of the correct boundary and image segmentation is one of the most important issues in the utilization of machine vision applications , such as traffic monitoring in urban transport systems ( 22 , 23 ) , medical applications ( 24 ) , video monitoring and target identification in air defense weapons ( 25 ) .
one problem in computer analysis of the thermal images is that the images should be obtained directly from the patient to avoid encountering with the problems during the analysis of such asymmetry .
it is difficult to separate cancerous tissue in thermal images ; the goal of this paper is to solve this problem .
the proposed models are the combination of surf and sift which are related to feature extraction .
whit regard to computer vision ; contour models describe the boundaries of shapes within an image .
few papers are in the field of thermography have used active contour method to separate but these are not pertinent to breast cancer .
active contour method has been adopted for segmenting masses on breast ultrasound images ( 26 ) .
previous models were not related to infrared image within the scope of breast cancer . and finally in the proposed method , lyapunov exponent has been used for detecting benign and malignant cancer .
lyapunov exponents are quantities that characterize the average rate of divergence or convergence of two neighboring trajectories in the ps .
the proposed method requires that body organs in the thermal image be separated into distinct parts . for this purpose , firstly
after thermogram someone took pictures from a patient , the image must be converted to gray image format using an appropriate threshold , so we can , the main organ extract from image by using of active contour for later analysis .
otsu s technique is adopted to obtain the optimal level of threshold in order to minimize the intra - class variance ( 29 ) .
detection of corners has been used in many aspects of image processing and machine vision ( fig .
1 ) . images obtained the method of edge detection finding all the corners , measure of the exact position of the corner and robustness of algorithm against noise is resistant to noise , are important in edge detection . by using specific characteristics , simpler picture of the structure of image
the corner is one of the special features widely used in the analysis of sense .
some of the important criteria for detection of corner includes : a ) all corners should be detected ; b ) anything wrong corner is not found ; c ) corners should be evident in their exact position ; f ) the corner detector should be robust against noise ( 3033 )
. methods of corner detection including the curvature , model of corner , peripheral curve . in this paper , using methods based on scale space , the corner position is extracted .
scale space allows the edges of the space with carefully down the space with high accuracy to be examined .
this work is done by applying the gaussian filter with different standard deviation ( 34 ) .
k is calculated by the following equation ( 35 ) :
k(u,)=x(u,)y(u,)x(u,)y(u,)(x(u,)2y(u,)2)1.5
where :
x(u,)=x(u)g(u,)x(u,)=x(u)g(u,)y(u,)=y(u)g(u,)y(u,)=y(u)g(u, )
and is the convolution operator , g(u, ) is gaussian function with standard deviation ,(u, ) , , g(u, ) , are the first and second derivatives of the gaussian function respectively . the original algorithms of css
are used the following for detecting corner points of an image :
canny edge detector is applied on the image gray levels and a binary edge map obtained.perimeter of edges is extracted from the map of edge , and distances between places are replenished , t connections are found.the curvature in a large scale ( high ) , is calculated for the environment of each edge.local maximum points are selected as the point s initial corner points .
the absolute size of curvature related to points must be higher than national threshold t and twice as one of local minimum of its neighbors.following corner points are applied in the largest scale to the smallest scale for improving their posture.comparison of t - fitting with the other corner and deletion of one corner points that is too close .
canny edge detector is applied on the image gray levels and a binary edge map obtained .
perimeter of edges is extracted from the map of edge , and distances between places are replenished , t connections are found . the curvature in a large scale ( high ) , is calculated for the environment of each edge .
the absolute size of curvature related to points must be higher than national threshold t and twice as one of local minimum of its neighbors . following corner points are applied in the largest scale to the smallest scale for improving their posture . comparison of t - fitting with the other corner and deletion of one corner points that is too close .
the scale - related algorithm has been used for finding the corner points and from multi- scale for establishing the corner points . among corner points of candidate , although some are a local maximum , but most of them will be removed with the help of the local threshold .
the endowment threshold is as follows :
t(u)=ck=c1l1+l2 + 1i = ul2u+l1k(i ) the average value of k , was used to display average curvature of covered area of ros .
this area is defined as the minimum of the local curvature adjacent to the next . in general
, a good corner must have been the desired angle , in order to be in a specific range .
this angle ( ci ) can be obtained from the following equation :
ci|tan1y1x1tan1y2x2|
in which :
x1=1l1i = u+1u+l1x(i)x(u) y1=1l1i = u+1u+l1y(i)y(u) x2=1l2i = ul2u1x(i)x(u) y2=1l2i = ul2u1y(i)y(u ) after this step , the set of candidate points is changed ; several iterations must be done for converting the points . using this criterion ,
segmented corner points may be removed due to noise and edgy detail and feature points of several sizes remain ( fig .
2 ) . finding the main points in the thermal image coordinate of a point 9 and 10 are maximum points in image of edge detection .
coordinates of the point s m , n , o , p , q can be calculated by the following equations .
currently methods used for feature extraction in thermal images for analysis , include geometrical features and wavelet moment ( 3641 ) . to be able to extract features that are resistant to the angle and rotation ,
our proposal is to use surf descriptor , this descriptor is an extended form of sift , and much more ( about 10 times ) is faster than sift algorithm . sift algorithm can calculate the gradient of any area in the size 16 16 , then it is normalized , while the surf algorithm is used by estimating the second order derivative of gaussian function , convolved in image(42 ) .
moreover instead of using time consuming calculations of sift , quick estimate , is used .
although surf and sift have their advantages and disadvantages , but surf algorithm works based on estimating the gradient of image pixels .
although the nature of the pixels change slightly ( due to convolution of gaussian function ) , it is desirable in other words , the pixel values remain constant ( 43,44 ) .
sift makes the pyramids of the image for finding the candidate points makes , each layer filters gauss law with increasing values of sigma and its acquired differences . on the other hand , surf makes use from hessian s matrix for selecting the candidate points with different sizes , as it is used in the hessian laplace . dominant angle over feature descriptor vector
is obtained , using haar - wavelet filters and employing the integral image . finally , using haar - wavelet filters
3 ) . feature extraction by using surf algorithm totally , surf utilizes a hessian based blob detector to find interest points .
the determinant of a hessian matrix expresses the extent of the response and is an expression of the local change around the area ( 45 ) .
the heart of the surf detection is non - maximal - suppression of the determinants of the hessian matrices . by determining a unique orientation for an interest point
finally , the descriptor is normalized , to achieve invariance to contrast those variations that will represent themselves as a linear scaling of the descriptor .
the interest points detected in the infrared image asmyd s assessment of the key point s detectors ( 46 ) shows that although harris s detector , is not robust enough to changes scale , it has superior performance compared to the rest of detectors .
the second moment matrix is used often for detection of features or to describe the internal structure of the image .
this matrix must be adjusted to changes in scale , so it makes in depend of the accuracy and picture clarity .
the second moment matrix is defined as follows ( 47 ) :
(x,i,d)=[11122122]=d2g(i)[lx2(x,d)lxly(x,d)lxly(x,d)ly2(x,d ) ] is integrated scale , d is differenced scale .
then the derivative is made average in the vicinity of point by smoothing with gaussian window to the size 1 .
eigen values of this matrix show the variation of the two signals in the neighborhood of a point .
larger value of this feature indicates that its point is high in both major curve ( such as corners , connector locations , etc . ) .
harris combines trace and second moment matrix determinant in the following form ( 48 ) :
r = det((x,1,d))trace2((x,1,d ) ) local maximum of harris ( r ) makes clear the location of the critical point .
harris detector is stable even in the presence of light that can provide same points .
also , harris s detector can reveal the same points even when there are changes in the angle of view ( 48 , 49 ) .
5 . detected points by a harris s method in the next step , points of interest identified by the surf and corner algorithm , combined and then used to segment cancerous tissue .
however , it is possible that some parts of the features obtained from the corner method , are not important .
so in the proposed method it is needed that the extracted features are combined together and used in both methods ( surf and sift ) .
initially extracted skeleton is partitionedand thenextracted features from the two methods are combined ( fig .
6 , areas 4 and 6 needs to be reviewed , because breast cancer is noticeable in 3 , 4 , 5 and 6 districts .
in addition , because areas 4 , 6 are common so next focus will be on this area .
the next step requires that the cancerous cancer be segmented from image , done using active contour methods .
active contour models are powerful tools for identifying and tracking images , used extensively in applications of machine vision and image processing . object detection with the help of active contour models is done based on tracking the boundaries of the target object . in this method ,
the contour curve is defined by the user or automatically around the target object , used from the extracted features for contour curves in this paper .
then this contour is deformed effected by the energy function , to be adapted with boundaries of target object ( 50 , 51 ) .
s(u)=i(x(u),y(u ) ) u= this curve is transformed under the influence of an energy function , and is guided towards the features of interest in an image .
points of contour moves in the space coordinates ( x , y ) , as long as curve is coincided to the favorite features of the desired object .
the energy function is defined as follows ( 5253 ) :
e=01esnake(s(u))du which includes the internal energy and the energy of the image :
e=01eint(s(u))+eimg(s(u))du it is best boundaries for contour , which has the lowest energy ( fig .
7 ) , so finding the boundary of the object , is equivalent to minimizing the energy function of contour .
segmentation by using a parametric active contour model ( 54 ) in which internal energy depends on the internal features of the contour such as elasticity rate and curvature , calculated as follows :
eint=2|us(u)|2 du+2|2u2s(u)|2 du the first part of the internal energy causes the contour , act like a spring in order to determine the elastic curve .
the second part determines the internal energy curve of the rate of resistance against bending . in the above equation , the coefficients ,
energy of image , direct the contour curves to the favorite features and distinct image such as edges , lines , corners and etc . and is calculated as follows ( 52 ) :
eimg = eedge=p|i(s)|2 parameter p is a huge amount of image energy , indicates the gradient operator .
hence , the total energy of the active contour is defined as follows :
e=2|us(u)|2du+2|2u2s(u)|2du+eedge(s(u))du if there is a visual prominent feature ( strong edge ) , energy function guides the contour curve towards the target correctly . unfortunately in the absence of strong edges , curve of contour becomes difficult to find the target object . for overcoming this problem ,
the new energy has been used called the strain energy of color , and is replaced by edge energy in equation 7(5557 ) .
this energy produces a compressive force , and contour is condensed toward the target object ( or is expanded ) .
the pressure energy of color can be defined as following :
epressure = p g(i(s))(su) where p is a parameter that determines the magnitude of the pressure energy and is loaded by the user .
g is a function , in accordance with equation 18 as ( 56 ) :
g(i(s))={+1 if it1 otherwise t is the intensity threshold of image .
considering that most features are in the district 4 , therefore the initial active contour should be created in the district 4 . the final frontier of active contour , as can be seen in fig .
adaptation of surf & sift algorithm with active contour implementation of active contours in steps 100 , 130 , 200 , 250 and extraction of the cancerous area from the thermal image as can be seen in fig .
the detection is performed using lyapunov exponent test el . by this test it is possible to distinguish accidental from non - accidental time series without statistical distribution .
we can express the similarity of data in a time series , so that period of effect data appears to predict the future .
suppose we have n observation of a chaotic time series available as follows :
xk , k=1,2, ,n in this case , to obtain the lyapunov exponent , divided m vectors is initially formed from these time series as follows :
xim=(xi , xi+1,
,xi+m1 ) ; i=1,2, ,nm+1 then among these vectors , all pairs of vectors proved in the following equation , are determined :
r0(m;i , j)=|ximxjm|r where r is a small positive number and || .
now with transfer time to the n - step ahead , this distance is computed again , thus :
dn(m;i , j)=rn(m;i , j)r0(m;i , j)=xi+nmxj+nmximxjm if these vectors are far apart we result that dn is the larger than one otherwise , smaller than 1 .
thus , the largest lyapunov exponent is calculated as follows :
l(m , n)=ijlog[dn(m;i , j)]n(n1 ) the positive value of l indicates that time series is chaotic and predicted in divergent way .
the negative value of l represents a definitive nature for time series and long - term predictability .
so if l accepts positive values close to zero , the system are weakly chaotic and medium - term prediction is possible , but predicted long - term is impossible . up to now
first distance of center related to the segmented area from it edge is calculated as time series and distance values are written in the same way , then lyapunov exponent test is employed .
in this section , the results of the proposed method are compared with mammography results .
bar chart on pixel area traced by radiologist versus balloon snake for validating the overall performance of the proposed method , the breast tumor regions obtained by the proposed method were compared with those plotted by the radiologist .
three error metrics were defined : the true - positive ratio ( tp ) , the false - positive ratio ( fp ) and the false - negative ratio ( fn ) ( 60 ) .
let aa be the pixel set of the rois determined by the proposed method and am be the pixel set of the rois determined manually by the radiologist ; the three error metrics are calculated as :
tp=|amaa||am|fp=|amaaam||am|fn=|amaaaa||am| when the tp ratio is higher and the fn ratio is lower , more real tumor regions are classified as
breast lesion regions , and when the fp ratio is lower , fewer normal tissue regions are classified as breast lesion regions .
lyapunov exponent for the segmented areas results that the rate of chaos for benign case is much less than the malignant cases . in another words ,
mammography can be considered as the golden standard method for breast cancer detection . applying mammographic screening
additional screening methods such as the use of thermograms may help lower the death rate from the breast cancer .
cancerous and pre - cancerous tissues have a higher metabolic rate resulting in the growth of new blood vessels to supply nutrients to the cancerous cells .
consequently , the temperature of the tissue surrounding the pre - cancerous tissue is higher than the other regions .
hence , pre - cancerous and cancerous tissues appear as hot spots in breast thermal images .
mammography detects anatomical changes while thermography detects physiological changes that occur much earlier than anatomical changes .
a combination of mammography and thermography methods can perform better in detecting invasive cancer and multifocal diseases .
the keys to obtaining higher accuracy would be ( a ) high sensitivity imaging to obtain reliable hot spot information related to metabolic activity in the breast , ( b ) to process thermogram to isolate these regions from the background , ( c ) to use a feature extraction algorithm such as the one described here that will capture information about the spatial distribution of these regions while being robust to translation and scale changes and ( d ) to use a good feature selection , fusion and classification algorithm such as ad boost .
the features extracted from a collection of images can be used for training and clustering of systems .
many previous studies have used only the difference in temperature between the affected area and normal ( asymmetric techniques ) , for breast cancer detection .
some researchers have suggested that distribution of the actual temperature difference between the thermal image and temperature data normalization ( ideally ) is a better way to detect cancerous areas ( 58 ) .
recently , intelligent computers that have features such the support of multimedia and data - mining have assisted the radiologist ( 59 ) .
although breast cancer is not a new disease , it has been increased in women to an unprecedented level in the world in recent decades .
if it is diagnosed early , it can be treated easily . in previous research , many methods have been proposed to form a mathematical model for pattern classification . in this paper
, we presented a method of completely automatic segmentation that can diagnose the breast cancer core in the breast thermal images .
this paper drew one combination model of feature extraction related to surf and corner algorithm that are robust .
ethical issues ( including plagiarism , informed consent , misconduct , data fabrication and/or falsification , double publication and/or submission , redundancy , etc . ) have been completely observed by the authors .
Output:
| background : the segmentation of cancerous areas in breast images is important for the early detection of disease .
thermal imaging has advantages , such as being non - invasive , non - radiation , passive , quick , painless , inexpensive , and non - contact .
imaging technique is the focus of this research.methods:the proposed model in this paper is a combination of surf and corners that are very resistant .
obtained features are resistant to changes in rotation and revolution then with the help of active contours , this feature has been used for segmenting cancerous areas.results:comparing the obtained results from the proposed method and mammogram show that proposed method is accurate and appropriate .
benign and malignance of segmented areas are detected by lyapunov exponent .
values obtained include tp=91.31% , fn=8.69% , fp=7.26%.conclusion : the proposed method can classify those abnormally segmented areas of the breast , to the benign and malignant cancer . |
PubmedSumm4801 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input:
Output:
| the objective of this study was to investigate a broad range of adverse health outcomes and their potential association to wood preservative used in daycare centers .
this article focuses on reproductive effects .
a sample of 221 exposed teachers was provided by the employer 's liability insurers .
a comparison group ( n = 189 ) insured by the same two organizations was recruited from nonexposed daycare centers . in a face - to - face interview ,
job history and reproductive history of 398 female teachers were ascertained .
data on exposure were provided , including measurements on concentration of pentachlorophenol ( pcp ) and lindane in wood panels , and of pcp , lindane , polychlorinated dibenzo - p - dioxins and dibenzofurans in indoor air .
an exposure matrix based on individual job history , independent exposure information from each center , and reproductive history was set up with regard to the vulnerable time windows for each pregnancy . using this approach , 49 exposed and 507 nonexposed pregnancies were identified , including 32 exposed and 386 nonexposed live births . for subgroup analyses
the observations were restricted to independent pregnancies , excluding multiple and consecutive births .
the data were analyzed with linear regression techniques , taking confounders into account .
the crude median difference between exposed and nonexposed was 175 g in birthweight and 2 cm in length .
controlling for confounders , the results show a significantly reduced but weight ( p = 0.04 ) and length ( p = 0.02 ) in exposed pregnancies , even after restricting the data to independent pregnancies and pregnancies for which data could be validated from the mother 's health cards .
these differences were not explained by differences in gestational age indicating that a toxic effect , which could cause small - for date newborns , might have affected the fetus.imagesfigure 1.figure 2.figure 3 . |
PubmedSumm4802 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the estimation of age is an important and is commonly carried in medico legal area .
assessment of age is often required while administering justice to an individual involved in the civil and the criminal litigation .
teeth are known to aid in personal identification and age estimation as they are highly durable and resist putrefaction , fire , chemicals etc .
dental age estimation in the living is mostly based upon non - invasive methods , which evaluate the timing and sequence of defined growth stages of the developing dentition and the sequence or modification of traits in the mature dentition and the surrounding tissues .
eruption of teeth is one of the changes observed easily among the various dynamic changes that occur from the formation of teeth to the final shedding of teeth .
the times of eruption of teeth are fairly constant and assessment of age of an individual by examination of teeth is one of the accepted methods of age determination .
this fact can be made use of in ascertaining the average age of eruption of the tooth .
the use of teeth for determining someone 's age has its origin 170 years ago when tooth eruption was first used for dental age estimation in connection with child labor . in response to the need for age estimation of factory children who were not allowed to be employed under the age of nine and with a restricted working time between 9 years and 12 years of age . in ancient times ,
age estimations of living adolescents were considered important . according to records in ancient rome adolescents
were judged to be fit for service , as soon as the second molars had erupted completely .
earlier charts and tables were used for the assessment of age during development period with the use of formation , eruption , and calcification of teeth . for this purpose ,
table of krenfild and logan was further modified by kronfild and schour ( 1939 ) is commonly used which has been accepted as standard for many years .
, described that during infancy and childhood , a fairly accurate estimate of age can be made from the study of teeth .
described that the teeth may give , reliable information as to age in childhood and youth . beyond adult life ,
scot stated that if the third molars are fully erupted , it indicates that the age of an individual is above 17 years , and on x - ray examination if the root formation is not complete , one can definitely conclude than the person was probably less than 25 years of age .
most of the earlier studies in european populations found differences in the pattern of deciduous tooth emergence in both different genders .
these studies have showed that the anterior dentition in males is developing early relative to the female dentition and the pattern reverses so that females lead males in the emergence of the posterior deciduous dentition .
little is known about sex differences in the dental development and the emergence of non - european populations .
the results supported that the pattern of developmental cross - over observed in other populations .
they concluded that there is a little evidence to support the hypothesis of tanguay et al .
camps has described that after birth and during a child is developing , it is possible to arrive at a close estimation of age by the presence of the deciduous dentition at its stages of eruption and also the mixed dentition period and its stages of eruption of the permanent teeth and loss of deciduous teeth .
he also pointed that state of eruption only gives an indication of age since eruption dates are subject to wide variations .
biggerstaff found that forensic dentist can estimate the age of a person by noting developing dentition . according to him
tedeschi et al . , have described that from birth to 6 months of life , accurate age estimation can be based on the mineralization of the deciduous crowns and from then up to 13 months of age , estimation may be determined by the state of eruption .
studies show that underprivileged children show comparative retarded eruption relative to their ethnic counterparts from higher socioeconomic status .
this observed difference have been attributed to the effect of nutrition as studies point to earlier eruption times in well - nourished children .
eruption of the deciduous teeth in moderate to severely malnourished children showed 5 - 29% increase in times of emergence .
the effect of nutrition on the time of eruption of the deciduous teeth can be further corroborated by studies , which try to link the effect of breastfeeding on the timing of eruption .
this is contrary to the observation by holman and yamaguchi who noted a selective effect of nutritional status on the timing of tooth eruption - poor nutrition was associated with delayed emergence , while medium nutritional status showed significant delay in the emergence of incisors and canines of the maxilla and all five teeth in the mandible .
they also noted a delay in the emergence of the upper incisors and accelerated emergence of the upper second molar in children not breast - fed in japan .
since the development of teeth occurs during the prenatal period , it is appropriate to hypothesize that a shorter postnatal development may influence the development of deciduous dentition .
it has been shown that dental development , dental eruption and tooth size may be delayed or reduced in low birth - weight ( lbw ) and prematurely born children .
a longitudinal study of dental development by fearne and brook in a group of lbw children was carried out to determine the tooth - crown size of primary molars and canines .
primary canines and molars were smaller in the lbw than the controls , with the significance values for the mesiodistal dimension of maxillary and mandibular canine compared to a non - significant difference for the buccolingual dimension of mandibular first primary molar . within the lbw group , there was a positive correlation between birth weight and mesiodistal tooth size .
small primary tooth size in lbw children may be influenced by both genetic and environmental factors . the shorter prenatal growth period and poor perinatal and early postnatal development
found that the development of early forming teeth ( permanent incisors and first 20 molars ) was significantly delayed in lbw children and individuals with the poorest height - forage had the greatest delay in tooth formation , but only teeth undergoing rapid differentiation neonatally were systematically affected .
seow and wan , compared the dimensions of the primary incisors from pre - term children and full - term controls .
the results showed that there was a dose - response effect of birthweight on the tooth size .
the very - low - birthweight teeth showed the smallest dimensions , the nbw controls the largest , and the low - birthweight teeth intermediate dimensions .
they hypothesized that primary incisors from children prematurely born with very lbw will have smaller dimensions compared with teeth from full - term children with nbw .
helm and prydso recorded permanent emergence of mandibular third molar at an early age of 14 years in 235 danish medieval skulls , 52 of whom were in various stages of mixed dentition .
they argued that assessment of age at death could be made fairly accurately for the age group 5 to 30 years .
kumar and sridhar studied a total of 1008 individuals in between 5 years and 14 years of age residing in tirupati , andra pradesh .
this study was community based on eruption times of permanent teeth to establish age of the individual .
the median age of the eruption was computed based on the concept of ex which is defined as the age at which specified percent of individuals shows eruption of a given permanent tooth . the median age
e50 was computed by transforming of percentages to probits and plotting a graph between age and probits .
the - individual 's age can be computed according to e50 value of permanent tooth , which erupted last .
given individuals probability being above or below the assessed age can be estimated by referring to graph and probit transformation table .
studied deciduous teeth emergence of 312 children aged 4 months to 31 months with punjabi parenthood . for calculating medium age of tooth emergence , they used probit analysis .
they found earlier tooth emergence in females than their male counterparts . in comparison with other population
, it was found that in general , mean number of emerged teeth in punjabi children is more at most ages and with lower medium age of eruption for most teeth .
variability in the eruption time was highest in 16 - 17 and 20 - 21 months .
thus , their study suggests that the number of teeth can be used as a parameter for estimation of age .
foti et al . studied for age determination both in living and dead children with the help of linear regression .
the equation can be applied based on the number of erupted teeth and tooth germs detected during the clinical examination and radiograph .
the use of teeth for determining someone 's age has its origin 170 years ago when tooth eruption was first used for dental age estimation in connection with child labor . in response to the need for age estimation of factory children who were not allowed to be employed under the age of nine and with a restricted working time between 9 years and 12 years of age . in ancient times ,
age estimations of living adolescents were considered important . according to records in ancient rome adolescents
were judged to be fit for service , as soon as the second molars had erupted completely .
earlier charts and tables were used for the assessment of age during development period with the use of formation , eruption , and calcification of teeth . for this purpose ,
table of krenfild and logan was further modified by kronfild and schour ( 1939 ) is commonly used which has been accepted as standard for many years .
, described that during infancy and childhood , a fairly accurate estimate of age can be made from the study of teeth .
described that the teeth may give , reliable information as to age in childhood and youth . beyond adult life ,
scot stated that if the third molars are fully erupted , it indicates that the age of an individual is above 17 years , and on x - ray examination if the root formation is not complete , one can definitely conclude than the person was probably less than 25 years of age .
most of the earlier studies in european populations found differences in the pattern of deciduous tooth emergence in both different genders .
these studies have showed that the anterior dentition in males is developing early relative to the female dentition and the pattern reverses so that females lead males in the emergence of the posterior deciduous dentition .
little is known about sex differences in the dental development and the emergence of non - european populations .
the results supported that the pattern of developmental cross - over observed in other populations .
they concluded that there is a little evidence to support the hypothesis of tanguay et al .
camps has described that after birth and during a child is developing , it is possible to arrive at a close estimation of age by the presence of the deciduous dentition at its stages of eruption and also the mixed dentition period and its stages of eruption of the permanent teeth and loss of deciduous teeth .
he also pointed that state of eruption only gives an indication of age since eruption dates are subject to wide variations .
biggerstaff found that forensic dentist can estimate the age of a person by noting developing dentition . according to him
tedeschi et al . , have described that from birth to 6 months of life , accurate age estimation can be based on the mineralization of the deciduous crowns and from then up to 13 months of age , estimation may be determined by the state of eruption .
studies show that underprivileged children show comparative retarded eruption relative to their ethnic counterparts from higher socioeconomic status .
this observed difference have been attributed to the effect of nutrition as studies point to earlier eruption times in well - nourished children .
eruption of the deciduous teeth in moderate to severely malnourished children showed 5 - 29% increase in times of emergence .
the effect of nutrition on the time of eruption of the deciduous teeth can be further corroborated by studies , which try to link the effect of breastfeeding on the timing of eruption .
this is contrary to the observation by holman and yamaguchi who noted a selective effect of nutritional status on the timing of tooth eruption - poor nutrition was associated with delayed emergence , while medium nutritional status showed significant delay in the emergence of incisors and canines of the maxilla and all five teeth in the mandible .
they also noted a delay in the emergence of the upper incisors and accelerated emergence of the upper second molar in children not breast - fed in japan .
since the development of teeth occurs during the prenatal period , it is appropriate to hypothesize that a shorter postnatal development may influence the development of deciduous dentition .
it has been shown that dental development , dental eruption and tooth size may be delayed or reduced in low birth - weight ( lbw ) and prematurely born children .
a longitudinal study of dental development by fearne and brook in a group of lbw children was carried out to determine the tooth - crown size of primary molars and canines .
primary canines and molars were smaller in the lbw than the controls , with the significance values for the mesiodistal dimension of maxillary and mandibular canine compared to a non - significant difference for the buccolingual dimension of mandibular first primary molar . within the lbw group , there was a positive correlation between birth weight and mesiodistal tooth size .
small primary tooth size in lbw children may be influenced by both genetic and environmental factors . the shorter prenatal growth period and poor perinatal and early postnatal development
found that the development of early forming teeth ( permanent incisors and first 20 molars ) was significantly delayed in lbw children and individuals with the poorest height - forage had the greatest delay in tooth formation , but only teeth undergoing rapid differentiation neonatally were systematically affected .
seow and wan , compared the dimensions of the primary incisors from pre - term children and full - term controls .
the results showed that there was a dose - response effect of birthweight on the tooth size .
the very - low - birthweight teeth showed the smallest dimensions , the nbw controls the largest , and the low - birthweight teeth intermediate dimensions .
they hypothesized that primary incisors from children prematurely born with very lbw will have smaller dimensions compared with teeth from full - term children with nbw .
helm and prydso recorded permanent emergence of mandibular third molar at an early age of 14 years in 235 danish medieval skulls , 52 of whom were in various stages of mixed dentition .
they argued that assessment of age at death could be made fairly accurately for the age group 5 to 30 years .
kumar and sridhar studied a total of 1008 individuals in between 5 years and 14 years of age residing in tirupati , andra pradesh .
this study was community based on eruption times of permanent teeth to establish age of the individual .
the median age of the eruption was computed based on the concept of ex which is defined as the age at which specified percent of individuals shows eruption of a given permanent tooth . the median age
e50 was computed by transforming of percentages to probits and plotting a graph between age and probits .
the - individual 's age can be computed according to e50 value of permanent tooth , which erupted last .
given individuals probability being above or below the assessed age can be estimated by referring to graph and probit transformation table .
studied deciduous teeth emergence of 312 children aged 4 months to 31 months with punjabi parenthood . for calculating medium age of tooth emergence , they used probit analysis .
they found earlier tooth emergence in females than their male counterparts . in comparison with other population
, it was found that in general , mean number of emerged teeth in punjabi children is more at most ages and with lower medium age of eruption for most teeth .
variability in the eruption time was highest in 16 - 17 and 20 - 21 months .
thus , their study suggests that the number of teeth can be used as a parameter for estimation of age .
foti et al . studied for age determination both in living and dead children with the help of linear regression .
the equation can be applied based on the number of erupted teeth and tooth germs detected during the clinical examination and radiograph .
the dental system is an integral part of the human body , its growth and development can be studied in parallel with other physiological maturity indicators such as bone age , menarche and height .
several authors have shown that dental parameters are more suitable for age estimation in children because the variability is lower since calcification rates of teeth are more controlled by genes than by environmental factors .
rate of formation of the permanent teeth is not affected by premature loss of the primary teeth .
gingival emergence also called tooth eruption represents only one stage in the continuous process of dental eruption .
many studies have concluded that tooth formation is a more reliable indicator of dental maturity than gingival emergence or eruption .
tooth eruption is mostly influenced by environmental factors such as available space in the dental arch , extraction of primary teeth , teeth tipping or impaction of teeth . until quite recently
, clinical eruption has been the only criterion used for dental maturity or dental age .
the demirjian scoring system based on the developmental stages of teeth is more useful since the tooth development is less influenced by environmental factors .
tooth development shows less variability than other developmental features and also low variability in relation to chronological age .
hortz observed a greater degree of association between dental age and chronological age than between dental and skeletal age .
Output:
| the developing dentition is used to assess maturity and estimate the age in many disciplines including anthropology , archeology , forensic science , pediatric dentistry and orthodontics .
there is evidence that dental development is less effected than skeletal development by malnutrition and hormonal disorders .
there are two methods of dental age assessment , radiographically and by clinically visualization of eruption of teeth .
the clinical method to assess dental age is based on the emergence of teeth in the mouth .
this method is more suitable since it does not require any special equipment , expertise and is more economical .
tooth formation is the best choice for estimating the age as variations are less as compared to other development factors .
eruption of teeth is one of the changes observed easily among the various dynamic changes that occur from the formation of teeth to the final shedding of teeth .
the times of eruption of teeth are fairly constant and this can be made use of in ascertaining the average age of eruption of the tooth .
assessment of age of an individual by examination of teeth is one of the accepted methods of age determination . |
PubmedSumm4803 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: with heart transplantation comes well - documented medical and psychosocial challenges [ 1 , 2 ] .
healthcare professionals are dedicated to educating and supporting transplant recipients and their families throughout this potentially difficult trajectory in order to promote engagement in self - management .
recipients are commonly prepared and supported during their transplant through a variety of modalities which include booklets , instructional videos , personalized teaching sessions , and peer mentorship . to better understand their needs
, we asked patients participating in this research study to reflect on their experience of being a transplant recipient .
this paper focuses on participants ' experiences and their perspectives on how to prepare and support recipients through the transplant process , which is one component of a larger study .
our interdisciplinary team employed a visual methodology which allowed us to interpret body gesture and spoken words with the understanding that images and words form a set of different representations highlighting emotions and experiences .
such methodology is useful as it provides an innovative framework to engage with the complexity of transplantation .
patient and graft survival , transplant outcomes , and side effects , as well as the ethics of organ transplantation [ 610 ] , have been extensively studied and will not be addressed in detail here .
the average life expectancy after cardiac transplantation is 10 years with a conditional life expectancy of 13 years based on survival to year one .
a large number of qualitative studies show improvement in quality of life ( qol ) , but poor return to work ( approximately 45% ) , as well as high general anxiety and distress among heart transplant recipients [ 13 , 11 , 12 ] .
dew and dimartini 's review incorporating nearly 150 studies confirms that depressive and anxiety - related disorders and associated distress are common post - transplant and that such symptoms are not confined to the initial stages of recovery , but might appear or be exacerbated at any time
one longitudinal qol study followed 156 patients over a four - year period post - transplant using the depression and anxiety subscales of the symptom checklist 90 .
high , clinically significant distress at all times [ 2 , page 1215 ] .
another 12% showed high distress over several years with low distress only at final assessment , whereas the remaining participants experienced low or fluctuating levels of distress for the duration of the study [ 2 , page 1215 ] .
approximately one - third of heart recipients , therefore , were found to experience substantial , sustained distress .
a multisite study investigating qol in 555 individuals at 510 years post - heart - transplant found that depression accounted for the variance both in overall qol and in health / functioning qol . in the transplantation literature , distress
refers to psychiatric diagnoses such as depression , anxiety , and psychosis [ 1522 ] .
psychoanalytic studies of recipients ' adjustment to an organ graft have identified common responses and coping mechanisms , such as overpowering feelings of gratitude to the donor family , guilt over the donor 's death , denial , and mourning of their own lost organ [ 2332 ] .
research conducted at a major transplant center in canada with adult transplant recipients using qualitative research methods demonstrated that 88% of heart transplant patients experience pervasive post - transplant distress .
. suggested that social isolation , especially when combined with depression scores in the clinical range , may be important for the prognosis of heart transplant candidates
the authors reported that patients who died or had worsening clinical outcomes had small social networks .
a qualitative investigation by kaba et al . explored coping strategies of individuals following heart transplantation .
recipients adopted various forms of coping strategies , but frequently were searching for better ways to cope .
kaba et al . highlighted the need for additional information for patients that outlines potential concerns post - transplant and strategies to address them .
kop highlighted that while waiting for a heart transplant , candidates experience a high level of psychological distress related to the potential unavailability of a donor heart and the life - threatening nature of heart failure .
the value of psychological interventions in supporting candidates in maintaining positive coping mechanisms and a healthy lifestyle was identified by kop , spaderna et al . , and zipfel et al . .
it is important to involve family and/or significant others in candidates ' daily care , because they are at risk for social isolation and their emotional well - being impacts their disease trajectory following a heart transplant . in a study conducted by haugh and sayler ,
the team reported that maintaining respect and dignity , being sensitive to family , sharing information , facilitating coping , and doing the extra little things , were helpful in supporting candidates who experience uncertainty while waiting for a donor heart .
an investigation by yorke and cameron - traub provides an in - depth description of patients ' perceptions of care from nursing staff while on a heart and lung transplant waiting list .
the author of this investigation highlights that nursing staff are central to the care of patients waiting for a heart transplant , because they provide information , maintain regular contact , provide familiarity , and have a positive attitude and compassion [ 38 , page 82 ] .
prior to discussing the study 's methods , we outline the preparation potential transplant recipients currently undergo . at the canadian academic teaching hospital where the research was conducted ,
patients being listed for heart transplant are prepared for the process in a variety of ways .
a nurse practitioner meets with them to provide information about what to expect while waiting for , and life after , transplant .
patients are also provided with a large educational manual and a videotape that explains the biomedical aspects of the transplant in lay terms .
they then meet with a social worker to discuss medication regimens , their social support network , employment , insurance , and available financial supports .
each potential recipient is offered a transplant mentor to provide support outside the program although not all choose to have one . while there is a formal process to become a mentor , how the relationship unfolds and what it provides each participant
there is no predetermined structure to the mentor / mentee relationship and having a mentor is not a requirement for recipient listing .
this preparation program has not been formally evaluated to determine which of these patient education modalities are most effective for individuals awaiting heart transplants .
an interdisciplinary team , composed of two advanced practice nurses , a cardiologist , a social worker , a sociologist , a psychiatrist , and a philosopher , engaged in a qualitative research study .
our visual methodology is oriented to the work of existential phenomenologist merleau - ponty [ 40 , 41 ] . like kvigne et al . , we begin from the basis that existential phenomenology is not a research method .
rather , it is an orientation and sensitivity that both text and body language are central to understanding and analysis .
visual methodology is a distinct body of research in the field of sociology that is concerned with ways in which bodily conduct and talk are both important characteristics in social interaction .
the assumption is that images and words form a set of different representations highlighting emotions and experiences . in our research
, this implies incorporating an analytic approach that makes meaningful links between various experiences , visual data , and other objects .
these two forms of media represent different types of knowledge that might be understood in relation to one another .
members of our unique interdisciplinary research team have extensive formal training in conducting qualitative research .
we bring together professors , scholars , and senior scientists in both the field of medicine and social sciences who all bring unique expertise and contributions to this research project . informed by the work of christian heath and sarah pink who are both well known for their use of visual methodology , our team designed our unique visual methodology .
we have published a number of papers that demonstrate how we have used video in concert with in - depth interviewing and field notes [ 3 , 43 , 44 ] .
the study was approved by the research ethics board ( no . 07 - 0822-be ) and took place in a heart transplant program of a large metropolitan hospital in the southern portion of an eastern province in canada . all individuals who met inclusion criteria
this was done so that potential study participants had the opportunity to decline to take part in the study and not feel obligated to the investigators .
when a potential participant showed interest in the study , a research associate discussed the study in detail and obtained informed consent .
thirty - six patients were approached , 6 declined to participate , and 3 did not follow through after they signed the consent .
sample size was in keeping with similar qualitative research studies and recruitment was stopped when we reached theoretical saturation .
the study included 27 post heart transplant patients , 2 videos were technically compromised ( audio recording failure ) which yielded 25 analyzable videos ( 70% men , mean age 53 yrs ( 13.8 ) , range 1872 ; mean time since transplant 4.1 yrs ( 2.4 ) ; 20 white , 2 black , 5 south asian ) .
participants were at least 18 years old , 110 years post - transplant , english speaking , and medically stable .
regardless of the time elapsed since transplantation , anecdotal and clinical involvement with transplant recipients tells us that they are able to communicate their experiences with immediacy and clarity .
we accept as true that memory is a process , and as such , all participant responses reflect their embodied experiences and enriched and informed our findings accordingly . individuals were given a choice of where their interview would take place .
all were conducted in nonclinical settings , mostly in their homes ( n = 19 ) .
all participants received instructions on how to switch off the recording equipment at any time .
the camera was purposely visible and static to film the embodied interaction of the interviewer and participant , a practice consistent with standard contemporary visual methods .
the use of a video camera in research has been widely debated [ 4648 ] . some argued that having a camera present has negligible or no impact on participants [ 4951 ] .
researchers have also suggested that video methods are valid only if used secretly or in triangulation with other methods which reduce contamination of the data such as respondent validation [ 6 , 8 , 1922 ] .
yet given our phenomenological orientation , we argue that these positions are not only ontologically and epistemologically incompatible with our process , but also run the risk of blinding themselves to the advantages of videoing as a method [ 25 , page 1154 ] . as visual methodologists , we espouse that we can not observe the world without being present in it ; hence , we believe that the use of camera was not neutral in the interview , but rather was a fundamental part of knowledge production . during the interviews , the completely exposed camera became inconspicuous for both the interviewer and the participant .
the interviews were conducted individually by one of two advanced practice nurses with extensive training in qualitative research and no involvement in the study participants ' clinical care , on average four and a half weeks after recruitment .
approximately 30 minutes was spent prior to each interview answering questions about the research , establishing rapport , and building trust with the participants .
participants were informed that they could refuse to answer any question , stop the interview at any point , or request erasure of anything they said . following standard procedures in semistructured qualitative studies , the interviewer asked participants open - ended questions and provided opportunities for them to raise their own concerns .
for example , participants were asked both how would you prepare someone for transplant ? and how would you support someone after transplant ? techniques such as nodding , allowing silences , and using phrases such as would you feel comfortable telling me more about that ? were utilized when necessary .
interviews took 3090 minutes . following every interview , the researcher compiled detailed field notes of observations .
coding conventions established by poland and pederson [ 54 , 55 ] , such as noting laughter , silences , and pauses in addition to dialogue , were used to professionally transcribe audio files verbatim .
digital video files , transcripts and field notes , were imported into the nvivo8 qualitative research software program .
the team met as a group together in the same room throughout the analysis process .
coding was informed by the work of visual methodologists pink [ 4 , 56 ] and heath [ 45 , 57 ] , using nvivo8 to organize the data .
the first phase of data analysis started with a transcript and videotape review in which they were simultaneously time logged , and
key moments included particular statements in transcripts and videotaped embodied responses such as expressive gestures [ 57 , 58 ] that located areas of difficulty on / in the body ( e.g. , hands on heart ; pointing to the heart ) [ 57 , 58 ] , expressive artifacts ( e.g. , open necked shirts showing surgical scars ) , and by the way syndrome , that is , the gestures and comments close to the end of interviews that ( re)asserted the significance or seriousness of a particular symptom / feeling [ 57 , 58 ] .
finally , incongruities between participants ' words and gestures were noted [ 57 , 58 ] .
upgrades , which represent speaking positively even when body comportment indicated distress ( i.e. , inability to maintain eye contact ; crying ; intense fidgeting ) , or downgrades when comportment appeared nondistressed ( i.e. , calm tone of voice ; relaxed posture ) even though words revealed the opposite [ 57 , 58 ] . in the next phase of data analysis , all audio visual data were collectively re - reviewed .
broad themes were developed by the team from transcript quotes and audio visual footage and where tagged to key moments .
these themes were defined , discussed , debated , and agreed on by the team before being collapsed into analytic categories .
the team then collapsed these analytic categories into a final set of themes which addressed the research question . to meet the highest standards of methodological rigor ,
an audit trail was maintained ( specific record of methodological and data coding decisions ) .
the flexible storage , cross - indexing , and quick retrieval features of nvivo8 made it easy to search for negative instances and universal findings .
attention was paid to data inconsistent with overall findings , and coding was discussed with all members of the team .
in reporting data in visual methods research , we are unable to use video footage to show our findings ; hence in this paper we rely solely on words to discuss results .
we have therefore adopted a very descriptive writing style to compensate for what can not be seen .
participants talked about that only someone who has gone through this process truly understands the complexity of their experiences .
other themes included the need to maintain hope , where a positive attitude was seen as essential in order to move forward .
participants reported that ongoing close connections with healthcare professionals ( hcps ) provided reassurance about their ongoing medical care .
the presence of family and friends was also seen as essential , as was their help in managing day - to - day activities .
mentorship programs provided a different and unique form of support between individuals who may share an understanding or experience .
the mentor - mentee relationship is often developed between an individual who is awaiting transplant and a transplant recipient .
fourteen patients ( 56% ) commented that only heart transplant recipients truly understood the experiences they were going through .
hence , transplant recipients were most able to prepare them for transplantation and support them afterwards .
participants expressed that living through heart transplantation can not be compared to any other medical condition .
they reported it was a very emotional , distressing , and physically demanding . to this end , all recipients felt their transplant experience was unique .
a thirty - year - old woman , who was interviewed in a room close to the heart transplant clinic area , slouched down in her chair while she said
i do not like to tell people unless they 've been through something similar , because the truth is that you can not really understand unless you 've been through the same thing ( ptx13 ) .
she seemed to have reconciled herself to the idea that other people just would not understand , and she had told few people about her ordeal . a fifty - six - year - old man , who was interviewed in his home , sat crossed legged on a couch with closed posture .
in a very monotone voice he spoke about what he would say to a potential recipient as follows : look , if you are really in a bad way , here is my phone number , here is my email .
i know exactly what you are going through , i know how bad it gets , you can not surprise me , just phone ( ptx12 ) .
he communicated this in a voice devoid of inflection and as if he had rehearsed this message .
another man in his early thirties , sitting at his kitchen table , used expressive gesture and voice said
i think education is important but sometimes you also have to live through it to understand it ( ptx21 ) . his message had a sense of urgency , emphasizing the difficulties associated with not being understood .
a man in his late fifties sitting at his kitchen table stated you know , you guys [ transplant team ] think you know what we went through , but you do not ( ptx10 ) .
the difficulty for him in communicating this was apparent in his low and flat tone of voice as he nervously twirled his fingers and avoided eye contact . maintaining their positive attitude after transplant was reportedly very important for 13 ( 52% ) of the recipients .
their statements included endorsements of not being told about potential transplant - related complications or personal struggles and receiving only encouraging words .
a fifty - four - year - old woman , who was interviewed at a large table in a dimly lit kitchen , said with a very worried look on her face well , you have to encourage this person
oh , my god , you know , tomorrow you are going to be worse , never say that to the person who went through a nightmare never discourage people ( ptx15 ) . as the inflection in her voice rose , in an effort to make her point clear
, she wrapped her arms around her body , as if comforting herself while sharing her difficult story . nervously giggling , a man , who had spoken previously in his interview of the emotional difficulty of going through a heart transplant , said that if he were to speak to another patient , he would say do not worry about it , everything is going to be fine i would tell him that he is going to feel good after .
as he completed his statement , he leaned forward with open arms to enforce that although his experience was difficult , he would only share positive outcomes with other potential recipient .
thirteen ( 52% ) recipients commented that hcps had provided the needed reassurance about their ongoing medical status and continuity between the transplant clinic and their home
. a fifty - six - year - old man who was seven years post - transplant stated my support system , i would have to say , are the transplant nurse coordinators because if ever there is a problem i could just call them , and they do phone back i just feel very protected and well taken care of whenever i had questions , all i needed to do was call , and they were answered ( ptx12 ) . at this point in his interview , the participant relaxed his posture and seemed to speak more freely about his experience .
another male participant stated that they [ hcp ] are there if you need them , but like i say , first couple of years you really depend on them , you feel so much better going there [ hospital] .
( ptx10 ) . he made this statement with a clear assertive voice and repeated it more than once .
another young man reported my support system , i would have to say it 's [ advanced practice nurses ' names ] , because if ever there is a problem , you know , i can just call them
i think in the whole that i just feel very , uhm , protected and well taken care off from there [ hospital ] , so whenever i have problems questions , all i needed to do was call ( ptx22 ) .
he represented this in a very matter of fact fashion , as if the answer was obvious .
family members and close friends were reported by 5 ( 20% ) recipients to have been an important part of their lives throughout the transplant experience .
[ wife 's name ] was there all the time , right with me , and there were a couple of really good friends who just made sure i was ok ( ptx12 ) .
he spoke as if his answers had been scripted , using a very monotonous tone of voice and a very controlled body posture .
a physically fit looking man who sat at a table stated i think they [ recipients ] need to have somebody around because the days are long they need to have somebody around that can , you know , they can gab with and hang out with , so you do not have all that time to think ( ptx14 ) .
a woman , sitting in a large , well - appointed living room stated there are lots of people in my life who have been really great trying to help me out .
she delivered her message with a lot of emphasis and certainty ; there was conviction in her voice .
i would imagine that driving people around would be all part of it , and being with them .
some of it is you need them there to do stuff for you , another is to commiserate with you ( ptx24 ) .
the transplant program offers every patient the opportunity to connect with a mentor , who is a transplant recipient . when participants were asked how to best support transplant recipients , 10 ( 40% ) spontaneously spoke of this mentorship program .
six of those 10 recipients reported having elected to be mentored and described it as a supportive experience .
the 4 participants , who had declined having a mentor , retrospectively thought being a mentee would have been beneficial .
a frail looking older married woman , sitting at her kitchen table , said how helpful it had been because you always wonder what it is going to be like after the transplant , and seeing someone by your bedside that has already had a heart transplant just saying everything is going to be fine
as she said the words everything is going to be fine , her body changed from being slouched forward with arms crossed and she became more engaged by using expressive gestures and increasing the tone and inflection of her voice . a retired man , who reported during his interview that the support of mentors was vital in his recovery , nervously chuckled as he said
i did hear a lot of people saying that they did not have much support as far as mentors
we met up and had a chat its nice to see somebody that 's had a transplant
i do not think anybody said too much negative , the only thing is i think they all , after a few years , forget the sort of bit of trauma you go through ( ptx11 ) .
others do not understand what recipients go through and that only someone who has a heart transplant truly understands the experience .
we do not understand led us to further explore why transplant recipients think that only someone who has lived through the transplant experience understands them .
conventional research methods have not been comprehensive or sensitive enough to understand the multifaceted aspect of patient experience because the focus has been on the written or spoken word .
such methods ask participants to speak or enumerate their experience of heart transplantation but fail to illuminate what can not be spoken .
as described by visual methodologist heath , suffering can be seen in the body through expressive gestures and tone of voice .
the use of visual methods enables researchers to interpret the expressive body , making visible what would otherwise remain hidden .
its use in the study reported here enabled us to innovatively engage with transplant recipients ' unique experiences and gain new insights into their ongoing suffering . to this end
, the interviews captured the very body showing everything the mind suffers : crying , moaning , lacking affect , dropping their tone of voice , speaking monotonously , stooped shoulders , head dropped forward , avoiding eye contact and legs crossed . in this paper , the notion of suffering captures participants ' affective experience of sadness or unpleasantness .
heath [ 58 , page 603 ] reports that through gesture and bodily conduct , patients transpose inner suffering , their personal subjective experience of their complaint , to the body 's surface and particular parts and areas of their physic .
as described in our findings , the interviewees ' bodily comportment characterizes the difficulty of receiving a heart transplant allowing the research team to witness their suffering . in order to better support our recipients , we turned to the work of frank [ 61 , page 355 ] to gain further insight about suffering.suffering is the unspeakable , as opposed to what can be spoken ; it is what remains concealed , impossible to reveal ; it remains in darkness , eluding illumination ; and it is dread , beyond what is tangible even if hurtful . suffering is loss , present or anticipated , and loss is another instance of no thing , and absence .
suffering is the unspeakable , as opposed to what can be spoken ; it is what remains concealed , impossible to reveal ; it remains in darkness , eluding illumination ; and it is dread , beyond what is tangible even if hurtful .
suffering is loss , present or anticipated , and loss is another instance of no thing , and absence .
if suffering is unspeakable , it explicates why more than half of the study participants felt only someone who has walked , lived , and suffered in their shoes could understand their plight .
it also demonstrates how the experience of post - transplant suffering might remain hidden from professionals , defying language and more standard research methods . taking this analysis further , it is possible to look at a wound as a metaphor for suffering .
a physician might look at the wound in diagnostic / clinical contexts ( i.e. , healing , infection ) , whereas for the patient , the wound is something experienced , felt , seen , and smelled .
recipients are assessed and measured : weight , blood pressure , and body temperature are recorded , blood work is reviewed , and biopsies are performed and examined all to ensure that the transplanted organ remains healthy and that the individual 's body is not rejecting the heart .
healthcare practitioners also value recipients ' psychological well - being and the importance of quality of life . yet recipients continue to report anecdotally , and in the study reported here , that most clinicians do not understand them , and yet they play an essential role in providing support related to the medical management
. there seems to be a divide between bodies that receive transplants and transplant recipients ' lived experience of these bodies . given that the recipients ' lived experiences are private , personal , and often indescribable , they are not accessible to hcps
this disconnect can not be overcome solely by asking recipients what their experience of living with a transplanted heart is like .
as highlighted by frank , when patients are asked to talk about difficult experiences such as their transplantation , they are unable to fully articulate their experience and tend to express it through particular complaints and concerns .
suffering is expressed in myth as the wound that does not kill but can not be healed
it follows that until patients ' suffering is understood , this existential wound can not heal .
each recipients ' suffering is rooted in their embodied experience , and as long as hcps do not engage with their embodied lived distress , a disconnect will continue .
our intent was to find ways to enhance clinicians ' knowledge of and ability to provide appropriate support .
when asked how to best do this , participants reported that providing encouragement and not focusing on potential negative disease sequelae were very important to maintain hope .
hope was described as an essential component in dealing well with illness and life - altering experiences .
they highlighted that it is essential to understand the function of hope when dealing with illness and the recovery process as it provides a coping mechanism in the face of what people may experience as the otherwise intolerable impacts of a health crisis , and maybe a common adaptive response [ 62 , page 569 ] .
they describe hope as having two components : hope as an expectation and hope as a want .
within the context of the research presented here , hope as an expectation in heart transplant recipients includes hoping that specific symptoms or events will not occur during one 's disease trajectory .
a heart transplant recipient might hope to meet the donor family or return to his / her old self .
to this end , our research team acknowledges that hcps should be aware of this nuanced understanding of hope to better support the patient , because it is conceivable that false hope could adversely affect recovery .
participants identified three major sources of support : their transplant team , family and friends , and transplant mentors .
when conceptualizing what participants discussed about support , we draw on the work of king et al . who studied social support processes of individuals with chronic conditions .
( allowing participants to achieve self - efficacy through direction and planning of approaches ) and emotional support ( being valued and accepted provides participants the sense of being believed in ) [ page 915 ] . these themes
are consistent with participants ' accounts in our study and will guide the following discussion .
participants reported that health care professionals provided instrumental support to transplant recipients through ongoing assessment of health status and guidance in their self - management of care .
participants were able to review their concerns with transplant professionals during clinic visits as well as through a sophisticated patient management telephone system , providing them not only with access to resources , but also with ongoing reinforcement to be able to manage their own care .
this type of support provided transplant recipients with strategies to ultimately enhance their competence taking on the onerous tasks of self - management .
such tasks include managing their medications , medical challenges , and adapting to their altered life with a transplanted organ . for some transplant recipients , the mentor / mentee relationship has continued throughout the transplant trajectory .
the ability for transplant recipients to connect with individuals , who have experienced a similar process , provides an opportunity for the provision of emotional support .
the mentor / mentee relationship offers a unique connection between transplant recipients that creates a sense of belonging .
emotional support is provided , people feel accepted and trusted , promoting a sense of being believed in .
hence , mentors who have been through a similar experience , allow transplant recipients to feel understood .
mentor / mentee relationships afford an additional benefit , in that providing and receiving support can be mutually beneficial .
in supporting another recipient , the mentor gains a sense of meaning and satisfaction , which in turn might improve adaptation to their own illness .
the presence and availability of family and friends provided great comfort to some transplant recipients .
assistance with day to day responsibilities and having others around even if they are just being there are both sources of comfort and support .
study participants talked about receiving support with household chores and help with tracking medications and medical appointments . having a family member or a friend present during clinic visits and invasive procedures similarly provided support to transplant recipients .
it is important for hcps to recognize the significance and complexity of the role that family and friends might play during the heart transplant recipient 's life trajectory .
participants , although ethnically and socioeconomically diverse , were all recruited from a single academic health care setting . they were recruited consecutively as they attended routine follow - up clinics to minimize bias .
our study population represents sex , ethnic , and social demographic groups that are comparable to our larger urban transplant program population .
both interviewers are researchers with this study , actively participating in all aspects of the research process , and are the main authors of this manuscript .
although all study participants were asked the same questions , in keeping with conventions of semistructured interviews , the discourse of the interview was not directed by the interviewer , allowing the conversation to evolve spontaneously .
consequently , not all participants spoke of the same topics , limiting the ability to draw conclusions about participants who did not report on certain themes .
participants felt that few people understood what they were going through and that only someone who has had a heart transplant truly understood the experience , the suffering , the hope , and a second chance at life .
if frank is correct , because of the unspeakable nature of suffering , key issues of the transplant experience remain hidden from the hcp and most researchers .
visual methods provide a portal to more comprehensively engage with the notion of suffering . they might allow researchers and ultimately hcps to understand and hence acknowledge heart transplant recipients concerns , thereby giving their experiences legitimacy . also ,
knowledge of the existential aspects of organ transplantation will provide hcps with a nuanced understanding of the patients ' transplant experience .
this will allow them to better prepare and support patients through the transplant process , and ultimately promote patient and caregiver self - management . in our research
, we found that despite others inability to truly understand the transplant experience , ongoing relationships with family , friends , and healthcare providers were none - the - less fundamental in the provision of continuous support . in an effort to build stronger support networks ,
we also need to look at innovative ways to educate individuals who will be providing support for transplant recipients .
written teaching materials and instructional videos should not be the exclusive recipient preparation modalities because interpersonal relationships and interactions , including the mentorship program , were considered more helpful and supportive .
strong efficacious mentorship programs need to be developed and evaluated , recipient support networks need to be encouraged , clinicians ' knowledge of the existential aspects of organ transplantation need to be enhanced .
Output:
| preparation for heart transplant commonly includes booklets , instructional videos , personalized teaching sessions , and mentorship .
this paper explores heart transplant recipients ' thoughts on their preparation and support through the transplant process .
twenty - five interviews were audio-/videotaped capturing voice and body language and transcribed verbatim .
coding addressed language , bodily gesture , volume , and tone in keeping with our visual methodology .
recipients reported that only someone who had a transplant truly understands the experience .
as participants face illness and life - altering experiences , maintaining a positive attitude and hope is essential to coping well .
healthcare professionals provide ongoing care and reassurance about recipients ' medical status .
mentors , family members , and close friends play vital roles in supporting recipients .
participants reported that only heart transplant recipients understood the experience , the hope , and ultimately the suffering associated with living with another persons ' heart .
attention needs to be focused not solely on the use of teaching modalities , but also on the development of innovative support networks .
this will promote patient and caregiver engagement in self - management . enhancing clinicians ' knowledge of the existential aspects of transplantation will provide them with a nuanced understanding of the patients ' experience , which will ultimately enhance their ability to better prepare and support patients and their caregivers . |
PubmedSumm4804 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: air - displacement plethysmography ( i.e. bod pod ) has gained popularity among body composition researchers since its introduction in 1995 .
this is mainly attributable to the non - invasive test - procedure and the lack of technical expertise required compared to the traditional hydrostatic weighing procedure . the bod pod is a single fiberglass unit composed of two chambers .
the test chamber accommodates the subject during testing and the reference chamber contains instrumentation for measuring changes in pressure between the two chambers .
the operating principles of the bod pod are detailed elsewhere [ 1 - 3 ] .
briefly , the volume of the test chamber is determined by pressure changes precipitated between the test chamber and reference chamber by a moving diaphragm mounted on the common wall between the chambers .
the pressure ratio relationships between the chambers are inversely related and are characterized by boyle 's law : where v1 and p1 are the volume and pressure prior to subject entry into the test chamber and v2 and p2 are the volume and pressure while the subject is in the test chamber . therefore , subject body volume will equal the volume of the test chamber before subject entry less the test chamber volume with the subject present .
because of difficulty maintaining isothermal conditions in the enclosed environment of the test chamber , the bod pod functions under adiabatic conditions ( i.e. air temperature is gaining / loosing heat ) , thus poisson 's law more accurately characterizes the pressure volume relationship in the testing chamber : where v1 and p1 are the volume and pressure prior to subject entry into the test chamber , v2 and p2 are the volume and pressure while the subject is in the test chamber , and is the ratio of the specific heat of a gas at constant pressure to constant volume ( 1.4 for air ) . moreover , isothermal air present in the test chamber during a body volume measurement will result in an underestimation of body volume because isothermal air is more easily compressed ( 40% ) than an equivalent volume of adiabatic air , resulting in a lower pressure output signal for a given body volume .
there is one source of isothermal air ( i.e. air in the lungs ) and several sources that are " isothermal - like " ( air trapped within the fabric of clothing and air trapped within hair on the head and body ) .
instructions and procedures have been recommended by the manufactures to correct and control for these sources of error . to avoid erroneous data the bod pod manufacturers recommend that testing be conducted prior to exercise , that the subject be dry , and that the testing environments temperature remain stable .
strict adherence to these conditions can sometimes prove difficult when testing large numbers of subjects in a short period of time and when testing people who are perspiring or have an elevated temperature due to illness .
in one study , bod pod measurements were performed following hydrostatic weighing , which resulted in a regression that significantly deviated from the line of identity .
however , other studies have reported significant differences when the bod pod preceded hydrostatic weighing .
thus , the specific effect of elevated body temperature and body moisture ( resulting from hydrostatic weighing ) on bod pod measurements needs clarification .
an increase in body temperature and moisture could increase the quantity of isothermal - like air surrounding the skin .
therefore , the purpose of this study was to determine the effect of increased body temperature and moisture on bod pod estimates of % fat , body volume , and body density .
we hypothesized that an increase in body temperature and moisture would result in an underestimation of % fat .
we also speculated that the increase in temperature , the increase in moisture , and total body surface area ( bsa ) would be positively associated with the magnitude of this underestimation .
thirty - two adult females ( 33 11 yr . , 64 14 kg . ,
167 7 cm ) representing a wide range of bmi ( 19 36 kg / m ) gave their informed consent to participate in the study .
approval for the use of human subjects was obtained from the institutional human subject review board from the university of alabama at birmingham .
height was measured using a wall mounted stadiometer while body weight was measured to the nearest 0.01 kg using the bod pod system electronic scale , as previously described and was calibrated prior to each bod pod test .
body temperature was measured in the right ear using a thermoscan irt 3520 orbital thermometer ( braun , san diego , ca ) .
the repeat measures , between multiple measurements for body temperature in eight healthy subjects had an intra - class correlation of r = 0.98 and a see = 0.03c .
after body temperature was determined and before hydrostatic weighing , the first bod pod ( bod podbh ) test was performed , subjects were then asked to shower ( this was done to keep the tank free of debris , wash off excess lotion , and sweat from the subjects ) and prepare for hydrostatic weighing .
hydrostatic weighing was performed as part of an alternative study objective , ( data not presented ) . immediately following hydrostatic weighing subjects dried off thoroughly using towels provided by the laboratory .
a second body temperature was determined and the second bod pod test was performed ( bod podfh ) . the moisture trapped in body hair and the fabric of the swimsuit was defined as the difference in body weight ( kg ) prior to hydrostatic weighing and upon completion of hydrostatic weighing ( after toweling dry ) .
whole body air - displacement was evaluated with the bod pod version 1.69 ( body composition system ; life measurement , incorporated , concord , ca ) as previously described .
thoracic gas volume ( tgv ) was measured in all subjects and bod pod conditions ( i.e. bod podbh and bod podfh ) according to the procedures described in the manual , while % fat was determined by the siri equation . in the calculation of body density for each testing condition ,
the body weight obtained in the dry state was used ; this was done to investigate the effect of moisture and temperature increases on estimates of % fat independent of effects caused by increases in body weight .
bsa was calculated according to the dubois formula : bsa = 71.84 weight ( kg) height ( cm ) .
same - day repeat measures of body density by the bod pod in our laboratory had an intra - class correlation of r = 0.98 and an see of 0.00365 ( g / cm ) .
group mean estimates of % fat , body volume , and body density , by the bod pod were compared using paired t - tests .
linear regression analysis and residuals from the regressions ( percent fat and body density ) were used to assess the agreement between bod podbh and bod podfh for body density and % fat .
estimates were not considered different if the regression slope did not differ from one or the intercept from zero ( line of identity ) . bod podfh % fat , body volume and density estimates were calculated using dry body weight to control for the effect of weight gain ( due to moisture ) .
pearson correlation coefficients were used to examine the relation between the changes in body temperature , moisture , % fat , body volume and bsa before hydrostatic weighing ( bod podbh ) and following hydrostatic weighing ( bod podfh ) .
the independent relationships of temperature ( difference in bod podbh temperature and bod podfh temperature ) , moisture , and bsa with % fat ( difference in bod podbh % fat and bod podfh % fat ) were determined using partial correlations .
all statistics were derived using spss statistical software ( version 10.0 ; spss inc . , chicago , il ) .
thirty - two adult females ( 33 11 yr . , 64 14 kg . ,
167 7 cm ) representing a wide range of bmi ( 19 36 kg / m ) gave their informed consent to participate in the study .
approval for the use of human subjects was obtained from the institutional human subject review board from the university of alabama at birmingham .
height was measured using a wall mounted stadiometer while body weight was measured to the nearest 0.01 kg using the bod pod system electronic scale , as previously described and was calibrated prior to each bod pod test .
body temperature was measured in the right ear using a thermoscan irt 3520 orbital thermometer ( braun , san diego , ca ) .
the repeat measures , between multiple measurements for body temperature in eight healthy subjects had an intra - class correlation of r = 0.98 and a see = 0.03c .
after body temperature was determined and before hydrostatic weighing , the first bod pod ( bod podbh ) test was performed , subjects were then asked to shower ( this was done to keep the tank free of debris , wash off excess lotion , and sweat from the subjects ) and prepare for hydrostatic weighing .
hydrostatic weighing was performed as part of an alternative study objective , ( data not presented ) . immediately following hydrostatic weighing subjects dried off thoroughly using towels provided by the laboratory .
a second body temperature was determined and the second bod pod test was performed ( bod podfh ) . the moisture trapped in body hair and the fabric of the swimsuit was defined as the difference in body weight ( kg ) prior to hydrostatic weighing and upon completion of hydrostatic weighing ( after toweling dry ) .
whole body air - displacement was evaluated with the bod pod version 1.69 ( body composition system ; life measurement , incorporated , concord , ca ) as previously described .
thoracic gas volume ( tgv ) was measured in all subjects and bod pod conditions ( i.e. bod podbh and bod podfh ) according to the procedures described in the manual , while % fat was determined by the siri equation . in the calculation of body density for each testing condition ,
the body weight obtained in the dry state was used ; this was done to investigate the effect of moisture and temperature increases on estimates of % fat independent of effects caused by increases in body weight .
bsa was calculated according to the dubois formula : bsa = 71.84 weight ( kg) height ( cm ) .
same - day repeat measures of body density by the bod pod in our laboratory had an intra - class correlation of r = 0.98 and an see of 0.00365 ( g / cm ) .
whole body air - displacement was evaluated with the bod pod version 1.69 ( body composition system ; life measurement , incorporated , concord , ca ) as previously described .
thoracic gas volume ( tgv ) was measured in all subjects and bod pod conditions ( i.e. bod podbh and bod podfh ) according to the procedures described in the manual , while % fat was determined by the siri equation . in the calculation of body density for each testing condition ,
the body weight obtained in the dry state was used ; this was done to investigate the effect of moisture and temperature increases on estimates of % fat independent of effects caused by increases in body weight .
bsa was calculated according to the dubois formula : bsa = 71.84 weight ( kg) height ( cm ) .
same - day repeat measures of body density by the bod pod in our laboratory had an intra - class correlation of r = 0.98 and an see of 0.00365 ( g / cm ) .
group mean estimates of % fat , body volume , and body density , by the bod pod were compared using paired t - tests . linear regression analysis and residuals from the regressions ( percent fat and body density )
were used to assess the agreement between bod podbh and bod podfh for body density and % fat .
estimates were not considered different if the regression slope did not differ from one or the intercept from zero ( line of identity ) . bod podfh % fat , body volume and density estimates were calculated using dry body weight to control for the effect of weight gain ( due to moisture ) .
pearson correlation coefficients were used to examine the relation between the changes in body temperature , moisture , % fat , body volume and bsa before hydrostatic weighing ( bod podbh ) and following hydrostatic weighing ( bod podfh ) .
the independent relationships of temperature ( difference in bod podbh temperature and bod podfh temperature ) , moisture , and bsa with % fat ( difference in bod podbh % fat and bod podfh % fat ) were determined using partial correlations . statistical significance was set at p 0.05 .
all statistics were derived using spss statistical software ( version 10.0 ; spss inc . , chicago , il ) .
the % fat ( 28.9 vs. 27.1 ) , raw body volume ( 61.1 l vs. 60.9 l ) , and corrected body volume ( 61.7 vs. 61.5 l ) were significantly higher for the bod podbh vs. bod podfh ( table 1 ) .
71.84 weight height * corrected for tgv and surface area artifact ( raw body volume - saa + 40%tgv ) saa : surface area artifact bod podbh : bod pod measures before hydrostatic weighing .
data are mean sd linear regression analysis revealed that the regression of bod podbh % fat vs. bod podfh % fat significantly deviated from the line of identity , p 0.005 ( figure 1 panel a ) , though no bias was found across the range of body fatness p = 0.66 ( figure 1 panel b ) .
however , bod podbh body density versus bod podfh body density did not significantly deviate from the line of identity ( figure 2 panel a ) and no significant bias was observed between body density estimates across the range of fatness p = 0.36 ( figure 2 panel b ) .
panel a is the regression of percent fat determined by bod podbh before hydrostatic weighing against percent fat determined by bod podfh following hydrostatic weighing .
the dotted line is the line of identity ( regression slope = 1 and regression intercept = 0 ) .
panel b are the residuals from linear regressions of the percent fat from the bod podbh on percent fat from the bod podfh .
the middle line represents the mean difference while the upper and lower dashed lines represent 2 sd from the mean .
panel a is the regression of body density ( g / cm ) determined by bod podbh before hydrostatic weighing against body density determined by bod podfh following hydrostatic weighing .
the dotted line is the line of identity ( regression slope = 1 and regression intercept = 0 ) .
panel b are the residuals from linear regressions of body density bod podbh on body density from the bod podfh .
the middle line represents the mean difference while the upper and lower dashed lines represent 2 sd from the mean .
following hydrostatic weighing ( i.e. bod podfh ) subjects demonstrated a significant increase in body temperature ( 36.9c vs. 36.3c ; p 0.001 ) and body weight ( 63.66 vs. 63.58 kg ; p 0.05 ) as compared to bod podbh ( table 1 and figure 3 ) .
scatter plot between the difference in % fat ( bod podbh and bod podfh ) and the difference in body temperature ( bod podbh and bod podfh ) .
%fat was not associated with temperature after controlling for bsa and moisture gain , similarly %fat was not associated with moisture gain after controlling for bsa and temperature ( table 2 ) .
however , bsa was positively correlated ( r = 0.30 , p < 0.05 ) with % fat after controlling for moisture gain and temperature ( table 2 ) .
partial correlations to test the independent effect of temperature , moisture and bsa on % fat .
% fat : bod podbh % fat bod podfh % fat*p < 0.05 bsa : body surface area temperature : bod pod moisture : bod podbh weight bod podfh weight
the effect of body temperature and moisture on % fat , body volume , and body density using the bod pod was addressed in the present study .
subjects underwent hydrostatic weighing between bod pod tests , analogous to spending 30 minutes in a bath of 40c water .
consequently , body temperature and body moisture were significantly elevated for the bod podfh measurement .
since subjects had not consumed any liquids or food , nor were they allowed to void between bod podbh and bod podfh measurements , it was assumed that the net body weight gain was due to water trapped on the skin , in the hair follicles , or within the fabric of the swimsuit . as a result of body volume
being underestimated ( 0.210 l ) , the estimation in % fat by the bod podfh was significantly lower ( 1.8 % fat ) than the estimation of % fat by bod podbh , independent of the weight gain due to moisture retention .
the precise mechanism by which elevated body temperature and moisture affect bod pod measures is unclear .
the bod pod operates under adiabatic conditions and therefore can accommodate changes in air temperature due to the presence of the test subject ( 1 ) .
isothermal air present in the thoracic cavity is corrected for using measures of tgv during testing .
the isothermal like air surrounding the skin is adjusted for using the surface area artifact , which is a correction factor calculated from bsa ( 1 ) . however , under the present aberrant conditions the changes in the internal environment may have been too rapid to be controlled .
furthermore , the isothermal - like air surrounding the skin may have increased in quantity and the usual correction ( saa ) may have been inadequate .
in addition , the release of water vapor from the skin surface , swimsuit , or hair may have altered the composition of the chamber air such that the correction constant ( 1.4 ) was no longer appropriate to control for the adiabatic conditions .
the reduction in % fat was not related to the change in body temperature or to the gain in body moisture .
this suggests that a larger bsa facilitates a greater dissipation of heat and/or water vapor into the bod pod testing chamber resulting in a greater underestimation of body volume .
we emphasize that the independent effects of body temperature and moisture on body volume measurement could not be assessed with the present study design .
the lack of correlation between temperature and % fat might be related to the small variability in the average change in temperature from the first and second bod pod measurements ( ~0.6c with range of 0.1 1.6c ) .
since the variability in the temperature change was truncated , a relationship may have been undetectable .
in addition , it is likely that the effects of moisture within the test chamber were not readily quantifiable by weight gain alone .
moisture on the skin and body hair was likely to be the variable of interest ; this could not be quantified independent of moisture in the swimsuit . in conclusion ,
the presence of excess heat and moisture in the bod pod testing chamber leads to a small but significant underestimation in estimates of % fat .
these findings are similar to those reported for the effects of clothing and body hair on bod pod measures .
the specific mechanism(s ) by which body heat and moisture effect estimates of body volume remain to be elucidated .
the results from this study lead to the following recommendation : the bod pod should always precede hydrostatic weighing or a bout of exercise .
daf participated in study design , participated in data collection data analysis and writing the manuscript .
pbh participated in data analysis and editing the manuscript , and making all tables and figures .
we thank the division of physiology and metabolism at the university of alabama in birmingham for laboratory supplies and equipment .
Output:
| backgroundto investigate the effect of body temperature and moisture on body fat ( % fat ) , volume and density by air - displacement plethysmography ( bod pod).methods%fat , body volume and density by the bod pod before ( bod podbh ) and immediately following hydrostatic weighing ( bod podfh ) were performed in 32 healthy females ( age ( yr ) 33 11 , weight ( kg ) 64 14 , height ( cm ) 167 7 ) . body temperature and moisture were measured prior to bod podbh and prior to bod podfh with body moisture defined as the difference in body weight ( kg ) between the bod podbh and bod podfh measurements.resultsbod podfh % fat ( 27.1% ) and body volume ( 61.5 l ) were significantly lower ( p 0.001 ) and body density ( 1.0379 g / cm3 ) significantly higher ( p 0.001 ) than bod podbh % fat ( 28.9% ) , body volume ( 61.7 l ) , and body density ( 1.0341 g / cm3 ) . a significant increase in body temperature ( ~0.6c
; p 0.001 ) and body moisture ( 0.08 kg ; p 0.01 ) were observed between bod podbh and bod podfh .
body surface area was positively associated with the difference in % fat independent of changes in body temperature and moisture , r = 0.30 , p < 0.05.conclusionthese data demonstrate for the first time that increases in body heat and moisture result in an underestimation of body fat when using the bod pod , however , the precise mechanism remains unidentified . |
PubmedSumm4805 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: past clinical understanding confined the burden of chronic hepatitis c infection ( hcv ) to later stages of hepatic impairment .
now it is known that hcv 's extrahepatic manifestations ( ehms ) and reduced health - related quality of life ( hrqol ) often develop before hepatic impairment .
diagnostically , this understanding helps uncover underlying hcv in people presenting with associated ehms and vice versa .
prognostically , it is unclear whether ehms independently lower hrqol in hcv patients and whether they respond to antiviral therapy with or without a sustained virological response ( svr ) .
answers to these questions would help to determine whether the burden of ehms in hcv patients merits additional management approaches beyond antiviral therapy .
poor baseline hrqol is partly psychosocial in origin , relating to the stigma of illness , a history of illicit drug use for a large proportion of patients , and high rates of fatigue , anxiety , and depression [ 2 , 3 ] .
mood - related aspects of hrqol may even be organically mediated by hcv colonization of brain microglia and activation of brain interleukins . however , hrqol is also impaired through somatic symptoms , which may be specific to hcv pathophysiology .
for example , hcv patients score worse than hepatitis b patients on somatic symptoms of the sf-36 questionnaire , and patients unaware of their hcv infection still score worse than the general population [ 2 , 5 ] .
furthermore , most evidence points to an improvement in hrqol as being associated with svr after treatment with pegylated interferon alone or with ribavirin [ 2 , 69 ] , which was confirmed by a meta - analysis that also suggests that a minimum change of 4.2 points on the sf-36 vitality scale is needed for a significant improvement in hrqol .
several trials , however , show improvements in hrqol independently of svr , raising the hypothesis that viral suppression alone can achieve significant physiological changes [ 6 , 8 , 10 , 11 ] . hcv associated ehms create somatic symptoms that probably contribute to patients ' lower hrqol scores ,
arthralgia and myalgia are among the common rheumatological symptoms associated with hcv , with one study displaying a prevalence of 23% and 15% for each , respectively .
less common rheumatological ehms include arthritis , vasculitis , sicca syndrome , sjgren 's syndrome , and systemic lupus erythematosus [ 12 , 13 ] .
mixed cryoglobulinaemia ( mc ) , which has been found in 160% of people with hcv , describes the presence of igm immunoglobulins ( rarely igg or iga ) that form complexes with monoclonal ( type ii ) or polyclonal ( type iii ) rheumatoid factors ( rfs ) .
types ii and iii mc are far commoner than simple cryoglobulinaemia ( type i ) that does not include rf complexes and is not associated with hcv .
however , reported prevalence of mc depends heavily on the accuracy of laboratory techniques in cryoprecipitation at low temperatures and measuring cryoglobulin concentrations .
deposition of mc immune complexes , alongside poor clearance and reduced complement fragments , can result in small - vessel vasculitis and study populations with idiopathic mc have high reported incidences for cutaneous , musculoskeletal , and renal manifestations . therefore , secondary mc may play a common role in ehms as 510% of hcv patients display an overt mc vasculitic triad of weakness , arthralgia , and purpura [ 13 , 14 ] .
multiple tropism of the virus , particularly to lymphocytes , may account for many ehms with or without development of mc .
the hcv virus seems to facilitate a state of increased autoantibody and cryoglobulin production by expanding b cells through the envelope protein e2 interacting with the cd81 receptor and increasing b - cell survival by activating the bcl2 proto - oncogene [ 13 , 16 , 17 ] .
a similar state may also be achieved by the virus molecular mimicry of host autoantigens [ 17 , 18 ] . as of yet , no factors specific to host background , environment , or viral genotype have been associated with the emergence of ehms . chronic pain in particular has been shown to impair hrqol in hcv patients .
however , apart from a specific role for mc in some cases of arthralgia , there is no overarching evidence for a pathogenic role of the virus in most presentations of chronic pain .
for example , histopathological presence of hcv in muscles of myalgia sufferers [ 13 , 20 ] and an increased prevalence of hcv in fibromyalgia patients have not been consistently found [ 21 , 22 ] .
antiviral therapy has some evidence for improving pain in the context of mc complicated hcv . in one study , arthralgia and myalgia
improved for approximately half the patients , and in those achieving svr fatigue and mc levels dropped significantly . in another study , interferon and ribavirin therapy cleared mc in 37.8% and arthralgia in 80% of patients .
however , to our knowledge no other studies have yet assessed therapeutic effects on ehms alongside measured hrqol changes in hcv patients .
investigate whether hrqol improves following antiviral therapy . investigate whether extrahepatic outcomes improve following antiviral therapy .
investigate whether improvement in hrqol or extrahepatic symptoms is dependent on svr after treatment .
investigate whether hrqol improves following antiviral therapy .
determine whether an association exists between extrahepatic symptoms and hrqol before and after treatment .
investigate whether improvement in hrqol or extrahepatic symptoms is dependent on svr after treatment . a study protocol for a cross - sectional epidemiological study into the prevalence of musculoskeletal symptoms among hcv positive adults in a brighton cohort
was proposed and granted ethics approval by the brighton east research ethics committee in january 2006 ( reference . 06/q/1907/134 ) . out of a cohort of 537 hcv patients managed at the digestive diseases unit at the brighton and sussex university hospital trust ( bsuh ) , in the uk
, we assessed the results of 118 patients who were not coinfected with hiv or hbv and who had completed standard antiviral treatment with pegylated interferon- and ribavirin .
participants answered the hepatitis quality of life questionnaire ( hqlq ) and a survey of symptoms affecting the spine , muscles , bones , and joints before treatment and six months after finishing treatment .
the hqlq is generically based on sf-36 health survey but is validated as a hepatitis - specific instrument in the measurement of hrqol .
outcome measures included presence of chronic widespread pain ( cwp ) according to the manchester criteria ( pain in the axial skeleton and at least two contralateral body quadrants for at least 3 months ) , the number of affected joints , pain intensity , and interference with daily life as scored on a visual analogue scale ( vas ) .
the binary cwp manchester criteria outcome was preferred over assessments of fibromyalgia , as the latter would require validation via physician led examinations ( self - reports of having a diagnosis of fibromyalgia at baseline were not considered ) .
a lack of physical examinations also excluded the presence of vasculitic rashes from our assessments . in the context of this study , patients were considered positive for sicca syndrome if they reported both mouth and eye sicca symptoms using standardized questions into xeropthalmia and xerostomia ; a full assessment of sjgren 's with antiro / ssa or other autoantibodies was not performed . a paired samples t - test or wilcoxon test was used to analyze changes in hrqol , vas , and number of painful joints from before treatment to 6 months after treatment . an independent samples t - test or mann - whitney u test ( nonparametric )
a pearson chi - square test was used in the number of patients with cwp , number of patients with pain for more than 3 months , or number of patients who agreed with the statement i ache all over .
exact p values of < 0.05 in the two - tailed tests were considered significant .
our cohort reflected a relatively young population with a mean age of 46 and an overwhelming proportion with a history of intravenous drug use due to brighton having one of the highest prevalence of ivdu in the uk .
although the presence of rf was common ( see table 2 ) , mc prevalence was low at only 5.9% , though laboratory techniques and unsatisfactory test completion rates should be taken into account .
there was a statistically significant improvement in scores in the following 6 out of the 12 domains of the hqlq : physical functioning , physical disability , social functioning , limitations due to hepatitis , health distress due to hepatitis , and general health ( see table 3 and figure 1 ) . there was a statistically significant deterioration in 3 of the domains ( positive well - being , health distress , and mental health ) , and there was no significant change in the rest of the domains ( body pain , role emotional , and vitality ) .
there were a high baseline prevalence of chronic pain symptoms and statistically significant declines after treatment in the number of patients with cwp ( 11% reduction , p = 0.015 ) , number of patients with pain for more than 3 months ( 11% reduction , p = 0.041 ) , or number of patients who agreed with the statement i ache all over
( 10.1% , p = 0.029 ) ( see table 4 ) . having cwp before treatment was significantly associated with worse pretreatment pain levels ( 5.7/10 versus 2.7/10 , p > 0.001 ) and their interference with daily life as reported on vas ( 5.0/10 versus 2.1/10 , p > 0.001 ) , though the overall vas pain scores and the average number of painful joints did not fall significantly after treatment . having cwp before treatment was also negatively associated with all hqlq domains ( significantly in all except vitality and health distress and hepatitis - specific distress ) , except for positive well - being where people with cwp scored significantly higher ( 75/100 versus 66/100 , p = 0.023 ) ( see table 5 ) . a remission of cwp after treatment was significantly associated with improvements in the hqlq domain of body pain ( 15.4 improvement in cwp remission versus 11.8 if it stays the same and 14.8 reduction if cwp develops , p = 0.024 ) , physical function ( p = 0.043 ) , and nearly role emotional ( p = 0.052 ) ( see figure 2 ) .
in contrast to pretreatment cwp , having cwp after treatment was only significantly associated with a worse role physical and body pain hqlq score ( p = 0.008 , p < 0.001 ) .
there were a small number of patients who matched the study 's criteria for sicca syndrome , and the decline after treatment was not significant ( 12.7% versus 11% , p = 0.804 ) .
after treatment 67% of patients achieved svr . there were positive nonsignificant associations between svr and changes in all hqlq scores and significant positive associations between svr and changes in cwp ( p = 0.038 ) ( see figure 3 ) .
patients in this study showed significant improvement in 6 of the 12 domains of hqlq following treatment , which on the whole improved the total score .
however , these improvements did not include an increase of more than 4.2 points on the vitality scale , which has been defined by spiegel et al . as the minimally clinically important difference in hrqol .
therefore , to argue that in this case antiviral therapy has had a positive effect on hrqol is dependent on the weighting given to different domains . in keeping with previous studies , hrqol improvement was seen in the domains relating to physical health [ 2 , 6 , 7 ] .
given the significant improvement in domains relating to general health , disease limitations , social functioning , and hepatitis - related distress , the deterioration in domains relating to mental well - being and positive well - being distress suggests a complex range of effects with antiviral treatment .
this may be an exacerbation of a high baseline incidence of anxiety and depressive symptoms , which are commonly reported among hcv - infected patients [ 11 , 27 ] .
these baseline symptoms may be related to a patient 's distress at being diagnosed with a chronic and serious illness , a history of illicit drug use , or a direct effect of the virus .
the exacerbation of these symptoms , on the other hand , may be caused by antiviral treatment itself , as interferon alpha is known to cause depression .
our results support the hypothesis that initial impairments in physical domains are more likely to be virus related than impairments in domains of mental health given that the former domains improved following treatment while the latter did not [ 1 , 31 ] .
our results reflect the direction of previous findings that fewer patients experience myalgia and arthralgia following treatment [ 23 , 24 , 32 ] .
interestingly , however , while patients with cwp , 3-month pain and i ache all over reported that pain levels all fell significantly , the average vas pain intensity and impact levels , bodily pain aspects of the hqlq , and the number of painful joints were all low and changed little with treatment .
this demonstrates that extrahepatic pain manifestations in hcv patients pool together in a subset of patients and are unaltered by treatment in the majority of cases . an analysis comparing patients with and without cwp before treatment revealed baseline hqlq scores to be significantly worse in 9 domains in those with cwp , though whether this was cause or effect is not ascertainable here .
the discrepancy of a greater positive well - being in patients with baseline cwp represents a psychological anomaly as mental health and other psychological domains were significantly worse in this subset .
cwp remission after treatment was also significantly associated with an improved body pain and physical function score , which changed little otherwise for the whole cohort .
this shows that having cwp before treatment is significantly associated with a worse hrqol and that the bodily pain aspect may be particularly responsive to treatment in this subset , which has not been illustrated in the literature before .
the clinical implications for this lie in better recognition of this subset of patients in order to discuss the potential effects of treatment for them specifically and in using appropriate additional management strategies such as analgesia or exercise .
if the observed trends in pain reflect the effects of a viral immunomodulatory process affecting a subset of patients , one would expect more patients to also undergo remission of sicca syndrome
. a lack of response to treatment may be due to unknown factors and an already underwhelming sicca prevalence in the cohort relative to other studies . .
however , a more evident response would be expected because sicca syndrome has an established viral pathogenesis where hcv exocrine gland tropism is strongly associated with lymphocytic infiltration , sometimes in combination with rheumatoid factor and autoantibodies and resultant xerostomia and xerophthalmia .
arthralgia on the other hand is more known to be associated with hcv through a mechanism of elevated autoantibodies and mc that promotes tissue injury , a biomarker which was rare in our cohort .
thus , our observed improvements in pain scores may also be due to unmeasured nonvirological changes , such as nutritional status improvements , reduced alcoholic consumption , and subsequent improvements in vitamin d levels that are associated with nonspecific musculoskeletal pain .
data from a meta - analysis of hrqol studies in hcv patients has suggested that svr is associated with improved hrqol . in this study , there was a general trend in that direction without statistical significance , which reflects the power of the sample size .
our results suggest that antiviral therapy can improve hrqol and pain scores in the absence of svr , which may be due to a placebo response , which this study did not control for , or due to the immunomodulatory effects of antiviral therapy , which have not been fully described yet .
for example , interferon has been found to have antiproliferative effects on mc and has been used on mc even before link with hcv was found .
furthermore , it has been suggested that this effectiveness may be irrespective of interferon 's antiviral properties .
conversely , other studies have shown that mc and subsequent vasculitic symptoms can persist despite svr , which supports the hypothesis of there being both memory ( virus - dependent ) and nave ( virus - independent ) autoimmune b cell expansion after hcv infection .
the main drawback of this study is the lack of a matched control group not undergoing antiviral treatment , due to there being only a minority of such patients , of whom many have concurrent psychiatric illness , ivdu , and alcoholism .
furthermore , concomitant use of vitamin d supplementation , analgesia , and anti - inflammatories during questionnaire completion was not controlled for . due to the small proportion of patients with the extrahepatic symptoms in this study
, a larger sample may be necessary to improve the power of measuring the effects of treatment and svr .
therefore , larger study participation with controls and longer followup are needed to validate the study 's results .
antiviral therapy with pegylated interferon- and ribavirin can significantly improve physical and functional aspects of hrqol as well as rheumatological cwp symptoms in hcv patients , despite no changes in vitality and deterioration in mental health and positive well - being . in our cohort ,
cwp prevalence is high , demonstrably related to hrqol , and unaccounted for through cryoglobulinaemia alone .
a role for the virus in cwp is purely speculative on the basis of these results , and other potential causes such as vitamin d deficiency were not measured .
of relevance to clinical practice , however , are the study 's observed cwp prevalence and response in hcv patients undergoing antiviral treatment .
an awareness of this finding may prompt earlier diagnosis and investigation of cwp in hcv patients and warrant chronic pain relief as an additional indication for antiviral treatment besides existing benefits on hepatitis and hrqol .
additional management strategies such as graded exercise and analgesia should be discussed in this subset of chronic pain sufferers for whom antivirals are deemed inappropriate .
Output:
| background .
hcv infection is associated with musculoskeletal manifestations such as chronic widespread pain , sicca syndrome , polyarthritis , and a reduced hrqol .
little data is available on the effect of treatment on these manifestations .
this study measured changes in extrahepatic symptoms and hrqol before and after antiviral treatment in a large uk patient cohort .
methods .
118 patients completed hqlq and rheumatological questionnaires before and after treatment with pegylated interferon- and ribavirin , with specific regard to chronic widespread pain , sicca syndrome , and sustained virological response .
results .
there was significant improvement in hqlq domains of physical functioning , physical disability , social functioning , limitations and health distress due to hepatitis , and general health .
there was significant deterioration in domains of positive well - being , health distress , and mental health .
there was a significant decline prevalence of cwp ( 26.3% versus 15.3% , p = 0.015 ) .
sicca syndrome prevalence fell insignificantly ( 12.7% versus 11% ) .
svr was associated positively with all hrqol changes and significantly with cwp remission
. conclusions .
hcv antivirals significantly improve poor hrqol scores and cwp . before treatment , both were common , coassociated , and unaccounted for through mixed cryoglobulinemia alone .
although a role of the hepatitis c virus in cwp can not be deduced by these results , symptomatic improvement via antiviral treatment exists for this subset of patients . |
PubmedSumm4806 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: cerebrovascular disorder , mainly including ischemic and hemorrhagic stroke , is the third cause of death after cardiovascular disease and cancer and the leading cause of long - term disability in adults in china .
although stroke mortality has declined in the past decades , its prevalence and morbidity increased dramatically because of enhanced stroke survival .
about 40% of stroke survivors have certain degree of impairment and 1530% are severely disabled .
up to date , many targets within the cascade of neuronal death have been identified . however , neuroprotective strategies in treating poststroke with sequela are controversial .
since neural progenitor and stem cells were discovered in the adult brain for the first time in 1992 , different experimental stroke models indicated that neural progenitor and stem cells with activities of migration and differentiation are activated by hypoxia in brain [ 7 , 8 ] .
increasing evidence from basic studies indicates that cord blood mononuclear cells , bone marrow mononuclear cells , and bone marrow stromal cells can survive in postischemia tissue and reduce neuronal damage when transplanted into rodents subjected to cerebral infarction [ 912 ] .
bone marrow - derived cd34 positive cells have previously been used to reconstitute the hematopoietic system after radiation or chemotherapy . recently
, cd34 positive cells have been widely reported to induce therapeutic angiogenesis in animal models of myocardial , peripheral , and cerebral ischemia [ 1315 ] . circulating bone marrow - derived immature cells , including cd34 positive cells ,
in addition , the level of circulating cd34 positive cells was decreased in patients with vascular - type cognitive impairment .
recently , the positive correlation between the number of circulating cd34 positive cells and patients with acute stroke stress has been demonstrated , which suggests that increased numbers of circulating cd34 positive cells might benefit neurologic function recovery .
although previous clinical data have demonstrated a positive benefit in patients with stroke , there are no clinical reports on autologous cd34 positive precursor cells in the treatment of poststroke . in our ongoing clinical study
, we designed a protocol to determine the safety and potential efficacy of g - csf mobilization of bone marrow - derived cd34 positive cells in the treatment of patients with a history of stroke . in the current study , we focused on the investigation of the safety of cd34 positive cell administration .
the study was approved by the institutional review boards of 323 hospital of pla ( xi'an , china ) .
the procedure of our ongoing clinical study was under steps criteria [ 20 , 21 ] .
eight male patients with a history of stroke and left sequela were the target population in this study . the inclusion and exclusion criteria
all patients were treated subcutaneously with 5 g / kg body weight g - csf for five consecutive days .
leukapheresis was performed using a cobe spectra cell separator ( cobe bct , lakewood , co ) .
blood pressure and heart rate were monitored , and a physician was available for any emergencies during the performance .
cd34 positive cells were extracted from leukapheresis products by immunoselection using an automated cell separation system ( miltenyi biotec , bergisch gladbach , germany ) based on the mechanism of selectivity of a monoclonal cd34 antibody conjugated to a magnetic particle [ 22 , 23 ] . for purity analysis of immunoselected cd34 positive cells ,
cells were evaluated by flow cytometry using cd34-pe - conjugated monoclonal antibody . then the immunoselected cd34 positive cell components were divided into multiunits stored in liquid phase nitrogen at 196c and will be infused later .
0.83.3 10 ( varying from different patients ) in 2 ml medium was used per time .
the cells from the good manufacturing practice ( gmp ) workshop were ensured to have been fully screened against potential pathogens and meet the eligible criteria for clinical use .
patients ' x - rays , computed tomography scans , and magnetic resonance images of spine were reviewed prior to administration .
intrathecal injection by lumbar puncture was repeated four or five times depending on the patient 's condition .
patients were given local anesthesia , and lumbar puncture was performed in the lateral decubitus position , prepped , and draped in sterile fashion , and the needle was placed in the lumbar cistern .
2 ml of cerebrospinal fluid was removed and replaced by 2 ml of immunoselected cd34 positive cell suspension .
clinical chemistry monitoring , including tests of blood count , liver function , renal function , lipids , and glucose , was performed before , 1 day , and 7 days after cell treatment , respectively .
in addition , nih stroke scale and barthel index , which are widely used in evaluation of functional disability , were documented at baseline and at 1st , 6th , and 12th months in the 12-month followup .
as shown in table 2 , 8 male patients ( age : 2258 yrs , median : 42 yrs ) with a history of stroke ( range : 17 yrs , median : 2 yrs ) were enrolled .
g - csf and leukapheresis were well tolerated in all patients during the clinical treatment course .
a mean of 1.8 10 of cd34 positive cells ( range 0.83.3 ) was collected by immunoselection .
flow cytometry analysis showed that cd34 positive cells in the immunoselected fraction were above 85% .
no allergic or immunological reactions were noted at the time of injection or while under observation . no chest pain and abnormal level of cardiac enzymes were observed .
in addition , there is no statistical difference of blood tests ( tables 3 and 4 ) before treatment , 1 day , and 7 days after treatment .
therefore , the above data indicated that cell infusion into the subarachnoid space was a safe procedure in patients with poststroke .
as shown in table 5 , we observed that the daily activities had a gradual improvement tendency in the 12-month followup .
mean of nih stroke scale and bi scores shifted from 7.5 and 43.8 at baseline to 4.4 and 64.4 in 12 months later , respectively .
the improvements of muscle tone , rigidity , and motor power were observed in all patients .
however , we must emphasize that patients with stroke do gradually improve their functions , and here it is not possible to define whether the therapy itself or the natural history of the disease is responsible for the improvements noted .
in the current study , we observed that g - csf administration , leukapheresis , and intrathecal administration of cd34 positive cells were safe and well tolerated in a group of patients with past cerebral infarction with 12-month followup .
g - csf has been used extensively in the last decades to mobilize cd34 positive hematopoietic stem cells in neutropenic patients and for reconstitution of bone marrow [ 24 , 25 ] . recently , g - csf as a promising drug candidate can reduce neuroinflammation and potentiate both neurogenesis and angiogenesis after ischemic stroke by promoting bone marrow cell migration into the ischemic brain [ 26 , 27 ] .
many years of clinical experience with g - csf have shown the safety of this agent in the general population .
increasing clinical studies indicated mobilization of cd34 positive precursor cells in patients with acute stroke by g - csf is safe and effective [ 2931 ] . in the current study ,
patients with past cerebral infarction were treated by g - csf ; subsequently , leukapheresis was performed for cd34 positive cells collection by immunoselection .
there were no emergencies , and adverse events , such as hyperviscosity syndromes , occurred in the whole process .
previously , it has been reported that intrathecal administration was safe with a variety of stem cells including adipose tissue - derived mesenchymal stem cells , embryonic stem cell - derived hematopoietic stem cells , and autologous bone marrow - derived hematopoietic stem cells in the treatment of neurological disorders [ 32 , 33 ] . in this study ,
intrathecal injection of the cd34 positive cells into subarachnoid space was performed , thereby migrating more efficiently into the injured area related to stroke through cerebrospinal fluid compared to the intravenous route .
what is more , there were no side effects including headache , low - grade fever , and meningism and vomit occurring in eight patients .
cd34 positive cells comprise a population enriched with endothelial progenitor cells whose contribution to neovasculature includes both direct participation in forming the neovessel and regulatory roles and the sources of growth / angiogenesis factors including vegf , hgf , and igf-1 , contributing to the maintenance of the microvasculature . the positive correlation between levels of circulating cd34 positive cells and neovascularization in patients with postcerebral ischemia
given the variance of age , transplantation cell numbers , and stroke history , the discrepant response to the treatment is apprehensible .
the current data showed a trend that cd34 positive cells might achieve clinical benefits in the treatment of patients with poststroke .
however , improvements do occur naturally in patients with stroke , and it is not possible to define whether the therapy itself or the natural history of the disease was responsible for the improvements noted . in conclusion , this study indicates that intrathecal administration of cd34 positive cells in patients with past stroke is a relatively safe and simple procedure with no long - term adverse effects .
however , further larger clinical studies with multiple groups including blinding and placebo controls will be required to confirm our findings in the current study .
Output:
| regenerative strategies in treatment of stroke have great potential .
the goal of the current study was to investigate safety of intrathecal administration of autologous cd34 positive cells in treatment of patients with poststroke .
a total of eight male patients with a history of stroke were enrolled .
the patients were treated subcutaneously with 5 g / kg body weight rhg - csf for 5 consecutive days , and then leukapheresis was performed to concentrate cells for cd34 positive immunoselection .
all patients underwent intrathecal administration of cd34 positive cells via lumbar puncture .
the primary outcome was safety evaluation for 12-month followup .
in addition , behavioral function was evaluated with nih stroke scale and barthel index 1 , 6 , and 12 months after the last treatment , respectively .
there were no major adverse events , and abnormal changes of blood tests during the whole treatment process included intrathecal administration and 12-month followup .
the main message from the current study was that administration of g - csf - mobilized autologous cd34 positive cells in patients with poststroke was safe .
future studies with larger population and control group are needed to confirm the safety and investigate the efficacy . |
PubmedSumm4807 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: its main characteristics are deficits in social communication and relationship , verbal communication and language impairments , and repetitive / restrictive behaviors and interests .
some of these children do not like to try new foods and have food selectivity .
children with autism intake vitamin b6 and vitamin e more than the controls . however , their take of vitamin b12 is less than that of the typical controls .
in addition , the level of vitamin b6 in plasma is very high in autism .
moreover , there are contradictory reports about the level of intake of proteins by children with autism .
for example , a study reported that the protein intake of children with autism is significantly less than the typical controls .
meanwhile , others reported that daily protein intake of children with autism is higher than that of the controls [ 3 , 6 ] .
children with autism suffer from deficiency of essential plasma amino acids displaying their poor protein intakes .
while the rate of at least one essential amino acid ( valine , leucine , phenylalanine , and lysine ) deficiency in autism was 58% , the rate in the control group was 4% .
another study compared plasma level of 25 amino acids between high - functioning autism children and the healthy controls .
the study showed that only the levels of glutamate and glutamine were different between the two groups .
while the level of glutamate was increased , the level of glutamine was decreased ( table 1 ) .
the levels of other amino acids were not different between high - functioning autism children and healthy controls .
the authors suggested that the plasma level of these two amino acids may differentiate high iq autism and normal children .
the deregulation of amino acids in autism was also reported in siblings and parents of these children .
glutamate is involved in neuroinflammation in autism . moreover , targeting glutamate receptors through glycine site on nmda receptor is supposed as a target for treating autism .
in addition , methionine sulfoximine may improve inflammation in autism . besides , many children with autism suffer from irritability and aggression .
the levels of homocysteine and glutamate are associated with each other , and this is supposed to be a target for treating aggression .
there is a positive correlation between cerebrospinal level of glutamate level and its plasma level .
therefore , the levels of amino acids in plasma , brain , and urine are reviewed . to the best of author 's knowledge
, no published review article about the levels of amino acids in autism has been published yet .
the high level of plasma glutamate level especially in children with normal iq is supposed to be a diagnostic screening test . the increased plasma level in adults with autism
higher glutamate level is not limited to plasma , and some studies confirmed its higher level in some brain regions ( amygdala - hippocampal regions but not in parietal region ) of patients with autism compared to the controls .
the increased plasma glutamic acid is not limited to patients with autism , but its level is increased in their siblings and parents . another study measured plasma amino acid levels in 14 young children with autism by high - pressure liquid chromatography ( hplc ) .
the low level of plasma glutamine level is suggested as a screening test for detecting autism in children especially those with normal iq .
the decreased level has been reported before in all children with autism [ 10 , 15 , 16 ] ( table 2 ) .
it is suggested that its higher level is a compensatory phenomenon for the increased glutamate level .
however , their subjects were taking supplements of folic acid and vitamin b12 before being included in the study .
therefore , the deficiency of vitamin may increase the level of homocysteine . meanwhile , other well - controlled study showed that the serum level of homocysteine is increased in autism [ 16 , 23 , 24 ] .
there are many reports about the increased plasma level of lysine in autism [ 8 , 10 , 16 ] .
meanwhile , a study reported that lysine level in autism is not different with in the controls .
all of the studies reported that the level of tryptophan is decreased in autism [ 16 , 17 ] .
this reduction may be due to the deficiency of folic acid and vitamins b6 and b12 .
in addition , the urinary levels of essential amino acids in both the untreated and treated autistic children are significantly less than those the controls .
the levels of alanine , a - aminobutyric acid , valine , leucine , isoleucine , threonine , serine , proline , asparagine , aspartic acid , glutamic acid , phenylalanine , a - aminoadipic acid , glutamine , glycine - proline , lysine , histidine , tyrosine , proline - hydroxyproline , tryptophan , and total essential amino acids in untreated autism in first urine of the morning are less than those of the controls .
current findings support that many children with autism suffer from amino acids metabolism impairment . nearly , all the studies reported higher levels of plasma glutamate in autism than those of the controls .
this increased glutamate level is compatible with the findings that the level of proteins involved in transforming glutamate to gaba is decreased .
a well - controlled study confirmed that the plasma glutamate level is increased while the level of glutamine is decreased in children with autism .
the increased serum level of glutamate in autism is weakly associated with severity of autism .
another study also reported that there was a statistically nonsignificant increase of platelet - poor plasma glutamate in autism . in summary ,
children with autism more likely have essential amino acids deficiency , and this may make them prone to a higher deficiency if they are under a specific diet .
there are many shortcomings in the current literature regarding the level of amino acids in autism .
further studies should investigate whether the levels of different amino acids are associated with age and gender in autism .
at least one study reported that the pattern of amino acids is associated with age while it is not associated with gender .
although it is suggested that the increased level of glutamate is stable in later ages , it needs to examine whether the findings can be generalized to different ages .
a study reported that some biomarkers are gender related in patients with asperger 's syndrome .
the rate of autism is gender dependent as well .besides , it is not examined whether the profile of amino acids in autism is associated with the developmental level , autism symptoms severity , and psychiatric disorders comorbidities .
the rate of psychiatric comorbidity is up to 74% . about half of children with autism
meet diagnostic criteria for adhd .autism is one of the disorders in the spectrum of pervasive developmental disorders . whether the pattern of amino acids is different between the different types of autism spectrum disorders needs to be clarified .
whether current findings can be generalized to all the types of autism needs to be investigated .
in addition , many children with autism have some medical comorbidities such as down 's syndrome , fragile x syndrome , epilepsy , and/or tuberous sclerosis .
the intelligent quotient of about two - thirds of children with autism is less than 75 . in other words ,
moreover , future studies should examine the possible role of any diet regime or food habits as covariate factors .
it should be clarified whether the possible profile of amino acids in autism is secondary to the food and diet pattern .
some instruments assess the diet or food pattern of children . however , these instruments are very different .
for example , some of them may evaluate the food pattern during a few days while others may assess it during a few months .
about one - fourth of them have at least one of the problems of constipation , abdominal pain , bloating , diarrhea , and/or nausea lasting three or more months .
is there any role for these problems to impact amino acids levels in autism?further studies should investigate why glutamate level is increased in autism .
is it due to dietary origin , metabolic problems , vitamin b6 involvement , glutamate receptor problems , and glutamate transporters problems or all of them ?
there is a speculation about the possible role of human gut microbiota in the etiology of autism .
some of the microbial metabolites may affect brain function through impacting aromatic amino acids metabolism .the ratio of the different amino acids is another item which needs to be considered in future studies . because one study indicated that several amino acids , individually or combined , differentiate autism spectrum disorder and healthy controls
the levels of some amino acids in urine of treated children with autism are different from those of untreated ones .body mass index and creatinine level may impact on amino acids levels.the technical method of assessment of amino acid should be considered to decrease the possibility of plasma contamination from other resources of amino acids such as platelets .
serum , platelet - poor plasma , and platelet - riched plasma should be differentiated .
further studies should investigate whether the levels of different amino acids are associated with age and gender in autism .
at least one study reported that the pattern of amino acids is associated with age while it is not associated with gender .
although it is suggested that the increased level of glutamate is stable in later ages , it needs to examine whether the findings can be generalized to different ages .
a study reported that some biomarkers are gender related in patients with asperger 's syndrome .
, it is not examined whether the profile of amino acids in autism is associated with the developmental level , autism symptoms severity , and psychiatric disorders comorbidities .
the rate of psychiatric comorbidity is up to 74% . about half of children with autism
autism is one of the disorders in the spectrum of pervasive developmental disorders . whether the pattern of amino acids is different between the different types of autism spectrum disorders needs to be clarified .
whether current findings can be generalized to all the types of autism needs to be investigated .
in addition , many children with autism have some medical comorbidities such as down 's syndrome , fragile x syndrome , epilepsy , and/or tuberous sclerosis .
these comorbidities need to be considered as covariates in further studies . the intelligent quotient of about two - thirds of children with autism is less than 75 . in other words ,
moreover , future studies should examine the possible role of any diet regime or food habits as covariate factors .
it should be clarified whether the possible profile of amino acids in autism is secondary to the food and diet pattern .
, some of them may evaluate the food pattern during a few days while others may assess it during a few months .
about one - fourth of them have at least one of the problems of constipation , abdominal pain , bloating , diarrhea , and/or nausea lasting three or more months .
is it due to dietary origin , metabolic problems , vitamin b6 involvement , glutamate receptor problems , and glutamate transporters problems or all of them ?
there is a speculation about the possible role of human gut microbiota in the etiology of autism .
some of the microbial metabolites may affect brain function through impacting aromatic amino acids metabolism .
the ratio of the different amino acids is another item which needs to be considered in future studies . because one study indicated that several amino acids , individually or combined , differentiate autism spectrum disorder and healthy controls .
the levels of some amino acids in urine of treated children with autism are different from those of untreated ones .
the technical method of assessment of amino acid should be considered to decrease the possibility of plasma contamination from other resources of amino acids such as platelets .
serum , platelet - poor plasma , and platelet - riched plasma should be differentiated .
Output:
| there are many reports about the significant roles of some amino acids in neurobiology and treatment of autism .
this is a critical review of amino acids levels in autism .
no published review article about the level of amino acids in autism was found .
the levels of glutamate and homocystein are increased in autism while the levels of glutamine and tryptophan are decreased .
findings regarding the plasma levels of taurine and lysine are controversial .
the urinary levels of homocysteine and essential amino acids in both the untreated and treated autistic children are significantly less than those in the controls .
the current literature suffers from many methodological shortcomings which needed to be considered in future studies .
some of them are age , gender , developmental level , autism symptoms severity , type of autism spectrum disorders , medical comorbidities , intelligent quotient , diet , concomitant medications , body mass index , and technical method of assessment of amino acids . |
PubmedSumm4808 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: i. b. , z. m. , p. c. , l. h. , and a. h. are employees of pfizer inc . and hold significant stocks and shares of pfizer inc .
Output:
| approximately 50% of rare diseases are evident in children . fatal disease prognosis and lack of treatments causes 30% of affected children to not live past their fifth birthday .
this clear sense of urgency demands innovation and acceleration in drug development .
a case study is discussed highlighting the need for datarich phase i study design , extensive use of modeling and simulation , use of diverse data sources , and input from collaborators to respond to this urgent call . |
PubmedSumm4809 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: rhinitis is the inflammation of the mucous lining of the nose , and it can lead to symptoms including rhinorrhea , nasal obstruction , post - nasal drip , itching , and sneezing .
the etiologies of rhinitis include infection , anatomical anomalies , immunological disorders , hormonal imbalance , and ciliary defects [ 1 , 2 ] .
similar nasal symptoms can be caused by different etiologies , making the diagnosis and treatment of rhinitis difficult .
methods for management of rhinitis include environmental control , pharmacotherapy , immunotherapy , surgical interventions , nasal irrigation , complementary , and alternative medicine .
the surgical indications for rhinitis include drug - resistant inflammatory mucosal hypertrophy , anatomical anomalies , and sinus drainage obstruction . complementary or alternative medicines such as traditional chinese medicine ( tcm ) , acupuncture , herbs , and probiotics are also being used for the treatment of rhinitis [ 46 ] .
recently , evidence - based guidelines with several algorithm - guided therapeutic schemes for the treatment of rhinitis are available [ 2 , 7 , 8 ] . yet , to our knowledge
, no studies have been conducted to determine the factors associated with the use of different treatment modalities .
therefore , the aim of this study was to investigate the factors associated with the use of treatment among patients with rhinitis in taiwan .
patients with physician - diagnosed rhinitis from the outpatient department of otolaryngology in taichung veterans general hospital , a medical center in central taiwan , were invited to participate in this cross - sectional survey study .
the diagnosis of rhinitis was based on patients ' reports of typical nasal symptoms persisting for two weeks or more and rhinoscopy examination .
typical nasal symptoms include rhinorrhea , nasal obstruction , postnasal dripping , itching , and sneezing .
physical examination with anterior rhinoscopy or nasal endoscopy was performed by two rhinologists ( rsj and kll ) .
all enrolled patients revealed signs of nasal inflammation including mucosal edema , nasal polyp , polypoid swelling , discharge ( purulent , mucous or serous ) , or crust .
the study was approved by the institutional review board of taichung veterans general hospital , and all participants gave written informed consent .
each patient completed a questionnaire with questions on sociodemographic status , lifestyle , general health status , disease - specific quality of life , and previous use of treatment modalities for rhinitis .
the treatment modalities were classified into four main categories : pharmacology , surgical intervention , tcm , and nasal irrigation .
the disease - specific quality of life was assessed using the chinese version of the 31-item rhinosinusitis outcome measure ( crsom-31 ) .
the crsom-31 is a validated instrument translated from the widely used rhinosinusitis outcome measure ( rsom-31 ) .
it contains seven domains including nasal symptoms ( 6 items ) , eye symptoms ( 3 items ) , sleep ( 3 items ) , ear symptoms ( 5 items ) , general symptoms ( 7 items ) , practical problems ( 4 items ) , and emotional consequences ( 3 items ) for evaluation of the rhinitis or rhinosinusitis - related impact on the quality of life . for each symptom
, there are two response scales : magnitude ( 0 to 5 ) and importance ( 1 to 4 ) .
the crsom-31 symptom - impact score is the product of the magnitude and importance scores , with higher scores indicating worse disease - specific quality of life .
continuous data were expressed as mean standard deviation ( sd ) , and categorical data were expressed as frequencies and percentages .
univariate logistic regression analyses were conducted to assess the odds ratios and 95% confidence intervals for each of the treatment modalities with the independent variables , including sex , age , body mass index ( bmi ) , marital status , educational level , alcohol use , smoking , regular exercise , general health status , crsom-31 symptom - impact scores , and four etiologies of rhinitis .
multivariate logistic regression analyses with backward stepwise selection method were used to evaluate the independent factors associated with the use of each of the treatment modalities . in all regression analyses ,
bmi was calculated as weight ( in kilograms ) divided by height ( in meters ) squared .
based on the definition from the bureau of health promotion , department of health , taiwan , the respondents were categorized as underweight ( bmi < 18.5 kg / m ) , normal weight ( bmi 18.523.9 kg / m ) , overweight ( bmi 24.026.9 kg / m ) , or obese ( bmi 27.0 kg / m ) .
educational levels were divided into elementary school or lower ( grade 1 to grade 6 ) and high school or above .
general health status of the patients was grouped into three levels ( poor or fair , good , and very good or excellent ) . crsom-31
a total of 279 patients with acute or chronic rhinosinusitis , allergic or nonallergic rhinitis were successfully interviewed between july and september 2011 .
the basic characteristics of the study participants are summarized in table 1 . in terms of the use of treatment modalities ,
85.7% of the patients had used pharmacology ( 77.1% had used oral medications and 65.9% had used topical medications ) , 38.4% had used surgical intervention , 34.4% had used tcm , and 34.1% had used nasal irrigation ( table 2 ) . in addition , 19 ( 6.8% ) patients had not used any treatment modalities , and 56 ( 20.1% ) , 63 ( 22.6% ) , 77 ( 27.6% ) , 36 ( 12.9% ) , and 28 ( 10.0% ) patients had used 1 , 2 , 3 , 4 , and 5 treatment modalities , respectively . regarding the severity of the rhinitis , since only 56 patients ( 20% ) used only a single treatment modality , there are too few individuals to provide statistically meaningful comparisons between the five treatment modalities .
nonetheless , when the total number of modalities ( 0 to 5 ) used by the patients was compared , we found that the crsom-31 scores in patients who had used all five modalities ( 269.4 130.3 ) significantly higher compared to those who had used fewer modalities .
no significant differences in crsom-31 scores were observed among those patients who had used 4 ( 196.6 107.1 ) , 3 ( 173.7 85.8 ) , 2 ( 162.6 93.3 ) , 1 ( 148.3 101.4 ) , or no ( 125.7 88.7 ) treatment modalities .
table 2 also showed the results of univariate logistic regression analyses for each of the six treatment modalities with all the independent variables .
furthermore , six separate multivariate logistic regression analyses were conducted to assess the association between each of the treatment modalities and their independent and significant factors ( table 3 ) .
educational levels of elementary school or below were significantly associated with the use of pharmacology treatment modality and also with the use of subgroup of pharmacology treatment modality ( oral or topical medications ) .
fair or poor general health status was significantly associated with the use of pharmacology treatment modality and especially with the use of topical medications , whereas very good or excellent general health status was inversely associated with the use of surgical intervention .
worse disease - specific quality of life ( crsom-31 symptom - impact score ) was significantly associated with the use of pharmacology treatment modality , oral medications , and traditional chinese medicine . in terms of the etiologies of rhinitis
finally , chronic rhinosinusitis , both with or without nasal polyps , was significantly associated with the use of topical medications , surgical intervention , and the use of nasal irrigation .
rhinitis and rhinosinusitis are common health problems that impact on the quality of life of their sufferers [ 11 , 12 ] .
the world health organization proposed a stepwise treatment for allergic rhinitis in the allergic rhinitis and its impact on asthma ( aria ) guideline .
oral antihistamine and topical corticosteroid are recommended for the first - line treatment for mild and moderate - severe allergic rhinitis by the aria guideline .
our results showed that most rhinitis patients had received pharmacological treatments ( 85.7% ) which included the uses of oral medications ( 77.1% ) and topical medications ( 65.9% ) , indicating that guideline - directed rhinitis treatment is widely adopted by both physicians and patients in taiwan .
in addition , our data showed that approximately a third of the patients ( 34.1% ) had used nasal irrigation to relieve their rhinitis symptoms .
nasal irrigation is used for various sinonasal condition and postoperative care after nasal surgery [ 1416 ] .
the mechanisms of nasal irrigation include physical cleaning , enhancement of mucociliary function , and removal of local inflammatory mediators .
although it is widely recommended and commonly used in taiwanese patients , there was no data reporting the proportion of nasal irrigation use in clinical settings .
about one third of our patients ( 34.4% ) had used tcm for their rhinitis symptoms .
the relatively common use of it could partly be explained by the health care system of taiwan because tcm services are fully reimbursed by the national health insurance program .
based on the results of an analysis of tcm outpatient reimbursement claims from 1996 to 2001 in taiwan , diseases of the respiratory system were found to rank at the top of the major disease categories for tcm visits , which accounted for 27% of all tcm visits .
understanding the factors associated with the use of different treatment modalities for rhinitis can be helpful for clinicians when they are considering the choice of treatment for their patients .
our results demonstrated that sex , educational levels , general health status , smoking habit , alcohol use , and disease - specific quality of life were independent factors associated with different treatment modalities .
these associations had been adjusted for the etiologies of rhinitis and remained statistically significant . in particular , male patients were more likely to receive surgical interventions , while lower educational levels were associated with the use of oral and topical medications .
patients with poor or fair general health status were associated with the use of topical medications .
a possible reason is that the occurrence of drug - to - drug interactions is relatively rare with topical medications and therefore , suitable for patients who were on medications for their other diseases .
it is of interest to note that very good or excellent general health status was inversely associated with surgical intervention . since surgery for rhinitis
is typically performed under local anesthesia , the general health status of a patient should not be a contraindication for surgery .
the reasons for the association between the use of surgical intervention and general health status will require further investigations . nasal irrigation is a method to relieve sinus symptoms by rinsing the nasal cavity with isotonic or hypertonic saline .
a cochrane systematic review on eight randomized controlled trials concluded that the use of topical saline could be included as a treatment adjunct for the symptoms of chronic rhinosinusitis . in our study , smoking was significantly associated with the use of nasal irrigation .
nasal irrigation has been claimed as a method to remove nicotine and tar buildup in the nasal passages for smokers , and this might explain the association between nasal irrigation and smoking observed in this study .
previous large - scale population studies have revealed that cigarette smoking and chronic rhinitis were associated in a dose - dependent manner .
in addition , past and current secondhand tobacco smoke exposure was reported to be a risk factor for allergic rhinitis .
subjects with secondhand tobacco smoke exposure and allergic rhinitis were significantly more likely to use nasal decongestants . however , no studies have specifically investigated whether smoking was associated with increased use of nasal irrigation .
finally , worse disease - specific quality of life , assessed by the use of crsom-31 , was found to be associated with the use of oral medications and tcm .
since it is likely that the chronicity of rhinitis symptoms is associated with a worse quality of life , patients with worse quality of life might seek alternative therapies including tcm as a way to minimize the adverse effects of chronic use of conventional medications .
the association between crsom-31 and the use of oral medications could be explained by the fact that oral medication is often used for moderate or severe cases not responsive to topical medications , which are likely to be cases with worse quality of life .
nevertheless , we have included crsom-31 symptom - impact scores in our multivariate analyses as a proxy to control for the effect of severity of rhinitis .
second , all patients were recruited from one medical center , and most of them had previously been treated for rhinitis by their primary care physicians .
results from the present study indicated that common treatment modalities in taiwanese patients with rhinitis included oral medications , topical medications , surgical intervention , tcm , and nasal irrigation .
the use of different treatment modalities among taiwanese patients with rhinitis was associated with different factors including sex , educational levels , general health status , smoking habit , alcohol use , and disease - specific quality of life , adjusting for etiologies of rhinitis .
Output:
| rhinitis is a common upper airway disease and can have great impact on patients ' quality of life .
factors associated with the use of common treatment modalities among 279 taiwanese rhinitis patients from the outpatient department of otolaryngology in a medical center were investigated using a cross - sectional survey study .
results from multiple logistic regression analysis , adjusted for etiologies of rhinitis , revealed that males were associated with surgical intervention ( or = 2.11 , p = 0.009 ) .
lower educational level was associated with oral ( or = 2.31 , p = 0.024 ) and topical medications ( or = 2.50 , p = 0.005 ) .
poor or fair general health status was associated with topical medications ( or = 4.47 , p = 0.001 ) , whereas very good or excellent general health status was inversely associated with surgical intervention ( or = 0.32 , p = 0.002 ) .
smoking was associated with the use of nasal irrigation ( or = 2.72 , p = 0.003 ) .
worse disease - specific quality of life was associated with oral medications ( or = 2.46 , p = 0.010 ) and traditional chinese medicine ( or = 5.43 , p < 0.001 ) . in conclusion ,
the use of different treatment modalities for rhinitis was associated with different combinations of independent factors . |
PubmedSumm4810 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: some patients show signs of wakefulness as demonstrated by eye opening , but are incapable of a meaningful reaction to stimuli .
this condition is known as the vegetative state ( vs).1 decisions on life - sustaining treatment for patients in the vs have been an issue of intense discussions over the last 40 years .
life - sustaining treatment can be defined as any treatment without which the patient would die from a life - limiting disease within a foreseeable time frame.2 such decisions are extremely challenging for professional care personnel and surrogate decision makers , who are quite frequently the patient 's next of kin .
cases that were legally contested by the patients ' next of kin have led to controversial public debates about the moral justification of the withdrawal of artificial nutrition and hydration ( anh ) for patients in a vs.3 meanwhile england , wales , germany and other countries have laws stipulating that a valid and applicable advance refusal is binding and that surrogates have to acknowledge the patient 's expressed will.4 the legal regulation in germany is such that a dialogue between the doctor and the legal surrogate forms the basis for the legal surrogate 's decision to agree or disagree with the application of treatment .
the doctor has to suggest which treatment goals can be achieved by means of therapeutic measures , which is often referred to as the medical indication of a treatment .
then it has to be investigated with the legal surrogate whether the proposed treatment is in accordance with the patient 's advance directive or presumed will .
treatment omission or withdrawal in accordance with the patient 's will is lawful in germany .
treatment decisions for patients in a vs have to be made despite a high level of uncertainty regarding diagnosis,5 therapeutic success and prognosis.6 even though it used to be a core diagnostic criterion , it has recently been challenged by neuroscientists whether all patients in a vs have actually lost consciousness.7 consequently , diagnostic classification has been questioned and bedside examination alone does not seem sufficient to make a reliable diagnosis .
an accurate diagnosis has implications for the course of a potential recovery8 and for symptom control treatment.9 traditionally , recovery from vs more than a year after a traumatic brain injury and 6 months after a non - traumatic brain injury is regarded as highly improbable10 but not totally impossible , seeing as some cases of late recovery have been published in the literature.6
11 decisions on limiting life - sustaining treatment should be made with reference to the ethical principles of the patient 's autonomy and best interests.12 usually the next of kin are advocated as surrogate decision makers , because they are thought to know the patient 's wishes and values best and are most interested in the well - being of the patient.13 yet , studies using hypothetical case scenarios have shown that surrogate decision makers may inaccurately represent the patient 's treatment wishes.14 it remains unclear whether surrogates in fact decide according to the patient 's will , especially in cases of vs where uncertainty is so prominent .
from 2009 to 2011 a total of 14 next of kin , who were taking care of 12 patients in a vs from throughout germany , were recruited with the help of the following gatekeepers : ( 1 ) the head nurse of a nursing home ward specialising in the long - term rehabilitation of patients in a vs , ( 2 ) a doctor working for a nationwide outpatient care service , ( 3 ) the case manager of a nationwide outpatient care service and ( 4 ) a counsellor for family caregivers for severely disabled patients .
gatekeepers either distributed invitation letters or contacted family caregivers directly to inform their clients of the study .
criteria oriented , purposeful sampling was conducted in order to have the maximum variety of cases according to the following characteristics : patient caregiver relationship ( parents , children and partners ) , duration of being in the vs ( short , medium and long term ) and care institution ( professional care institutions and private homes ) .
interviews were conducted until a satisfactory sample of perspectives on limiting life - sustaining treatment was found ( rejection of treatment limitation , consideration of treatment limitation under circumstances , agreement with limitation of treatment ) .
inclusion criteria , with reference to the patient , was being in a condition where recovery was highly improbable , so at least 6 months after non - traumatic brain injury and 12 months after traumatic brain injury.10 participants were required to be able to speak german fluently .
the interviews were carried out by two interviewers : the first author , a psychologist , and the second author , a doctor , both skilled in qualitative interview methods .
the interviews were conducted with three mothers , eight spouses ( one fiance , one ex - wife ) and three sons of mothers in a vs. except for one relative , all were the legal surrogates of the patient .
demographic data of the sample the patients lived in the following settings : ( 1 ) a nursing home ward specialising in the long - term rehabilitation of patients in a vs , ( 2 ) community homes for patients requiring 24-h respiratory or intensive care service and ( 3 ) private homes . at the time of the interview ,
the patients had been in a vs for 9 months ( in a case of hypoxic brain injury ) to 15 years .
we conducted semistructured interviews on the participants ' decision making about life - sustaining treatment .
we also investigated the caregivers ' understanding of the illness and their burden , which will not be reported in this article .
the caregivers were asked , among other questions , the following : have you ever asked yourself , if it would be better not to administer life - sustaining treatment in his / her [ ie , the patient 's ] case ? please narrate. the interviews took place at the institutions where the patients were in care or at a neutral place in the university hospital where the authors worked .
they were audio recorded , transcribed following adapted transcription rules and verified by one of the interviewers .
the transcripts were analysed by means of the maxqda software ( verbi gmbh , berlin , germany ) using the qualitative content analysis method according to mayring.15 meaningful parts of the material were selected inductively to answer the research question : how do family surrogates of chronic vs patients deal with previously expressed wishes and the presumed will of the patient regarding life - sustaining treatment? the participants ' key statements in answer to the research question were selected .
the entire material was analysed and sorted according to the abstract categories by using a coding guide . for the purpose of this publication ,
the interview guide , transcription rules and coding guide can be obtained from the authors upon request .
the results of the content analysis of the patients ' wishes and their representations are illustrated in table 2 . in half of the studied cases , family caregivers reported statements made prior to vs by the patient that could be applied to the current situation .
categorical analysis of the representation of the patient 's wishes in interviews with family caregivers the type of representation of the patient 's wish , the content of the wish and the tendency for or against life sustaining treatment are shown .
those family caregivers that did not report knowledge of prior wishes interpreted a will to live in the patient 's survival or non - verbal behaviour .
the following comment was made with reference to a moment in which a doctor , while standing at the patient 's bedside , made the suggestion to discontinue life - sustaining treatment , and at that moment , the patient opened her eyes .
the decision was actually there from the beginning , because i know my daughter and at the moment when he [ ie , the doctor ] said , she ca n't do that [ ie , opening the eyes ] , and she did it , as though she had heard it , i knew : no. in two interviews conducted with the sons of a patient , one reported knowing of an advance directive and orally expressed wishes by his mother , in which artificial nutrition had been refused without explicit reference to a vs condition . at the time of the interview both of her sons shared the view that artificial nutrition should be maintained , yet resuscitation may be withheld . ( ) with regard to her advance directive , yes it exists .
it actually prohibits artificial nutrition , so yes , she crossed that off ( ) .
but this situation we have through this acute , through this unforeseen , through this brain haemorrhage as well as ( ) through the uncertainty of how the condition is progressing , like how can it be .
( ) we have never seen the situation that way , as an actual artificial way of maintaining life , but rather as as a recovery process or a a kind of process where i think to myself : that makes sense .
and that is still not neglecting her wishes. this particular son had difficulties explaining his thoughts , which became evident by the interrupted grammatical structure and his repetition of words .
he weighed his mother 's wishes against his own impression of the illness and his own assessment of her recovery potential .
he reached the decision that he would not accept intensive care measures or surgery for his mother in case of complications or comorbidity . yet
, if there was a treatment option that would improve her condition , for example neurosurgery , he would agree to it .
a family caregiver had previously spoken with his wife about life - sustaining treatment measures while the patient 's father had been care dependent .
the patient 's wish was clear to the spouse , even though the topic of their discussion was not the vs. he was determined to comply with her wishes .
he was convinced that if she had a chance to end her life , to jump from a bridge , she would do it .
well she did n't want life - prolonging treatment under any circumstances. this patient was continuously artificially nourished and hydrated , but the relative did not perceive the anh as being a form of life - sustaining treatment .
he was of the opinion that because healthy people would also be nourished , anh was neither artificial nor invasive . to him
he said , he would consent to antibiotics that could cure pneumonia , but not if there was a more serious and complicated infection .
thus , the effectiveness of the treatment also influenced his decision on where to draw the line .
now we have to differentiate between life sustaining and life prolonging , am i right ? ( ) it depends on what her chances are in each concrete situation . in case of a lung infection one
agrees [ ie , with the administration of antibiotics ] , but if the condition deteriorates severely i would decide according to her wish. instead of considering having the anh withdrawn , he thinks back counterfactually to his standpoint ; if he could have foreseen the outcome of the surgery , he would not have agreed to it .
in contrast to anh , surgery was a treatment measure that he could have rejected .
) known what the the the consequences would be ( ) how the condition would be , i would not have agreed to it . because i 'm quite sure that she would n't want what she has now under any circumstances. in a similar case , the husband of a patient rejected artificial respiration after his wife had a sepsis .
a family caregiver used a double standard in making surrogate decisions for the patient and making decisions for herself .
she reported that the hospital referred her to a lawyer who could have advised her on the possibility of discontinuing nutrition .
many family members do that now , they stop the nutrition , and only provide fluids .
that takes about 23 months , but i mean no ! i could n't do something like that .
and he already had problems with his stomach and still for me it is starvation .
so i would n't do it . if his heart were to fail now and he would n't be brought back , that 's something different .
i could n't do that. it is most important for her that the patient is not harmed and does not have to suffer from either treatment or treatment withdrawal .
later , she was asked by the interviewer ( i ) what she would want if she had the same condition .
what the respondent ( r ) had termed inhumane for her husband is exactly what she wished for herself : r : unplug everything.i : everything?r : everything.i : including the artificial nutrition?r : yeah , everything .
but if you experience something like that for yourself , then no.i : but you 've just said that starvation is inhumane.r :
yes , for others . for myself , phh [ non - verbal expression , to say i do n't mind].(wife , p. 10
but if you experience something like that for yourself , then no. i : but you 've just said that starvation is inhumane. r : yes , for others . for myself , phh [ non - verbal expression , to say i do n't mind]. the patient 's will was not precisely against living in a vs. according to his wife he never wanted to live in a wheelchair .
the wife justifies this wish by deciding to withhold resuscitation treatment , if the patient were to experience cardiac arrest again .
she would not like to inflict pain upon the patient and sees resuscitation as a measure that would not cause him pain if omitted .
she is a relative who no longer has any great hope of the patient recovering .
the results of the content analysis of the patients ' wishes and their representations are illustrated in table 2 . in half of the studied cases , family caregivers reported statements made prior to vs by the patient that could be applied to the current situation .
categorical analysis of the representation of the patient 's wishes in interviews with family caregivers the type of representation of the patient 's wish , the content of the wish and the tendency for or against life sustaining treatment are shown .
those family caregivers that did not report knowledge of prior wishes interpreted a will to live in the patient 's survival or non - verbal behaviour .
the following comment was made with reference to a moment in which a doctor , while standing at the patient 's bedside , made the suggestion to discontinue life - sustaining treatment , and at that moment , the patient opened her eyes .
the decision was actually there from the beginning , because i know my daughter and at the moment when he [ ie , the doctor ] said , she ca n't do that [ ie , opening the eyes ] , and she did it , as though she had heard it , i knew : no.
in two interviews conducted with the sons of a patient , one reported knowing of an advance directive and orally expressed wishes by his mother , in which artificial nutrition had been refused without explicit reference to a vs condition . at the time of the interview both of her sons shared the view that artificial nutrition should be maintained , yet resuscitation may be withheld . ( ) with regard to her advance directive , yes it exists .
it actually prohibits artificial nutrition , so yes , she crossed that off ( ) .
but this situation we have through this acute , through this unforeseen , through this brain haemorrhage as well as ( ) through the uncertainty of how the condition is progressing , like how can it be .
( ) we have never seen the situation that way , as an actual artificial way of maintaining life , but rather as as a recovery process or a a kind of process where i think to myself : that makes sense . and that is still not neglecting her wishes. this particular son had difficulties explaining his thoughts , which became evident by the interrupted grammatical structure and his repetition of words .
he weighed his mother 's wishes against his own impression of the illness and his own assessment of her recovery potential .
he reached the decision that he would not accept intensive care measures or surgery for his mother in case of complications or comorbidity . yet ,
if there was a treatment option that would improve her condition , for example neurosurgery , he would agree to it .
a family caregiver had previously spoken with his wife about life - sustaining treatment measures while the patient 's father had been care dependent .
the patient 's wish was clear to the spouse , even though the topic of their discussion was not the vs. he was determined to comply with her wishes .
he was convinced that if she had a chance to end her life , to jump from a bridge , she would do it .
well she did n't want life - prolonging treatment under any circumstances. this patient was continuously artificially nourished and hydrated , but the relative did not perceive the anh as being a form of life - sustaining treatment .
he was of the opinion that because healthy people would also be nourished , anh was neither artificial nor invasive . to him
he said , he would consent to antibiotics that could cure pneumonia , but not if there was a more serious and complicated infection .
thus , the effectiveness of the treatment also influenced his decision on where to draw the line .
now we have to differentiate between life sustaining and life prolonging , am i right ? ( ) it depends on what her chances are in each concrete situation . in case of a lung infection one
agrees [ ie , with the administration of antibiotics ] , but if the condition deteriorates severely i would decide according to her wish. instead of considering having the anh withdrawn , he thinks back counterfactually to his standpoint ; if he could have foreseen the outcome of the surgery , he would not have agreed to it .
in contrast to anh , surgery was a treatment measure that he could have rejected . if i had known back then when they operated ( . )
known what the the the consequences would be ( ) how the condition would be , i would not have agreed to it . because i 'm quite sure that she would n't want what she has now under any circumstances. in a similar case , the husband of a patient rejected artificial respiration after his wife had a sepsis .
a family caregiver used a double standard in making surrogate decisions for the patient and making decisions for herself .
she reported that the hospital referred her to a lawyer who could have advised her on the possibility of discontinuing nutrition .
many family members do that now , they stop the nutrition , and only provide fluids .
that takes about 23 months , but i mean no ! i could n't do something like that . (
, i still do n't know if he is able to perceive things . and he already had problems with his stomach and still for me it is starvation .
so i would n't do it . if his heart were to fail now and he would n't be brought back , that 's something different . but apart from that everything will proceed as it was .
i could n't do that. it is most important for her that the patient is not harmed and does not have to suffer from either treatment or treatment withdrawal .
later , she was asked by the interviewer ( i ) what she would want if she had the same condition .
what the respondent ( r ) had termed inhumane for her husband is exactly what she wished for herself : r : unplug everything.i : everything?r : everything.i : including the artificial nutrition?r : yeah , everything .
but if you experience something like that for yourself , then no.i : but you 've just said that starvation is inhumane.r :
phh [ non - verbal expression , to say i do n't mind].(wife , p. 10
) r : unplug everything. i : including the artificial nutrition? r : yeah , everything .
but if you experience something like that for yourself , then no. i : but you 've just said that starvation is inhumane. r : yes , for others . for myself , phh [ non - verbal expression , to say i do n't mind]. the patient 's will was not precisely against living in a vs. according to his wife he never wanted to live in a wheelchair .
the wife justifies this wish by deciding to withhold resuscitation treatment , if the patient were to experience cardiac arrest again .
she would not like to inflict pain upon the patient and sees resuscitation as a measure that would not cause him pain if omitted .
she is a relative who no longer has any great hope of the patient recovering .
for the family caregivers we interviewed , patient autonomy had only a minor impact on them and did not guide treatment decisions .
we found a discrepancy between patients ' wishes against prolongation of treatment in severe conditions such as the vs and the surrogates ' decisions to continue anh and other forms of life - sustaining treatment .
the caregivers in our study considered anh as a form of basic care that could not be rejected .
the patients ' wishes were overruled by three types of reason : ( a ) the expected recovery of the patient , ( b ) the family caregiver 's definition of life - sustaining treatment and ( c ) the moral obligation to not cause the patient harm or pain .
we found a type of family caregivers who was ambivalent towards decisions about life - sustaining treatment .
they try to balance their own moral and medical assumptions and the patients will and come to inconsistent decisions for and against treatment measures .
a lack of representation of patient autonomy in decisions about life - sustaining treatment was also described in an interview study with older patients in nursing homes in norway.16 the authors argued that relatives wanted to continue life - sustaining treatment to avoid the loss or to avoid a bad conscience not having done enough for the patient . in an early study with family caregivers of patients in the vs it was reported that even when family caregivers did not expect the patient to improve , the majority wanted the patient to undergo almost all therapeutic interventions including surgery.17 another qualitative study identified how surrogates come to their decisions on life - sustaining treatment .
the majority of the surrogates based their decisions on knowledge of the patients ' wishes or advance directives .
a minority planned to make decisions based on a sense of shared values or on their own personal beliefs about acceptable quality of life of the patient , which in some cases did not match what they knew about their loved one 's beliefs.18 it is remarkable that half of the family caregivers reported knowing the treatment wishes of their patients , mostly referring to advance directives or previous oral statements .
however , not all wishes were exactly related to the vs and needed interpretation and application by the caregivers , who were the legal surrogates in all cases but one .
especially when there was a lack of knowledge about the patient 's expressed wishes , the family caregivers interpreted the patient 's non - verbal behaviour as purposeful expressions of a will to live .
the problem of interpreting aversive or cheerful behaviour with regard to end - of - life decisions is well known from dementia patients.19 loved ones of patients in a vs may be especially tempted to read meaning into the patient 's involuntary behaviour to recognise the patient 's identity and in order to share or even delegate the responsibility to the patient .
however , it could be possible that some of the patients are misdiagnosed as being in a minimally conscious state ( mcs ) or incomplete locked - in syndrome and thus being able to show purposeful behaviour or even to communicate rudimentarily .
misdiagnosis rates of 40% have been reported before.5 yet being in a mcs does not necessarily mean the patient has a higher quality of life,12 but has a better prognosis.8 the differential diagnosis is also relevant for attitudes towards end - of - life issues .
it was shown in a recent european survey that doctors and nurses have different believes about patients ' pain perception20 and different attitudes towards end - of - life decisions for patients in the vs compared to patients in the mcs , considering it more acceptable to stop treatment in a chronic vs.21 the hope for a remarkable recovery of the patient has been described in the literature and is considered crucial for the caregivers ' successful coping with the situation.22 it can partly be explained by the uncertainty of prognosis . although the current guidelines see only a small probability for the recovery of patients in a vs in the chronic state , like the ones we referred to in this study,10
11 there are scientific reports of late recovery , as well.6 wijdicks and rabinstein described three types of families dealing with decisions about life - sustaining treatment : ( 1 ) realists that understand the gravity of the situation and know that prolonged care for a patient in a vs would be futile , ( 2 ) procrastinators who were unsure or have heard of unexpected recoveries and ( 3 ) fighters who were willing to sacrifice themselves for the patient and put trust in a miraculous recovery.23 some of the interviewed family caregivers in our study hoped that the patient might eventually be able to communicate verbally again , others were in acceptance of the current condition as the final stage of recovery and a third type was preparing themselves for the patient 's death .
it has been investigated in prior studies that family caregivers of patients in the vs go through phases of shock , bereavement and finally adaption in which the family caregivers develop an increased ability to let go of the patient.24 we found a fourth type of family caregivers being ambivalent between hope , anticipatory grief and acceptance of the condition . the term life - sustaining treatment measures was often interpreted differently than how it would be defined medically .
conversely , respiration , surgery and resuscitation were seen as technical or invasive medical procedures that may be omitted . a moral distinction between various forms of treatment
is well known from studies of clinical practice.25 one of the reasons underpinning the reluctance to forego anh is the fear of letting the patient starve to death. another fear of withdrawing anh or artificial respiration is the fear of legal consequences , which reveals a lack of knowledge of the legal framework in germany that actually allows omission and withdrawal of treatment . suffering from starvation could only be the case if the patient was indeed aware .
but even then , the evidence from studies about the withdrawal of food and fluids in older people or dementia patients argue against suffering and show that dehydration can even be a palliative means leading to a peaceful death.26 removing foods but not fluids leads to a prolonged dying phase with cachexia that may indeed cause severe suffering in those patients able to perceive it . interventions fostering advance care planning have been recommended for dementia patients.27 advance care planning is usually understood as an alliance with the patient ( or future patient ) .
it may also be applicable to the situation of incompetent patients , like patients in a vs , where the family surrogates could be the main target of this process and the result is an advance directive by proxy or a prospective care plan.28 we identified a high uncertainty regarding the legal framework of limitation of treatment measures . to inform family caregivers on legal matters and the ethical weight of patient autonomy
in addition , counselling and access to psychological support for surrogates could be an important factor in improving their decision - making process for the sake of the patients and for their own sake .
it should be investigated more closely whether decisions on life - sustaining treatment are made intuitively or rationally , and whether the arguments we found are reasons or justifications for the surrogate 's intuitive decisions .
a prospective study should look at how caregivers ' perspectives change during the course of the illness .
gatekeepers might have selected role model caregivers that were engaged in the care of the patient . there was a cultural bias in excluding participants that did not speak german fluently . in
that we encouraged the participation without further incentives other than helping to improve knowledge on the issue , we were unable to reach disengaged caregivers .
legal guardians of other patients in a vs might have decided during the early stages to discontinue life support .
furthermore , we do not know if the participants were always willing to reveal their knowledge of the patients ' wishes in the interviews .
even advance directives are not always easy to interpret and we did not investigate the patients advance directives , but depended solely on the participant 's narration .
prospective study designs would be necessary in order to provide a representative picture of caregivers of patients in a vs. our sample was too small to investigate whether the social roles in the relationships between caregivers and patients had an impact on decision making .
it can be hypothesised that mothers of patients are more reluctant to forgo treatment than husbands of patients , but this has to be confirmed in quantitative studies with larger samples .
the vs diagnoses of the patients in this study were not examined by the researchers . in germany , vs and mcs29 are not yet consistently discerned , so it is possible that the patients in our study may in fact be in a mcs , but are labelled as being in a vs.5
practically , the family caregivers of several patients in a vs in the long - term care made their own decisions and did not necessarily base them on the patients ' will .
there was a discrepancy between the patients ' wishes against prolongation of treatment and the surrogates ' decisions to continue anh and other forms of life - sustaining treatment .
the caregivers considered anh as a form of basic care that could not be rejected .
we also identified a group of ambivalent caregivers who are hesitant to make irreversible decisions .
Output:
| backgrounddecisions on limiting life - sustaining treatment for patients in the vegetative state ( vs ) are emotionally and morally challenging .
in germany , doctors have to discuss , together with the legal surrogate ( often a family member ) , whether the proposed treatment is in accordance with the patient 's will .
however , it is unknown whether family members of the patient in the vs actually base their decisions on the patient 's wishes.objectiveto examine the role of advance directives , orally expressed wishes , or the presumed will of patients in a vs for family caregivers ' decisions on life - sustaining treatment.methods and samplea qualitative interview study with 14 next of kin of patients in a vs in a long - term care setting was conducted ; 13 participants were the patient 's legal surrogates .
interviews were analysed according to qualitative content analysis.resultsthe majority of family caregivers said that they were aware of aforementioned wishes of the patient that could be applied to the vs condition , but did not base their decisions primarily on these wishes .
they gave three reasons for this : ( a ) the expectation of clinical improvement , ( b ) the caregivers ' definition of life - sustaining treatments and ( c ) the moral obligation not to harm the patient .
if the patient 's wishes were not known or not revealed , the caregivers interpreted a will to live into the patient 's survival and non - verbal behaviour.conclusionswhether or not prior treatment wishes of patients in a vs are respected depends on their applicability , and also on the medical assumptions and moral attitudes of the surrogates .
we recommend repeated communication , support for the caregivers and advance care planning . |
PubmedSumm4811 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: proteomic profiling based on enzyme activity is assuming significance in drug discovery as it becomes possible to profile selectivity of drugs and their mechanism of action .
such an approach focuses on protein function , an aspect which has been missing from expression proteomics . a functional proteomic profiling approach has the potential not only to help identify targets for diagnosis and therapy , specifically in personal medicine [ 3 , 4 ] , but also to reveal the underlying mechanisms of action of disease - sustaining proteins .
methods for global analysis of protein expression and function , including liquid chromatography with mass spectrometry ( ms ) for shotgun analysis [ 6 , 7 ] , yeast two - hybrid methods , and protein microarrays , have been crucial in developing the field of proteomics , but they do not provide an accurate assessment of functional states of proteins in cells and tissues .
activity - based protein profiling ( abpp ) was first demonstrated for serine hydrolyses and has now been applied to other enzyme classes such as kinases , phosphatases , and histone deacetylates [ 10 , 12 ] .
abpp typically uses active site - directed covalent probes to interrogate specific subsets ( families ) of enzymes in complex proteomes to provide a quantitative assessment of the functional state of individual enzymes in the family .
the probe - bound enzymes can be visualized with sds - page or purified using affinity tools for peptide or labeling site identification with ms .
although this approach is promising , it is limited by the availability of suitable synthetic probes . also , while abpp categorizes the active site in enzymes , it does not measure the functional kinetics of enzymes and therefore can be considered only as an indirect measure of protein function .
it forms the central component of the workflow strategy , which has the potential to identify functional biomarkers from natural cellular sources .
the proposed method would fill an unmet need for research in drug response and biomarker discovery for investigations in natural cellular source environments .
the physiological relevance of working with natural cellular sources is especially significant for discovery , which targets proteins whose function may be altered by post - translational modification , noncovalent regulatory factors or splice variants . such an approach may help to reconcile data from high - throughput screening of recombinant proteins to natural cellular sources .
it is anticipated that select subproteomes will be subjected to downstream characterization by liquid chromatography mass spectrometry ( lc - ms ) , and other suitable identification methods in common use , so as to annotate sequence and structure to function . while the term functional proteomicsencompasses a variety of phenotypic descriptions of known or measurablefunctional consequencesincluding cellular response to stimuli and binding interactions [ 14 , 15 ] , etc . , the model approach reported herein is limited to characterizing enzyme kinetic properties .
the proposed profiling strategy starts with subfractionation of complex proteomes using serafile ( uspto 20040106131 , profact proteomics , monmouth junctions , nj , usa ) .
this proprietary protein separations platform is configured as a surface library with associated interrogation methods designed to retain bioactivity of the samples . as a result
, subproteome pools obtained after serafile separations can be characterized for their enzyme activity properties ( e.g. , enzyme activity with and without inhibitors , activators , or cosubstrates ) .
then , a collective functional profile of the original proteome is generated as an integrated profile of the functional properties of the characterized subproteomes .
this approach provides multiple data points to characterize and compare samples , thereby increasing the robustness and reliability of analysis .
this profiling method can compare one proteome sample to another ( intersample analysis , e , g . , tissue type versus tissue type , or normal versus diseased tissue ) and can compare different subproteomes of the same complex proteome ( intrasample analysis ) .
the cyclic nucleotide phosphodiesterases ( pdes ) enzyme family has been used in this study as a model class of proteins to demonstrate the proposed strategy .
pdes are enzymes that hydrolyze the second messenger adenosine 3 , 5-cyclic monophosphate ( camp ) or guanosine 3 , 5-cyclic monophosphate ( cgmp ) , or both .
these small molecules along with other nucleotides , lipids , and ions function as secondary messengers .
the second messenger camp mediates a wide variety of actions of hormones and neurotransmitters and influences cell growth , differentiation , survival , and inflammatory processes .
class i pdes ( found in protozoa and metazoa ) are camp specific ( pde4 , 7 and 8) or cgmp specific ( pde5 , 6 and 9 ) or can hydrolyze both camp and cgmp ( pde1 , 2 , 3 , 10 , and 11 ) [ 17 , 19 , 20 ] . a comprehensive review of pdes can be found in [ 17 , 19 , 21 ] .
pdes are widely acknowledged and explored as drug targets in pulmonary , neurodegenerative , and vascular diseases , and in diabetes , osteoporosis , cancer , rheumatoid arthritis , and depression .
inhibitors of pde5 and pde3 are already in clinical use , but numerous other pde inhibitors have not been used for therapeutic purposes due to side effects such as nausea and emesis . the proposed approach to proteomic profiling
is guided by the principle that , by discriminating and characterizing pde variants in natural sources , greater disease - specific therapeutic inhibition / activation can be achieved along with a better understanding of disease pathway dynamics .
this research article demonstrates functional proteomic profiling of camp - hydrolyzing phosphodiesterases from bovine and rat brains .
although earlier studies have documented the presence of different types of pdes in rat and bovine brains , a comprehensive comparative profile of pde proteomes based on function and content / identity has not been established .
it is known that bovine brain exhibits calmodulin - activated pde activity ( pde1 ) , as well as pde2 , and pde4 activity [ 25 , 26 ] .
the camp hydrolysis activity of pdes in bovine brain can be stimulated or inhibited by cgmp .
studies on rat brain have identified calmodulin - stimulated pdes [ 2931 ] ( pde1 ) , as well as pde4 isoforms [ 3234 ] .
serafile was first applied for fractionation of each brain homogenate ( sample proteome ) into subproteomes , in order to reduce the complexity of pdes in the sample proteome .
then , these subproteomes were interrogated for camp hydrolysis activity in the presence and absence of cgmp .
cgmp is another substrate of pdes and is used as a challenge condition in these experiments .
the results were compiled into a signature profile of camp hydrolysis characteristics of each sample proteome , defined as an integrated profile of characteristics of serafile - generated subproteomes .
the hypothesis was that serafile and associated interrogation methods would generate distinct profiles of enzyme catalyzed camp hydrolysis - activities from bovine brain and rat brain homogenates because these are different mammalian species .
the serafile inventions encompass the surface characteristics and protocols suitable for differential proteomic fractionation .
each surface architecture was designed to have moderate binding capacity and was prepared with nugel epoxy ( biotech support group inc . , monmouth junction , nj , usa ) .
the epoxy - coated silica was modified by reacting it with different ligands to generate unique surfaces selectivities and was based on the premise that important ligand protein interactions include hydrogen bonds , ionic interactions ( salt bridges ) , hydrophobic interactions and ring structures .
table 1 illustrates the differences in the properties of the surfaces in the library ; however for proprietary protection , details of the surface chemistries remain undisclosed .
an initial screen of 13 surfaces from the library ( table 1 ) and one underivatized control was performed .
further study was limited to a set of five surfaces ( a , b , d , m , and n ) from the surface library because the subproteomes obtained from these surfaces had the most distinguishing characteristics ( enzyme activity and its response to rolipram / vinpocetine / calmodulin , protein concentrations , and sds profile , data not shown ) .
rat brain homogenate ( rbh ) and bovine brain homogenate ( bbh ) were supplied by lampire biologicals ( pipersville , pa , usa ) .
whole bovine or rat brain was homogenized in a prechilled blender using 100 ml of extraction buffer for every 50 g of brain tissue .
extraction buffer for bbh was 0.1 m tris , 2 mm edta , and ph 7.5 , and for rbh it was 1 mm edta , 10 mm hepes , and ph 7.4 .
each extraction buffer was made with protease inhibitor cocktail ( roche , indianapolis , in , u.s.a . ) .
homogenized brain - buffer mixtures were centrifuged at 4c , and the supernatant was used for the experiments .
rbh and bbh samples were mixed with cleanascite ( biotech support group , monmouth junction , nj , u.s.a . ) in a 1 : 16 ratio of cleanascite - to - homogenate , to remove lipids and particulates .
clarified homogenates were obtained by following mixing and centrifugation steps as given in the manufacturer 's protocol .
the pretreated homogenates were each subjected to separation by five serafile surfaces ( a , b , d , m , and n ) [ 3538 ] . for separation of each homogenate ,
50 mg of each surface contained in a spin - x tube ( corning inc .
, corning , ny , u.s.a . ) was equilibrated with binding buffer ( 0.05 m hepes , 1 mm mgcl2 , and ph 6.5 ) .
clarified bbh and rbh were diluted in the binding buffer , to ph 6.5 - 6.6 , and 200 l of each diluted homogenate ( load , 1.16 mg of total protein ) was added separately to each of the five surfaces , mixed for 10 mins , and then centrifuged .
( note that the total protein amounts used for serafile separations were based on the sensitivity of the camp hydrolysis assay used in our experiments for downstream analysis .
the serafile methodology is nevertheless amenable to protocols that can use g amounts of protein loads ) .
the flowthrough was collected as the 1st serafile fraction , represented as subproteomes a1 , b1 , d1 , m1 , and n1 , from surfaces a , b , d , m , and n , respectively .
the proteins bound on the surfaces were eluted with 200 l of elution buffer ( 0.05 m hepes , 1 mm mgcl2 , 0.5 m nacl , and ph 8.0 ) using mixing and centrifugation steps as above .
the flow - through collected in this process was the 2nd serafile fraction , represented as subproteomes a2 , b2 , d2 , m2 , and n2 , from surfaces a , b , d , m , and n , respectively .
mixing steps were performed using a mixmate ( eppendorf , hauppauge , ny , u.s.a . ) at 1150 rpm following an initial pulse of mixing on a vortex mixer .
centrifugation steps were performed using a tabletop centrifuge at 16873 rcf for 3 mins .
each brain homogenate , bovine and rat , was used for separations in triplicates .
activity of camp hydrolysis in each subproteome was measured using a real - time kinetic assay [ 39 , 40 ]
. this assay links camp hydrolysis to nadh oxidation using coupling enzymes ( adenylate kinase , pyruvate kinase , and lactate dehydrogenase ) , and nadh loss can be measured at 340 nm . for each assay ,
a mixture of reaction buffer and coupling enzymes was equilibrated at room temperature for 16 mins ( stage i ) .
then , subproteomes were each individually added to the reaction mix , and loss in absorbance was measured for 16 mins ( stage ii ) . finally , substrate camp or a mix of camp and cgmp
was added to the assay , and the loss in absorbance was measured as above ( stage iii ) .
final concentrations of assay components were as follows : 9 mm mgcl2 , 0.46 mm cacl2 , 46 mm kcl , 46 mm hepes , 1 mm phosphoenolpyruvate , 46 m atp , 0.4 m nadh , 50 m camp , 0.8 units pyruvate kinase , 4 units lactate dehydrogenase , and 0.06 units adenylate kinase ( sigma , st .
louis , mo , u.s.a . ) with 6.25 l of each enzyme sample .
the camp hydrolysis activity of each sample was measured as the basal activity ( in the absence of cgmp ) and as challenged activity ( in presence of 25 m cgmp or 50 m cgmp ) .
volume - normalized enzyme assays were performed on each replicate subproteomes in a 96-well format using a multiskan mmc346 plate reader ( thermo scientific , hudson , nh , u.s.a . ) . to measure camp hydrolysis activity in the unfractionated brain homogenates ,
the clarified homogenates were diluted with binding buffer to obtain 5 - 6 dilutions of each homogenate , which were then used for the assays as described above .
protein content of all rbh and bbh proteomes and subproteomes was measured using a bca assay kit ( pierce , rockford , il , u.s.a . ) .
( a ) the camp hydrolysis activity of each sample was calculated as follows :
( 1)enzyme activity ( nmoles ml1
min1 ) = path length correction factorcorrected pde rate ( min1)reaction volume ( ml)dilution factormolar absorption coeffcient ( m1 cm1)sample volume ( ml ) ,
where corrected pde rate is a340
nm(min ) stage ii , molar absorption coefficient is 1.25 10 m cm , dilution factor is 1 , and path length correction ( to 10 mm ) is 3.16 .
( b ) the % change in camp hydrolysis activity of each sample was calculated as follows :
( 2)% change in camp hydrolysis activity=(challenged enzyme activitybasal enzyme activity)100basal enzyme activity ,
where challenged enzyme activity is camp hydrolysis activity in presence of cgmp , and basal enzyme activity is camp hydrolysis activity in absence of cgmp .
cleanascite [ 4144 ] , a solid - phase , nonionic adsorbent for lipid removal , significantly improved the clarity of brain homogenates and eliminated clogging of the surfaces during the serafile process . a 1 : 16 ratio of cleanascite to untreated bbh gave optimal results , with minimum loss of camp hydrolysis activity .
consequently , the same ratio of cleanascite to brain homogenate was used for rbh clarification .
enzyme activity and protein analysis of the unfractionated brain homogenates showed that the mean specific activity of clarified rbh and bbh was comparable , between 8 and 8.8 units / mg , measured at 50 m camp concentration .
a comparison of the basal and challenged camp hydrolysis activities in the dilutions of each homogenate is shown in figure 1 .
as expected , increase in activity ( basal and cgmp challenged ) was observed with increasing concentration of clarified homogenates .
the comparison also shows that at relatively lower concentrations of the homogenates , cgmp inhibited camp hydrolysis , while , at higher concentrations , camp hydrolysis activity increased .
in addition , the change in camp hydrolysis activity was more pronounced in the presence of 50 m cgmp than 25 m cgmp .
specifically , at 50 m cgmp ( figures 2(a ) and 2(b ) ) , the change from inhibition to activation of camp hydrolysis activity occurred above ~1.5 mg / ml protein in rbh and above 4 mg / ml protein in bbh proteomes .
thus , it is a characteristic in the pdes of rbh and bbh , that the effect of cgmp on camp hydrolysis is a function both of the concentration of the homogenate and of the concentration of cgmp .
buffer - diluted , protein - normalized , and clarified rbh and bbh samples were used for separations .
each subproteome obtained was analyzed for protein content and camp hydrolysis activity under basal and cgmp - challenged conditions , and then the change in camp hydrolysis activity was calculated . to ensure that the observed properties of the subproteomes were not an effect of the dilution of the sample proteome ,
the properties of rbh and bbh proteomes and their respective serafile subproteomes were compared ( figures 2(a ) and 2(b ) ) .
the data in figure 2(a ) show that not all rbh subproteomes follow the activity versus protein content relationship of the rbh proteome .
data show that some subproteomes do share the activity versus protein content relationship of the sample proteome , likely indicating a comparable distribution of camp hydrolyzing pdes to total proteins . to generate an intersample functional proteomic profile of rbh and bbh proteomes , the change in camp hydrolysis activity of each subproteome due to cgmp challenge was calculated and plotted as shown in figure 3 .
a functional proteomic profile of the brain homogenates in these experiments is defined by the collective response of individual serafile subproteomes to cgmp challenge .
a comparison between the functional profiles of the two homogenates ( figure 3 ) shows that , overall , these two profiles have a similar pattern ( i.e. , % change in camp hydrolysis is similar , positive or negative , in comparable fractions of the two homogenates ) .
however , a major difference is found in subproteome m2 of rbh and bbh ( refer to figure 3(a ) versus figure 3(e ) , and figure 3(c ) versus figure 3(g ) . subproteome m2 of rbh shows over 190% increase in camp hydrolysis in the presence of cgmp ( both 25 m and 50 m ) , while subproteome m2 of bbh shows over 90% decrease in camp hydrolysis in the presence of cgmp ( both 25 m and 50 m ) .
thus , subproteome m2 is a differentiating feature of this inter - sample analysis and therefore can be used for further sample characterization .
these model data demonstrate that our proposed methods of protein separation generate subproteomes that are sufficiently differentiated for intersample functional analysis . as a result
, these methods can be potentially applied to effectively differentiate functional properties of complex proteomes and can be used to localize subset of proteins attributable to sample - specific responses .
the localized proteins can then be used for further analysis , characterization , and subsequent ms identification ( gene sequence annotation / reconciliation ) .
serafile separations use mild - to - moderate elution conditions with buffers like phosphate or hepes that are commonly used in the laboratory .
in addition , the solid - phase surface ( 50 derivatized silica ) can be easily removed by filtration .
thus serafile separations methods do not introduce substances like urea or sds that may restrict downstream compatibility with existing reporting assay and lc - ms detection methodologies .
therefore , the proposed methodology is considered to have a broad scope of applicability within the pathway to identification and can be potentially applied to profile narrowly defined therapeutically important classes of enzymes such as kinases or cyclic nucleotide phosphodiesterases .
another important characteristic of serafile separations methodology is its reproducibility at different protein loads . in separate experiments , surface separation of 0.25 mg to 1 mg protein per 50 mg of surface
the reproducibility in sample separation can be significant for heterogeneous samples of clinical origin .
incremental increase in ph was applied for enrichment of alkaline phosphatase ( data not shown , ) with an enrichment factor up to 20x .
the applications of serafile separations can be based on two basic types of sample and data analysis of ( i ) intersample analysis whereby samples such as tissues , cellular models , or biofluids are compared and contrasted and ( ii ) intrasample analyses , or differential analysis within a sample whereby the subproteomes are monitored with respect to a challenging modulation condition such as in drug response profiling .
inter - sample analysis of complex proteomes , as demonstrated , potentially applies to disease and nondisease comparisons , to identify differences in samples by compartmentalizing the most distinctive subproteomes associated with disease .
deeper characterization of these fractions with enrichment ( e.g. , with ph optimization of serafile separations , or with conventional separations 2de or hplc ) , followed by lc - ms analyses , can help identify prospective biomarkers .
it is important to recognize that any biomarker panel selected in this context would require more characterization , with larger sample sets and statistical validation .
intra - sample analysis , on the other hand , can be used to catalogue or index the effects of functional modulation of the daughter subproteomes .
this will be especially valuable for establishing localized panels of proteins that are responsive to modulation with drug compounds , with the same caveats as the aforementioned inter - sample analyses .
the two data analysis strategies , profiling between samples , and cataloging within samples , are complementary insofar as molecular profiles that characterize and compartmentalize drug - responsive proteins from complex mixtures , can potentially , through coincident iterations with disease profiling , create a bulls - eye effect for drug repurposing .
we envision that , for the drug development industry , the proposed methods for localizing proteins with known functional attributes offer new resources for biomarker discovery , complementing conventional methods of identification and sequence annotation . for
drug compounds , a challenge / response method , as described , can help address the problems of drug promiscuity and discern the subtleties of protein attributes ; when the same or similar underlying sequences , have multiple conformations and functions , and when different sequences sometimes perform the same or similar function . as a way to begin sifting through these biological complexities , a more efficient method to characterize protein function and
starting with the enrichment of prospective functional biomarkers in localized subproteomes , we suggest that structural and sequence relationships can be determined .
such an approach has the potential to provide new and useful service to biomarker discovery and personalized medicine .
Output:
| functional proteomic profiling can help identify targets for disease diagnosis and therapy .
available methods are limited by the inability to profile many functional properties measured by enzymes kinetics .
the functional proteomic profiling approach proposed here seeks to overcome such limitations .
it begins with surface - based proteome separations of tissue / cell - line extracts , using serafile , a proprietary protein separations platform .
enzyme kinetic properties of resulting subproteomes are then characterized , and the data integrated into proteomic profiles . as a model , serafile - derived subproteomes of cyclic nucleotide - hydrolyzing phosphodiesterases ( pdes ) from bovine brain homogenate ( bbh ) and rat brain homogenate ( rbh )
were characterized for camp hydrolysis activity in the presence ( challenge condition ) and absence of cgmp .
functional profiles of rbh and bbh were compiled from the enzyme activity response to the challenge condition in each of the respective subproteomes .
intersample analysis showed that comparable profiles differed in only a few data points , and that distinctive subproteomes can be generated from comparable tissue samples from different animals .
these results demonstrate that the proposed methods provide a means to simplify intersample differences , and to localize proteins attributable to sample - specific responses
. it can be potentially applied for disease and nondisease sample comparison in biomarker discovery and drug discovery profiling . |
PubmedSumm4812 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: a substantial proportion of patients who repeatedly present to hospitals with symptoms for which conventional pathology can not be identified , show evidence of psychological distress that is either not expressed or is unrecognized in the general practice consultation .
the phenomena has two aspects : the expression of psychological illness through physical symptoms , and repeated medical help - seeking for multiple medical symptoms without organic disease .
somatization diagnosis is a prevalent , expensive , and a difficult - to - treat problem for general practitioners .
it is also reported that some cultures stigmatize psychological disorder more than others . to overcome the confusion around the term somatization ,
neither somatized mental distress nor somatization disorders adequately account for most patients seen with mups .
patients show up at hospitals with symptoms for a variety of reasons , including the disruption caused by the severity of the symptoms and the patients concerns about what they mean .
there was a paucity of studies done on mups in kerala , a south indian state .
the objective of this study was to examine the sociodemographic and other clinical variables associated with mups .
the clinical sample was taken from the general / internal medicine outpatient clinic of the government medical college , thrissur , kerala , india .
the medical doctor , with psychiatry experience , saw the potential patients together with the physicians on mondays in the clinic .
the referred cases meeting the criteria for mups were enrolled for the study , for approximately three years .
the medical doctor discussed the cases with the consultant psychiatrist ( pk - second author ) and confirmed the diagnosis .
the criteria for mups were one or more physical symptoms after appropriate investigation , which could not be explained by a general medical condition , and the symptoms caused clinically significant distress or impairment in social and occupational functioning , in excess of what would be expected from the history and physical examination and laboratory findings .
the medical doctor with psychiatry experience completed the questionnaire , which included the sociodemographic profile , with details regarding frequency of physical complaints , duration of symptoms , the number of visits to the doctor , investigations done , psychosocial and environmental stressors , and personality disorder .
the symptoms were assessed using the symptom enquiry checklist used in the world health organization international study on somatoform disorders ( 1994 ) , which had 73 questions . in this cross - sectional study ,
we provide descriptive information on the sociodemographic variables , summarized in table 1 , and clinical variables , summarized in tables 2 and 3 , of 48 participants enrolled in this exploratory study .
there were a total of 274 symptoms , which is an average of 5.7 symptoms per patient .
in contrast to the female - to - male ratio of 5 : 1 ( dsm - iv - tr ) , we found a female - to - male ratio of 7 : 1 .
this may be because of the difference in the western population versus the indian population .
the medical knowledge of urban people may be discouraging them from reporting psychological distress as a physical disease .
consistent with dsm - iv - tr , our study also showed that avoidant and obsessive compulsive personality disorders were commonly associated with mups .
in contrast , we did not find an association between mups and paranoid , histrionic , and antisocial personalities .
the preponderance of females in this study is not consistent with the usual hospital data in india . in conditions where community data shows a higher prevalence of females , hospital data shows male predominance .
however , the findings were contrary in case of mups in this study . for physical manifestations arising from psychological distress ,
. the severity , chronic nature , and social acceptance of symptoms may be the reasons for this discrepancy .
it may be that the predominance of adults in this study reflects the usual hospital patient population . seeking out treatment
however , in the eca study done in us , in 3,132 community respondents with somatization disorder , the majority was unmarried or divorced , which is consistent with the western culture . in india , women may be bearing the strain of marital conflict , expressing it through culturally acceptable physical symptoms .
this has been reported in a study from the neighboring state of tamil nadu , another southern state in india .
consistent with our results , headache was the most common symptom and obsession scores were also high in the quoted study done in tamil nadu .
a medical doctor in india has relatively insignificant exposure in psychiatry during the medical school / college training period .
after the training they practically have no avenues to get further exposure to psychiatry as a mental health professional 's work , in isolation .
hence , a physician who is not a psychiatrist is without adequate confidence to diagnose a psychiatric syndrome .
the more the patient is investigated , the more a patient is convinced about the physical basis . on account of the psychogenic etiopathophysiology ,
although it has been estimated that 5% of the patients in general practice present with severe forms of somatization , this disorder is clearly underdiagnosed , and on many occasions physicians tend to repeatedly pursue an organic etiology for the patients complaints , using multiple test procedures , medication , and surgical operations instead of recognizing a somatization disorder.[1216 ] finally , patients with a somatization disorder tend to withdraw from pleasurable activities and have less productivity because of discomfort , fatigue or fear of exacerbation of their symptoms . in a review on somatizing and psychologizing patients
, there were no consistent differences between people with psychiatric disorders , who presented with psychological symptoms versus who presented with physical symptoms .
although 25% of the affected patients present with only psychological symptoms , the remainder may accept the possibility of a psychosocial component to their physical symptoms , even if they do not volunteer it during the consultation .
practical reasons , such as lack of time , or a sense that problems are not relevant or amenable to treatment , seem more important than failure to recognize their own mental distress , which may explain why patients choose not to disclose psychological problems during consultations .
one of the few longitudinal studies identified a pattern whereby symptoms occurring at a time of newly increased stress tended to be attributed to stress .
patients came to doctors with mups only if the stress persisted . in our study , a medical doctor with psychiatry experience who was not a psychiatrist easily elicited the stressors .
lack of time is not a restraining factor to elicit stressors / stress , only an orientation and an inclination for it is required .
patients may often perceive doctors as denying the validity of their symptoms.[92022 ] even as doctors have medical models of illnesses ; patients also have lay models , which are complex and broadly consistent .
these include the name of the condition and its symptoms , the personal consequences of it , how long will it last , and the extent to which it can be controlled or cured .
there are eight dimensions proposed : four on the etiology ( stress , environment , lifestyle , and weak constitution ) , three concerning mechanism ( wearing out , internal structure , and internal function ) , and a final dimension of concern raised by the symptom proposed .
patients are able to accept a medical opinion when doctors develop non - blaming models of conditions with their patients and form constructive alliances against the illness.[92022 ] illness belief models explore how patients see illness as threatening .
the doctors seek to reduce that threat through treatment and reassurance . unfortunately , reassurance is not always effective ; between a third and half of the patients report a continuing concern about serious illness after normal cardiac ultrasound or angiography .
psychological models of threat reduction suggest two separate processes : emotional - heuristic ( calming , protecting , and threat - avoiding ) , and cognitive - systematic ( information - seeking and threat - analyzing ) .
although emotional , threat avoiding , verbal and non - verbal reassurance may be effective in alleviating distress in the short term , it may not be effective to weaken illness representations .
if symptoms recur , repeated reassurance is likely to produce a cycle of reassurance seeking and giving that is self - perpetuating .
in contrast , the cognitive model of threat analyzing is more threatening for patients in the short term , but more likely to produce long - term changes , which in turn , may be associated with improvement
. the physician tends to be initially concerned to rule out treatable medical conditions , and when none are found , leads to excessive help - seeking behavior .
patient relationship , as the patients sense that their doctor has lost interest in them or view them as bothersome .
although many physicians are eager to refer the patient for psychiatric evaluation and treatment , patients might see the referral as their doctor 's way of questioning the reality of their symptoms .
this challenge has encouraged the development of treatment approaches for somatization disorder that meet the different demands of the patient and the referring physician .
kaiser - permanente , a us health maintenance program has shown that somatizing patients could bankrupt the healthcare financing system and these patients can be helped leading to reduced healthcare costs . the affective cognitive behavioral therapy is recommended for physicians , for the treatment of mups , which includes the following : providing continuity of care , avoiding unnecessary tests and procedures , providing frequent , brief , and regular office visits , always performing a physical examination , avoiding making disparaging comments like , your symptoms are all in your head , setting reasonable therapeutic goals like maintaining the functioning despite ongoing pain . in a review on human psychoneuroimmunology studies , authors found that immune modulation by psychosocial stressors or interventions could lead to actual health changes .
the major strength of this study is the large sample size ( n=48 ) in an indian population .
one more strength is the unique clinical sample having the features of both a rural setting and a tertiary care hospital . in our study
, we could not calculate the prevalence , because we did not have the total number of patients who showed up at the medicine clinic on mondays .
our study included subjects with mups and not with a dsm - iv - tr diagnosis of somatization or somatoform disorder .
however , somatization disorder terminology will be changed to simple and complex somatic symptom disorders in dsm - v .
another limitation of this study was that we could not analyze an association between mups and comorbid psychiatric diagnoses . in the hospital where this study was done
, the patients presenting to the clinics had only their prescriptions , without a documented diagnosis .
to our knowledge this is the first psychosocioeconomic study of mups done in kerala , india .
more studies are warranted focusing on non - pharmacological treatment and psycho - education on mind
future studies should also shed light on specific cytokines associated with mups for personalized management , which is a national institute of mental health mission and priority .
there is also a need for studies to examine the effect of a combination of antidepressants and cognitive behavioral therapy on mups .
Output:
| background : there is a paucity of studies done on medically unexplained physical symptoms ( mups ) in kerala , india .
the objective of this study was to examine the sociodemographic and other clinical variables associated with this condition.materials and methods : the clinical sample was taken from the general medicine clinic of a tertiary care hospital , in kerala .
the referred cases meeting the criteria ( n=48 ) for medically unexplained physical symptoms were enrolled for this cross - sectional study .
the medical doctor with experience in psychiatry completed the questionnaire.results:most of the patients were middle - aged females from rural areas .
the most common symptom reported was headache .
most of the patients had symptoms for five years or more and had seen two - to - five consultants .
a majority of the patients had undergone special investigations and a few had expensive and invasive investigations .
cluster c personality disorders were the most common associated personality disorders with medically unexplained physical symptoms.conclusions:to our knowledge this is the first psychosocioeconomic study on medically unexplained physical symptoms , done in kerala , india .
medically unexplained physical symptoms cause loss of productivity and economic burden and are a major public health problem .
future studies are warranted focusing on non - pharmacological treatment , psycho - education on mind
body association , and medical models on specific cytokines associated with medically unexplained physical symptoms for personalized management , and to examine the effect of a combination of pharmacotherapy and cognitive behavioral therapy . |
PubmedSumm4813 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: immunoglobulin a nephropathy ( igan ) is the most common form of primary glomerulonephritis worldwide , and is associated with a poor prognosis , resulting in end - stage kidney disease in approximately 40% of cases.13 because the poor prognosis of igan is partly a result of delayed diagnosis , strategies for early diagnosis leading to early and effective medical intervention are urgently needed .
pathological analysis of renal biopsy tissue is the gold standard for diagnosis of igan as well as assessment of disease activity and renal prognosis .
however , the findings may differ according to the timing of renal biopsy during the 20-year course of igan.1,2 different intervention periods may yield different findings on renal biopsy . for example , in studies using a renal biopsy database from the southern usa , igan was commonly identified in renal biopsy tissue specimens from patients aged < 40 years , whereas focal glomerulosclerosis was reportedly the primary finding in patients aged 40 years.4 the authors pointed out that although primary focal glomerulosclerosis was most common in non - white individuals aged 40 years , secondary focal glomerulosclerosis was more likely in caucasians because of burned - out igan .
moreover , renal biopsy is not frequently performed because of procedural risks and/or limitation of insurance coverage .
these observations emphasize that renal biopsy provides only a snap - shot of the disease status and thus also has limitations in the assessment of disease activity .
furthermore , even if biopsy is performed early in the course of disease , findings may be inconclusive and prognosis may be difficult to predict .
even mild igan , presenting as hematuria or mild proteinuria with mild histological lesions at the time of renal biopsy , progresses to renal failure in 30% of cases.3,5,6 to determine disease stage , a noninvasive , real - time activity assessment method separate from renal biopsy is desirable .
urinalysis is often used to assess disease activity , although this method also has limitations and restrictions . however , to date , there is no clear method to distinguish proteinuria from acute glomerular inflammatory lesions such as cellular crescents or burned - out sclerotic glomerulus in igan .
therefore , the rationale for treatment indication based on urinary protein levels in many clinical guidelines must be rigorously limited .
in addition to an objective method to assess disease activity , a simple and safe method of early diagnosis using valid biomarkers based on the pathogenesis of igan should be established .
levels of the polymeric form of iga are elevated in the serum of igan patients , whereas glomerular iga in this disease is mainly of the iga1 subtype.7,8 iga1 has a longer hinge region , which can be glycosylated with various o - linked - glycans with n - acetylgalactosamine ( galnac ) , galactose , and sialic acid , depending on the activity of specific glycosyltransferases.9 previous reports have indicated that glomerular iga1 in igan is either under - galactosylated.10,11 therefore , aberrantly glycosylated iga1 has long been considered as a possible cause of igan.12 in recent years , an increase in serum galactose - deficient iga1 levels in patients with igan was quantitatively confirmed for the first time by moldoveanu et al by use of an enzyme - linked immunosorbent assay using helix aspersa agglutinin lectin , which recognizes galnac residues.13 moreover , suzuki et al established immortalized b - cell lines that produce iga1 from peripheral blood b cells obtained from igan patients and analyzed the characteristics of gdiga1.14 iga1 from igan was polymeric - dominant and galactose - deficient or over - sialylated on terminal galnac.9,13 in addition , enzyme analysis revealed abnormal enzymatic activity , such as a decrease in 1,3-galactosyltransferase and an increase in 2,6-sialyltransferase activities , which are critical for incorporation of galactose and sialic acid into galnac , respectively.14 recent studies have shown that these enzymatic activities are possibly regulated by genetic mechanisms and dysregulation of mucosal immunity.1517 a question arises regarding where such gdiga1 is generated .
some clinical evidence , such as exacerbation of igan after upper respiratory tract infection , suggests mucosal contribution in the pathogenesis of igan .
indeed , some japanese groups demonstrated aberrant glycosylation in iga from palatine tonsils of igan patients,18,19 whereas some chinese groups reported abnormal cytokine profiles in the tonsils leading to an imbalance in 1,3-galactosyltransferase and an increase in 2,6-sialyltransferase,20,21 indicating that palatine tonsils may be the primary site of gdiga1 .
moreover , patients demonstrating a relatively large decrease in serum iga levels ( > 10% ) achieved better clinical outcomes after tonsillectomy,22 suggesting that nephritogenic iga may play a role in the decrease in iga after tonsillectomy .
indeed , high serum iga levels ( > 315 mg / dl ) and serum iga / c3 ratio ( > 3.01 ) in association with hematuria ( more than five red blood cells per high power field ) and proteinuria ( > 0.3 g / day ) have a diagnostic value for igan.23 to further confirm this idea , we directly evaluated changes in serum gdiga1 levels by helix aspersa agglutinin lectin enzyme - linked immunosorbent assay before and 4 weeks after tonsillectomy.24 igan patients who demonstrated a significant decrease in serum gdiga1 levels after tonsillectomy achieved significantly better improvement in hematuria , strongly indicating that at least some factors associated with nephritogenic gdiga1 are delivered from the palatine tonsils.24 to determine whether gdiga1 is the sole effector molecule of igan , gharavi et al noted increased serum helix aspersa agglutinin - reactive gdiga1 levels in patients with igan compared with those in their relatives ; however , serum gdiga1 levels in the relatives were still elevated compared with those in normal individuals who were not blood relatives , regardless of the absence of nephropathy.25 thus , igan pathogenesis can not be explained on the basis of elevated gdiga1 levels alone , because other pathological factors may be involved in the continued progression of igan .
in addition , the concentration of immune complexes containing iga , specifically gdiga1 , is increased in the blood and urine of igan patients.8,9,12,26 serum levels of gdiga1-iga and gdiga1-igg in immune complexes are increased in igan.27 suzuki et al have recently reported that the igg autoantibodies that recognize glycan - containing epitopes on gdiga1 exhibit unique features in the complementarity - determining region 3 of the variable region of their heavy chains.28 furthermore , serum levels of igg autoantibodies specific for gdiga1 correlated with disease severity , as assessed by magnitude of proteinuria.28 the onset and progression of igan is believed to require gdiga1 ( first hit ) , as well as endogenous anti - glycan antibodies ( second hit ) and subsequent immune complex formation ( third hit ) and glomerular depositions of both ( fourth hit).29 these multi - hit steps in disease progression were also reported in murine models of igan .
igan - prone mice have elevated serum levels of mucosally regulated polymeric forms of iga with aberrant oligosaccharide contents at the iga hinge region30,31 and disease severity is not correlated with serum levels of iga but rather with iga immune complexes.32 indeed , complement activity , including the lectin pathway , was strongly induced in the murine igan model.33
the above - described clinical and experimental findings suggest that gdiga1 and its related immune complexes with anti - glycan autoantibodies are essential effector molecules in igan pathogenesis ; thus , serum levels of these molecules have shown potential as diagnostic markers for the clinical severity of igan.13,25,27,28 recent studies demonstrated that increased gdiga1 levels were associated with worsening proteinuria and a greater risk of deterioration of renal function in igan.34,35 in addition , the combination of high serum gdiga1 levels and circulating levels of advanced oxidation protein products were correlated with a more rapid decline in estimated glomerular filtration rate , suggesting that oxidative stress linked to gdiga1 may be involved in the pathogenesis of igan.35 although these reports did not analyze serum iga immune complex levels , berthoux et al reported that serum levels of igg and iga autoantibodies ( specific for gdiga1 ) at the time of diagnostic biopsy were significantly associated with clinical progression of igan towards dialysis / death.36 the findings of previous reports further confirmed the multi - hit hypothesis for the disease mechanism of igan,29 and indicate the possibility that evaluation of not only serum levels of the autoantigen ( gdiga1 ) but also those of autoantibodies to gdiga1 or immune complexes with such antibodies27,28 should be required as disease markers for igan .
our recent study further demonstrated the value of these biomarkers for the assessment of disease activity.37 we evaluated changes in serum levels of gdiga1 and immune complexes with autoantibodies and demonstrated correlations with changes in urinary abnormalities in 50 igan patients , who showed complete or partial clinical remission following tonsillectomy with steroid pulse therapy before and 35 years after treatment .
cross - sectional analysis revealed that the degree of hematuria and proteinuria was significantly associated with serum levels of gdiga1 and iga immune complexes .
in addition , longitudinal analyses showed that improvement of urinary abnormalities was well correlated with decreased serum levels of gdiga1 and iga immune complex from baseline values before treatment .
because the disease course of igan is slowly progressive , clinical studies to investigate the efficacy of therapy with hard end - point evaluations as observed in diabetic nephropathy , will take a long time to complete . however , these findings emphasize the potential value of these effector molecules as practical surrogate markers for evaluation of the efficacy of therapies for igan .
higher serum levels of gdiga1 and related immune complexes indicate their diagnostic value for igan.13,25,27,28 however , previous studies have also shown elevated serum levels of gdiga1 and immune complexes in some healthy individuals as well as other chronic kidney disease patients.13,14,25,27,28 in our analysis , 41% of igan patients had elevated serum gdiga1 levels and 91% of these patients exhibited gdiga1-specific igg levels above the 90th percentile of healthy controls,38 consistent with a prior report.39 although up to 25% of controls with chronic kidney disease , particularly those with immune - mediated glomerular diseases including lupus nephritis , also had elevated serum levels of gdiga1-specific igg , most igan patients had elevated levels of gd - iga1-specific antibody of both isotypes .
such a substantial overlap in serum levels of individual biomarkers between patients with igan , controls with chronic kidney disease , and healthy controls suggests that no single biomarker was sufficiently specific for igan.38 serum levels of gdiga1-specific igg were significantly higher in igan patients with elevated gdiga1 levels ( p<0.001 ) .
however , approximately 91% of igan patients with normal serum gdiga1 levels also exhibited elevated levels of gdiga1-specific igg,38 suggesting that auto - antibody production may occur independently of gdiga1 .
although serum levels of gdiga1-specific autoantibodies have excellent predictive properties to discriminate igan patients from healthy controls and patients with non - immune - mediated kidney disease , the specificity is lower for discriminating igan patients from those with other types of immune - mediated kidney disease.38 indeed , the assessment of gdiga1-specific igg showed the best performance for diagnosis of igan , with a sensitivity of 89% and specificity of 92% .
however , these findings also suggest that a panel of such serum biomarkers may be helpful to differentiate igan from other glomerular diseases . in addition , other related markers , such as urinary gdiga1 and immune complexes , should be assessed for addition to a panel in a larger cohort .
indeed , a multicenter trial of the diagnostic use of the panel with these biomarkers has already been initiated in japan .
although their capability as prognostic markers to separate progressors and nonprogressors to end - stage kidney disease must be of keen interest , it would take more time because the prognostic value should be evaluated by more follow - up data about igan activity assessment with these biomarkers .
specific curative treatment is required for igan , which is the most common form of glomerulonephritis and is associated with poor prognosis .
however , such specific treatments may require early diagnosis of igan through specific targets before progression of commonly induced pathways that result in further kidney damage , such as sclerotic lesions , and an appropriate clinical trial with practical and disease - specific surrogate markers .
as explained in this report , recent clinical and experimental studies emphasize that one of prospective diagnostic and disease assessment markers for igan are gdiga1 and anti - glycan autoantibodies derived from the mucosa - bone marrow axis,40 and subsequent immune complexes ( figure 1 ) .
therefore , noninvasive and real - time testing with such reasonable biomarkers on the basis of pathogenesis is critical to accomplish this goal .
Output:
| immunoglobulin ( ig ) a nephropathy ( igan ) is the most common form of glomerular disease worldwide and is associated with a poor prognosis .
thus , development of a curative treatment and strategies for early diagnosis and treatment are urgently needed .
pathological analysis of renal biopsy is the gold standard for the diagnosis and assessment of disease activity ; however , immediate and frequent assessment based on biopsy specimens is difficult .
therefore , a simple and safe alternative is desirable . on the other hand ,
it is now widely accepted that multi - hit steps , including production of aberrantly glycosylated serum iga1 ( first hit ) , and igg or iga autoantibodies that recognize glycan containing epitopes on glycosylated serum iga1 ( second hit ) and their subsequent immune complex formation ( third hit ) and glomerular deposition ( fourth hit ) , are required for continued progression of igan .
although the prognostic and predictive values of several markers have been discussed elsewhere , we recently developed a highly sensitive and specific diagnostic method by measuring serum levels of glycosylated serum iga1 and related iga immune complex .
in addition , we confirmed a significant correlation between serum levels of these essential effector molecules and disease activity after treatment , suggesting that each can be considered as a practical surrogate marker of therapeutic effects in this slowly progressive disease .
such a noninvasive diagnostic and activity assessment method using these disease - oriented specific biomarkers may be useful in the early diagnosis of and intervention in igan , with appropriate indication for treatment , and thus aid in the future development and dissemination of specific and curative treatments . |
PubmedSumm4814 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: non-24-hour sleep wake syndrome is a sleep disorder in which the sleep wake cycle exceeds 24 hours , and this occurs not only in blind subjects but also in sighted individuals.1,2 however , this syndrome hardly occurs in sighted individuals;2 the exact mechanism in sighted individuals with non-24-hour sleep
some evidences suggested that a long circadian period more than the normal range of entrainment is likely a risk factor.3 there have been several reports that non-24-hour sleep wake syndrome may be successfully treated with melatonin,46 vitamin b12,7 and phototherapy8 ; however , not all patients respond to these treatments.9 depressive symptoms are more commonly reported among patients with circadian rhythm sleep disorders .
wake schedule with social obligations.10 we report the case of a sighted woman with non-24-hour sleep wake syndrome and depressive symptoms .
sleep times were recorded at intervals of 30 minutes in a sleep diary by the patient . the circadian period ( tau - value ) of wake
sleep cycles was determined from the data obtained for a length of 4 consecutive weeks using periodogram algorithm , and venous blood samples were collected every 4 weeks for assay of the plasma valproic acid concentration .
the valproic acid concentration was determined using a vitros valp reagent assay kit ( ortho clinical diagnostics , raritan , nj , usa ) according to the manufacturer s instructions .
sberg depression rating scale ( madrs)11 ; remission of depressive symptoms is defined as a score of 8 on the madrs.12 blood sampling and depression assessment were performed at the same time of day .
a written informed consent was obtained from the patient after the procedures had been fully explained .
the study protocol was approved by the ethics committee of sato hospital , koutokukai and the ethics committee of graduate school of pharmaceutical science , tohoku university , and standard procedures were followed for clinical trials involving vulnerable participants in japan .
the patient was a 24-year - old woman who was first referred to our hospital , which is a special outpatient clinic for depression as a major depressive disorder , from another psychiatric hospital .
she had already been treated with several antidepressants by the clinicians at the referring psychiatric hospital . her depressive symptoms , including fatigue and sleep disturbance , interfered with her social obligations ; therefore , she could not attend work .
based on the diagnosis provided by the clinicians at the referring psychiatric hospital , we also began treatment for depression .
based on her treatment response , however , we found that she did not have a conventional sleep disorder and instead suspected that she had non-24-hour sleep
the patient had kept a sleep diary over the past 5.5 years , starting from 2008 ( figure 1 ) .
this diary showed that her sleep wake cycle free - ran on a regular period of 24.55 hours standard deviation 0.30 hours ( n=47 periods , where 1 period is 4 weeks ) , consistent with a diagnosis of non-24-hour sleep wake syndrome .
none of her symptoms had responded to treatment with standard doses of paroxetine ( 1030 mg / day ) , fluvoxamine ( 2575 mg / day ) , imipramine ( 525 mg / day ) , amitriptyline ( 20 mg / day ) , milnacipran ( 12.525 mg / day ) , mirtazapine ( 1530 mg / day ) , duloxetine ( 20 mg / day ) , or amoxapine ( 28 mg / day ) .
her mean madrs score over the same period was 17.012.3 points ( n=47 , figure 2 ) , and was unstable during episodes of non-24-hour sleep
although the patient was treated with generally accepted therapeutic doses of mood stabilizers such as lithium ( 200600 mg / day ) , lamotrigine ( 2575 mg / day ) , and valproic acid ( 400800 mg / day ) , these were ineffective for treating depressive symptoms and non-24-hour sleep wake syndrome .
additionally , her sleep disorder did not respond to 2- or 4-week trials of hypnotics .
ramelteon is an mt1/mt2 melatonin receptor agonist with greater affinity for melatonin receptors and a longer half - life than melatonin.13,14 the initial dosage of ramelteon was 8 mg / day for 3 weeks .
but i had to reduce ramelteon ( 24 mg / day ) as she appealed to me to reduce the dosage for depressive symptoms such as lassitude .
non - pharmacologic measures , including several treatments of phototherapy ( 20,000 lux ) and efforts to improve sleep hygiene by avoiding daytime sleeping , also failed ( figure 2 ) . the patient continued to complain of difficulty in falling asleep and waking , and reported persistent anxiety , irritation , and fatigue .
laboratory investigations , including serum hormone and immunologic profiles , and magnetic resonance imaging of the brain were normal .
although treatment with valproic acid at the generally accepted dose was ineffective , we considered that treatment with low - dose valproic acid may achieve complete entrainment to a 24-hour sleep cycle .
wake cycle synchronized to 24.030.05 hours ( n=19 periods , figure 3 ) at a valproic acid concentration of 5.02.7 g / ml .
the mean madrs score dropped down to 10.712.7 ( n=19 ) during synchronization without antidepressants , although the improvement was not statistically significant ( f2,65 = 0.487 , p=0.066 , student s t - test ) .
her sleep onset time , wakeup time , and sleep time were 1:04 am 64 minutes , 9:26 am 81 minutes , and 9.31.1 hours during synchronization , respectively . by communicating with the patient
, we learned that her symptoms of fatigue and non-24-hour sleep wake syndrome relapsed because she discontinued the low - dose valproic acid .
thereafter , she restarted treatment with the low - dose valproic acid in an attempt to control her symptoms .
however , as she did not visit our hospital during this time , we could not evaluate the changes in the valproic acid concentration .
the patient was a 24-year - old woman who was first referred to our hospital , which is a special outpatient clinic for depression as a major depressive disorder , from another psychiatric hospital .
she had already been treated with several antidepressants by the clinicians at the referring psychiatric hospital . her depressive symptoms , including fatigue and sleep disturbance , interfered with her social obligations ; therefore , she could not attend work .
based on the diagnosis provided by the clinicians at the referring psychiatric hospital , we also began treatment for depression .
based on her treatment response , however , we found that she did not have a conventional sleep disorder and instead suspected that she had non-24-hour sleep
the patient had kept a sleep diary over the past 5.5 years , starting from 2008 ( figure 1 ) .
this diary showed that her sleep wake cycle free - ran on a regular period of 24.55 hours standard deviation 0.30 hours ( n=47 periods , where 1 period is 4 weeks ) , consistent with a diagnosis of non-24-hour sleep wake syndrome .
none of her symptoms had responded to treatment with standard doses of paroxetine ( 1030 mg / day ) , fluvoxamine ( 2575 mg / day ) , imipramine ( 525 mg / day ) , amitriptyline ( 20 mg / day ) , milnacipran ( 12.525 mg / day ) , mirtazapine ( 1530 mg / day ) , duloxetine ( 20 mg / day ) , or amoxapine ( 28 mg / day ) .
her mean madrs score over the same period was 17.012.3 points ( n=47 , figure 2 ) , and was unstable during episodes of non-24-hour sleep
although the patient was treated with generally accepted therapeutic doses of mood stabilizers such as lithium ( 200600 mg / day ) , lamotrigine ( 2575 mg / day ) , and valproic acid ( 400800 mg / day ) , these were ineffective for treating depressive symptoms and non-24-hour sleep wake syndrome .
additionally , her sleep disorder did not respond to 2- or 4-week trials of hypnotics .
ramelteon is an mt1/mt2 melatonin receptor agonist with greater affinity for melatonin receptors and a longer half - life than melatonin.13,14 the initial dosage of ramelteon was 8 mg / day for 3 weeks .
but i had to reduce ramelteon ( 24 mg / day ) as she appealed to me to reduce the dosage for depressive symptoms such as lassitude .
non - pharmacologic measures , including several treatments of phototherapy ( 20,000 lux ) and efforts to improve sleep hygiene by avoiding daytime sleeping , also failed ( figure 2 ) .
the patient continued to complain of difficulty in falling asleep and waking , and reported persistent anxiety , irritation , and fatigue .
laboratory investigations , including serum hormone and immunologic profiles , and magnetic resonance imaging of the brain were normal .
although treatment with valproic acid at the generally accepted dose was ineffective , we considered that treatment with low - dose valproic acid may achieve complete entrainment to a 24-hour sleep cycle .
wake cycle synchronized to 24.030.05 hours ( n=19 periods , figure 3 ) at a valproic acid concentration of 5.02.7 g / ml . the mean madrs score dropped down to 10.712.7 ( n=19 ) during synchronization without antidepressants , although the improvement was not statistically significant ( f2,65 = 0.487 , p=0.066 , student s t - test ) .
her sleep onset time , wakeup time , and sleep time were 1:04 am 64 minutes , 9:26 am 81 minutes , and 9.31.1 hours during synchronization , respectively . by communicating with the patient , we learned that her symptoms of fatigue and non-24-hour sleep wake syndrome relapsed because she discontinued the low - dose valproic acid .
thereafter , she restarted treatment with the low - dose valproic acid in an attempt to control her symptoms . however , as she did not visit our hospital during this time , we could not evaluate the changes in the valproic acid concentration .
valproate is a mood stabilizer with a broad range of actions , but its mechanism of action remains incompletely understood .
valproic acid and divalproex ( a combination of sodium valproate and valproic acid ) have been licensed for the treatment of bipolar disorder since the 1990s.15 the therapeutic range of valproic acid for bipolar disorder is 50125 mg /
l ( 350850 m).15 valproate is associated with increased levels of acetylated histones via its action as a histone deacetylase inhibitor.16 a particularly interesting finding is that the bimodal effect of valproate resulted in a difference in the transcription of tyrosine hydroxylase at low and high concentrations.17 consequently , the pharmacologic effects of low - dose valproic acid may differ from those of the generally accepted therapeutic dose .
although whether changes in the transcription of tyrosine hydroxylase contributed to the improvement in this patient s non - entrained sleep remains unclear , it is notable that the generally accepted therapeutic dose range of valproic acid was ineffective for the treatment of her non-24-hour sleep
our patient had non-24-hour sleep wake syndrome , which is not a conventional sleep disorder .
this may result in the development of depressive symptoms , such as anxiety , irritation , and fatigue .
non-24-hour sleep wake syndrome is rare ; therefore , without a sleep diary , even expert psychiatrists have difficulty diagnosing this condition .
in fact , the patient in this case was referred to our hospital for the treatment of major depressive disorders .
her sleep had not been entrained and her depressive symptoms had not been alleviated by several antidepressants and mood stabilizers , including generally accepted therapeutic doses of valproic acid .
antidepressants or mood stabilizers may not be effective for treating depressive symptoms when a patient is affected by non-24-hour sleep wake syndrome . in this case ,
the relapse and remission of symptoms that occurred when the patient discontinued and restarted valproic acid therapy on her own initiative gives us confidence that this was a genuine therapeutic effect .
the patient s depressive symptoms tended to improve , and the madrs score during synchronization of her sleep wake cycle improved in association with the remission of her symptoms .
additionally , the patient experienced several episodes of remission during synchronization without antidepressants ; therefore , it may be important to note that her depressive symptoms did not fully improve by synchronization .
another explanation for the incomplete response of her depressive symptoms is that regular social stresses ( such as work ) and the possibility that she had another sleep disorder
sleep - phase syndrome18 ( as revealed by her sleep diary ) were an influence .
moreover , her depressive symptoms did not respond to doses of several antidepressants during episodes of her non-24-hour sleep
wake syndrome , and the patient had several periods of remission during synchronization without antidepressants .
therefore , the improvement in her depressive symptoms may have been secondary to the improvement in her non-24-hour sleep
although melatonin has been shown to improve depression in patients with circadian rhythm sleep disorders,19 major depressive disorders should be carefully differentiated from circadian rhythm sleep disorders with depression .
in addition , circadian rhythm sleep disorders should be carefully differentiated from conventional sleep disorders by a sleep diary . in this case ,
any circadian rhythm sleep disorder requires continuous treatment.8 therefore , it should be considered difficult to conclude that the previous bright light treatment had a carryover effect on entraining circadian rhythm .
the patient with sleep wake syndrome was successfully treated and her depressive symptoms tended to improve by treatment with low - dose valproic acid .
wake syndrome resistant to conservative management strategies and treatment with melatonin - related drugs , vitamin b12 , and phototherapy .
further research will be needed to illuminate the therapeutic benefits and mechanism of action of valproic acid in patients with non-24-hour sleep
effects of low - dose valproic acid may be a clue used to solve the mechanism in sighted individuals with non-24-hour sleep
we hope that many researchers will treat the circadian rhythm sleep disorders using low - dose valproic acid in the future .
Output:
| a woman was diagnosed with non-24-hour sleep wake syndrome and depressive symptoms .
her depressive symptoms did not respond to standard doses of several antidepressants or mood stabilizers .
furthermore , her sleep wake cycle remained non - entrained despite treatment with a melatonin - related drug , vitamin b12 , and phototherapy . ultimately , her sleep
wake rhythm was restored to a 24-hour pattern with a low dose of valproic acid , and her depressive symptoms tended to improve as a result of synchronization without antidepressants .
low - dose valproic acid appears to be one of the effective means of entraining circadian rhythms in patients with non-24-hour sleep
wake syndrome , which in turn likely improves associated depressive symptoms . |
PubmedSumm4815 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: neuraminidase ( na ) is one of the two major surface antigens of influenza viruses .
the enzymatic activity of na contributes to efficient viral replication as it enables spread in a host by cleavage of new virions from infected cells to permit dispersal of aggregated virions .
,
neuraminidase may also digest decoy receptors that impede the access of virions to respiratory epithelial cells .
antibodies that inhibit na activity reduce viral replication in cell culture and decrease the size of plaques formed on cell monolayers .
,
animal challenge experiments have shown that the presence of naspecific immunity can reduce disease severity upon infection ,
and retrospective epidemiological studies have supported similar conclusions in the human host .
the known influenza a viruses are classified into nine na subtypes according to serological properties . in the typical serotyping assay , a substrate with complex carbohydrates that contain terminal sialic acid residues , is subjected to digestion by viral na in the presence or absence of subtypespecific serum .
detection of liberated sialic acid correlates with na activity , so that inhibition of this signal by serum is attributed to functional antina antibodies . in the classical na assay
, sialic acid is cleaved from fetuin , a highly glycosylated protein , and detected by the periodatethiobarbituric acid reaction .
na inhibition ( ni ) can be quantified using the same method to measure na activity of a defined target virus in the presence of serial dilutions of serum .
in conventional protocols for this assay , such as
described in the world health organization manual on animal influenza diagnosis and surveillance ,
all steps for incubation of virus with serum and substrate and chemical reactions are performed in glass test tubes .
several steps are required after the incubation of virus and serum with fetuin substrate , beginning with addition of periodate to oxidize the free sialic acid product .
subsequent steps include the addition of arsenite to stop the oxidation reaction ; addition of thiobarbituric acid ( tba ) followed by heating to convert the product to a chromophore ( formylpyruvic acid ) ; extraction of the chromophore into an organic phase ; and measurement of absorbance .
a nonquantitative microtiter plate form of the assay to expedite na subtyping was previously reported .
the aim of this study was to develop a quantitative , miniaturized format for the classical tba method which would provide a more practical way to quantify ni antibody titers in large numbers of samples .
ni assays can be susceptible to background interference by haspecific antibodies that hinder the substrate s access to the na catalytic site .
,
,
therefore , we generated viral reagents by cloning and reverse genetics to contain the relevant na gene in combination with h6 ha , a novel subtype for humans which has been used in past ni assays .
,
after establishing optimized conditions for the miniaturized assay , its sensitivity and specificity were tested using ferret and human sera against n1 and n2 antigens of recent seasonal influenza vaccine strains , and compared directly with results obtained using the conventional protocol . a clinical study in which volunteers were challenged with wildtype influenza virus showed a correlation between serum ni titer and protection against illness in individuals vaccinated with either an inactivated or liveattenuated vaccine .
to evaluate the use of our miniaturized assay to identify responses
following vaccination , we analyzed responses to na in groups of volunteers immunized with the 2006/2007 formulation of either trivalent inactivated vaccine ( tiv ) or liveattenuated influenza vaccine ( laiv ) .
influenza a virus a / new caledonia/20/1999 ( h1n1 ) was supplied by the united states centers for disease control and prevention ( cdc ) ; and a / wisconsin/67/2005 nymc x161b ( h3n2 ) was supplied by dr .
a virus derived by traditional reassortment between h6n1 virus a / turkey / massachussettes/3740/1975 ( a / tk / mass/75 ) and a / puerto rico/8/34 ( pr8 ) was contributed by dr .
for reverse geneticsderived viruses used , the na gene segments of a / new caledonia/20/99 and a / wisconsin/67/2005 and the ha segment of a / tk / mass/75 were amplified by pcr with universal primers
and cloned into the plasmid phw2000 .
reassortant viruses bearing na of a given vaccine strain , h6 ha of a / tk / mass/75 , and the complementary six gene segments of pr8 were rescued by 8plasmid reverse genetics , as previously described .
the viral constructs bearing na of a / new caledonia/20/1999 and a / wisconsin/67/2005 are referred to as h6n1newcal/99 and h6n2wis/05 , respectively .
ha crossreactivity between the h6 viral constructs and ferret sera specific to a / new caledonia/20/1999 or a / wisconsin/67/2005 was undetectable by standard ha inhibition tests
using chicken erythrocytes .
all viruses were propagated in 10day fertilized chicken eggs , harvested , and concentrated by ultracentrifugation through 25% sucrose .
ferret sera supplied by the cdc , influenza virus surveillance and diagnosis branch , were collected from nave ( normal ) or virusinfected animals .
human serum specimens were collected from volunteers before and 4 weeks after immunization with ( split ) tiv or laiv seasonal vaccines ( 20062007 season ) at brooke army medical center ( fort sam houston , tx , usa ) under an irbapproved protocol and after obtaining informed consent .
the miniaturized format of the ni assay was developed by reduction and optimization of the conventional assay described in the 2002 who manual on animal influenza diagnosis and surveillance
and is summarized below .
fetuin was diluted in phosphatebuffered saline ( pbs ) to 25 mg / ml , except where noted .
each virus was titrated in pbs ( ph 74 ) containing 01% bovine serum albumin ( pbs01% bsa ) to determine the dilution that yields an optical density at wavelength 550 nm ( od550 ) of 10 in the final extracted chromophore layer .
please note that nas of some other h1n1 and h3n2 strains have shown a marked dependence on divalent cations in diluent ( e.g. , saline with titrated cacl2 or dulbecco s pbs with caand mg ) for optimal activity .
twofold serial dilutions of serum were made in duplicate across wells of a 96well polypropylene pcr plate ( eppendorf , hamburg , germany ) .
six sera were typically titrated across seven dilutions in one plate that included controls . in each well , 5 l serum diluted in pbs was mixed with 5 l virus and incubated for 3045 minutes at room temperature .
next , 5 l fetuin ( 25 mg / ml ) was added per well . four fetuin control wells for background signal contained the substrate alone with respective buffers in place of serum and virus , and four virus control wells for noninhibited signal contained all components except serum ( pbs in place of serum ) .
the plates were sealed , mixed , and incubated at 37c in a pcr thermocycler or cabinet incubator for 1516 hours or for 2 hours , where noted .
detection of free sialic acid was initiated with addition of 5 l periodate reagent per well ( 200 mm naio4 , 53% h3po4 , stored in the dark ) for a 1520 minutes incubation at room temperature .
each well then received 25 l arsenite reagent ( 1 m asnao2 , 700 mm na2so4 , 03% concentrated h2so4 ) , and the plate was agitated until the yellow color disappeared .
next , 50 l of tba reagent ( 50 mm tba , 625 mm na2so4 , ) was added per well , wells were closed with cap strips , and the plate was incubated 15 minutes at 99c on a pcr thermocycler block with heated lid .
warrenoff reagent ( 95% 1butanol , 5% concentrated hcl ) was dispensed at 75 l per well , wells were sealed with cap strips or microamp optical adhesive film ( applied biosystems , foster city , ca , usa ) , and each plate was vortexed vigorously until the extraction of pink chromophore to the organic layer was clearly evident .
plates were centrifuged at 250 x g for 5 minutes to separate phases , and 50 l of the upper phase per well was transferred to costar 96well half area flat bottom plates ( corning life sciences , corning , ny , usa ) .
sample absorbance was analyzed on a victor v multilabel reader with a 550 nm filter ( perkinelmer , waltham , ma , usa ) .
bsa , fetuin , and chemical compounds , including pure nacetyl neuraminic acid ( nana ) , were purchased from sigmaaldrich ( st .
the mean background absorbance obtained in fetuin control wells ( no virus or serum ) was subtracted from readings of all other wells . based on the results of an empirical test to determine the ratio of sample absorbance of 50 l in a 96well half area plate and in a standard spectrophotometer ( data not shown ) , the backgroundcorrected readings were multiplied by 31 to derive od values as defined in a 1cm cuvette spectrophotometer .
assay results were accepted if the mean od550 values of virus control samples ( no serum ) was 0713 and fetuin control samples were < 01 .
ni titers were defined as the inverse of the highest serum dilution at which the mean absorbance was 50% of the mean signal of virus controls .
human samples with titers < 5 were assigned a value of 25 for the purpose of calculating geometric mean titers .
the conventional ni assay was performed in test tubes as described in the 2002 who manual ,
with the following adjustments and differences from the miniaturized assay .
each virus preparation was diluted in pbs01% bsa to a concentration providing na activity that yielded an end od549 reading of 05 by a cuvette spectrophotometer in the absence of serum ( using a fetuin control sample to blank the instrument ) .
following incubation of 50 l virus with an equal volume of each serial dilution of serum for 30 minutes at room temperature , 100 l fetuin solution ( 125 mg / ml ) was added per sample and incubated at 37c for 1516 hours .
volumes of periodate , arsenite , tba , and warrenoff reagents added per sample were 01 , 10 , 25 , and 30 ml , respectively .
arsenite reagent contained 770 mm asnao2 and 500 mm na2so4 , with 03% h2so4 , while tba reagent contained 42 mm tba and 500 mm na2so4 .
absorbance was measured in 1cm cuvettes with a smartspec 3000 spectrophotometer ( biorad laboratories , hercules , ca , usa ) at wavelength 549 nm .
the intraassay variability of the miniaturized assay was determined by performing 12 replicate titrations of a human serum sample , prepared separately and tested against h6n1newcal/99 and h6n2wisc/05 antigens . to generate continuous data sets for analysis of variance ,
dilution factors were transformed ( log2 ) and 50% endpoint titers were determined using nonlinear regression ( graphpad prism , graphpad software , la jolla , ca , usa ) . in accordance with the previous analysis of traditional ni assay data ,
the standard deviation ( sd ) of log2transformed ni titers from each data set was calculated by sum of squares analysis .
influenza a virus a / new caledonia/20/1999 ( h1n1 ) was supplied by the united states centers for disease control and prevention ( cdc ) ; and a / wisconsin/67/2005 nymc x161b ( h3n2 ) was supplied by dr .
a virus derived by traditional reassortment between h6n1 virus a / turkey / massachussettes/3740/1975 ( a / tk / mass/75 ) and a / puerto rico/8/34 ( pr8 ) was contributed by dr .
for reverse geneticsderived viruses used , the na gene segments of a / new caledonia/20/99 and a / wisconsin/67/2005 and the ha segment of a / tk / mass/75 were amplified by pcr with universal primers
and cloned into the plasmid phw2000 .
reassortant viruses bearing na of a given vaccine strain , h6 ha of a / tk / mass/75 , and the complementary six gene segments of pr8 were rescued by 8plasmid reverse genetics , as previously described .
the viral constructs bearing na of a / new caledonia/20/1999 and a / wisconsin/67/2005 are referred to as h6n1newcal/99 and h6n2wis/05 , respectively .
ha crossreactivity between the h6 viral constructs and ferret sera specific to a / new caledonia/20/1999 or a / wisconsin/67/2005 was undetectable by standard ha inhibition tests
using chicken erythrocytes .
all viruses were propagated in 10day fertilized chicken eggs , harvested , and concentrated by ultracentrifugation through 25% sucrose .
ferret sera supplied by the cdc , influenza virus surveillance and diagnosis branch , were collected from nave ( normal ) or virusinfected animals .
human serum specimens were collected from volunteers before and 4 weeks after immunization with ( split ) tiv or laiv seasonal vaccines ( 20062007 season ) at brooke army medical center ( fort sam houston , tx , usa ) under an irbapproved protocol and after obtaining informed consent .
the miniaturized format of the ni assay was developed by reduction and optimization of the conventional assay described in the 2002 who manual on animal influenza diagnosis and surveillance
and is summarized below .
fetuin was diluted in phosphatebuffered saline ( pbs ) to 25 mg / ml , except where noted .
each virus was titrated in pbs ( ph 74 ) containing 01% bovine serum albumin ( pbs01% bsa ) to determine the dilution that yields an optical density at wavelength 550 nm ( od550 ) of 10 in the final extracted chromophore layer .
please note that nas of some other h1n1 and h3n2 strains have shown a marked dependence on divalent cations in diluent ( e.g. , saline with titrated cacl2 or dulbecco s pbs with caand mg ) for optimal activity .
twofold serial dilutions of serum were made in duplicate across wells of a 96well polypropylene pcr plate ( eppendorf , hamburg , germany ) .
six sera were typically titrated across seven dilutions in one plate that included controls . in each well ,
5 l serum diluted in pbs was mixed with 5 l virus and incubated for 3045 minutes at room temperature .
next , 5 l fetuin ( 25 mg / ml ) was added per well .
four fetuin control wells for background signal contained the substrate alone with respective buffers in place of serum and virus , and four virus control wells for noninhibited signal contained all components except serum ( pbs in place of serum ) .
the plates were sealed , mixed , and incubated at 37c in a pcr thermocycler or cabinet incubator for 1516 hours or for 2 hours , where noted .
detection of free sialic acid was initiated with addition of 5 l periodate reagent per well ( 200 mm naio4 , 53% h3po4 , stored in the dark ) for a 1520 minutes incubation at room temperature .
each well then received 25 l arsenite reagent ( 1 m asnao2 , 700 mm na2so4 , 03% concentrated h2so4 ) , and the plate was agitated until the yellow color disappeared .
next , 50 l of tba reagent ( 50 mm tba , 625 mm na2so4 , ) was added per well , wells were closed with cap strips , and the plate was incubated 15 minutes at 99c on a pcr thermocycler block with heated lid .
warrenoff reagent ( 95% 1butanol , 5% concentrated hcl ) was dispensed at 75 l per well , wells were sealed with cap strips or microamp optical adhesive film ( applied biosystems , foster city , ca , usa ) , and each plate was vortexed vigorously until the extraction of pink chromophore to the organic layer was clearly evident .
plates were centrifuged at 250 x g for 5 minutes to separate phases , and 50 l of the upper phase per well was transferred to costar 96well half area flat bottom plates ( corning life sciences , corning , ny , usa ) .
sample absorbance was analyzed on a victor v multilabel reader with a 550 nm filter ( perkinelmer , waltham , ma , usa ) .
bsa , fetuin , and chemical compounds , including pure nacetyl neuraminic acid ( nana ) , were purchased from sigmaaldrich ( st . louis , mo , usa ) .
the mean background absorbance obtained in fetuin control wells ( no virus or serum ) was subtracted from readings of all other wells .
based on the results of an empirical test to determine the ratio of sample absorbance of 50 l in a 96well half area plate and in a standard spectrophotometer ( data not shown ) , the backgroundcorrected readings were multiplied by 31 to derive od values as defined in a 1cm cuvette spectrophotometer .
assay results were accepted if the mean od550 values of virus control samples ( no serum ) was 0713 and fetuin control samples were < 01 .
ni titers were defined as the inverse of the highest serum dilution at which the mean absorbance was 50% of the mean signal of virus controls .
human samples with titers < 5 were assigned a value of 25 for the purpose of calculating geometric mean titers .
the conventional ni assay was performed in test tubes as described in the 2002 who manual ,
with the following adjustments and differences from the miniaturized assay .
each virus preparation was diluted in pbs01% bsa to a concentration providing na activity that yielded an end od549 reading of 05 by a cuvette spectrophotometer in the absence of serum ( using a fetuin control sample to blank the instrument ) .
following incubation of 50 l virus with an equal volume of each serial dilution of serum for 30 minutes at room temperature , 100 l fetuin solution ( 125 mg / ml ) was added per sample and incubated at 37c for 1516 hours .
volumes of periodate , arsenite , tba , and warrenoff reagents added per sample were 01 , 10 , 25 , and 30 ml , respectively .
arsenite reagent contained 770 mm asnao2 and 500 mm na2so4 , with 03% h2so4 , while tba reagent contained 42 mm tba and 500 mm na2so4 .
absorbance was measured in 1cm cuvettes with a smartspec 3000 spectrophotometer ( biorad laboratories , hercules , ca , usa ) at wavelength 549 nm .
the intraassay variability of the miniaturized assay was determined by performing 12 replicate titrations of a human serum sample , prepared separately and tested against h6n1newcal/99 and h6n2wisc/05 antigens . to generate continuous data sets for analysis of variance ,
dilution factors were transformed ( log2 ) and 50% endpoint titers were determined using nonlinear regression ( graphpad prism , graphpad software , la jolla , ca , usa ) . in accordance with the previous analysis of traditional ni assay data ,
the standard deviation ( sd ) of log2transformed ni titers from each data set was calculated by sum of squares analysis .
the tba method was miniaturized by reducing volumes of all constituents sufficiently for a 96well plate format .
viral antigen concentrations were standardized for a balance of robust signal quantification and sensitivity to serum inhibition . because the miniaturized assay was conducted in wells of a pcr plate , the incubation step conventionally performed in a boiling water bath
sealing plates with cap strips or adhesive film permitted all incubations and the extraction of chromophore to be conducted within a closed container .
rapid colorimetric analysis of samples was performed with a microplate reader . to assess the linear range for free sialic acid quantification in the miniaturized na assay format , we analyzed twofold serial dilutions of nana that were dispensed in duplicate wells ( 15 l / well ) .
od550 signal increased in direct proportion to sialic acid quantity across a 0720 nmol range ( 0127 od550 , figure 1a ) .
the levels of sialic acid detected after overnight fetuin incubation with serially diluted h6n1newcal/99 and h6n2wis/99 were proportional to virus concentration within approximately the same od550 limits ( figure 1b ) .
a value of 10 od550 was selected as the target for na antigen dilutions in the miniaturized ni assay .
( a ) serial dilutions of purified nacetyl neuraminic acid were added to duplicate wells of a 96well pcr microplate , converted to chromophore by the miniaturized periodatethiobarbituric acid reactions , extracted , and measured in terms of absorbance at 550 nm .
( b ) allantoic fluid stocks of reverse geneticsderived viruses h6n1newcal/99 and h6n2wis/05 were serially diluted and incubated overnight with fetuin substrate in duplicate microplate wells . liberated sialic acid was assayed in the same manner as nacetyl neuraminic acid was assayed in ( a ) . for subsequent ni antibody analysis ,
error bars represent the standard deviation ( sd ) of replicate wells . at some data points ,
the sd is not large enough for bars to be visible . to demonstrate specificity of the assay , sera harvested from ferrets previously infected with a / new caledonia/20/1999 or a / wisconsin/67/2005 vaccine strain viruses were tested for ni activity against h6n1newcal/99 and h6n2wis/05 viral antigens .
each ferret antiserum inhibited the homologous na , but did not inhibit na of the other subtype ( figure 2 ) .
the 50% inhibition titers determined with the miniaturized assay equaled or exceeded the corresponding titers obtained using the conventional assay ( table 1 ) .
analysis of ferret antiserum ni activity against homologous and heterosubtypic na antigens in miniaturized colorimetric assay .
serial dilutions of normal ferret serum ( nfs ) , ferret antia / new caledonia/20/1999 , and ferret antia / wisconsin/67/2005 were incubated for 30 minutes with ( a ) h6n1newcal/99 or ( b ) h6n2wis/05 antigens in duplicate wells of a 96well microplate .
comparison of ni results using conventional and miniaturized assays ni , neuraminidase inhibition ; na , neuraminidase . * ferret antia / new caledonia/20/1999 . * * ferret antia / wisconsin/67/2005 . * * * sera were collected 4 weeks after influenza vaccination .
neuraminidase activity in the miniaturized assay was also measurable using a 2hour incubation of virus with fetuin substrate , and this signal was enhanced moderately by doubling the fetuin concentration ( data not shown ) .
however , an increased amount of virus was necessary in the 2hour fetuin incubation to provide adequate dynamic range for reliable quantification of serum ni activity ( e.g. , a signal of at least 05 od550 )
. a consequence of increased virus concentration is reduction in sensitivity to serummediated inhibition . for example , assaying ferret antia / new caledonia/20/1999 in the 2hour format , with h6n1newcal/99 antigen at a sixfold greater concentration than in the overnight format , resulted in a reduction of ni titer from 1280 to 320 .
similarly , assaying ferret antia / wisconsin/67/2005 in the 2hour format , with h6n1wis/05 at a threefold greater concentration than in the overnight format , resulted in a reduction of ni titer from 80 to 20 . to compare the sensitivity of conventional and miniaturized ni assay methods , both were used to analyze ferret and human sera .
ni titers determined for ferret antih1n1 and antih3n2 sera against homologous antigens were four and twofold lower , respectively , when measured by the conventional assay ( table 1 ) .
four pairs of adult human serum collected before and after vaccination with a seasonal laiv ( containing the a / wisconsin/67/2005 strain ) , were analyzed for ni titers against h6n2wis/05 by the two methods .
higher antin2 ni titers were obtained with the miniaturized assay , and shifts in titer following vaccination using either of the two assays were comparable ( table 1 ) .
for some of the prevaccination serum samples the conventional assay yielded no detectable titer at the lowest tested dilution of serum ( < 5 ) , whereas the miniaturized assay was sensitive enough to determine a titer of 5 or 10 .
the increased sensitivity of the miniaturized assay did not diminish its capacity to detect a rise in ni titer following vaccination ; in one case it measured a greater increase than the conventional assay .
the effect of ha subtype on ni titer determinations with the miniaturized assay was assessed in the postvaccination sera of nine human volunteers .
most of these sera caused more inhibition of na when assayed against hamatched h1n1 virus than against hamismatched h6n1 virus ( table 2 ) , which is evidence that the h6n1 antigen permits more accurate determination of antina antibody activity .
the impact of ha specificity when assaying n2specific titers was less pronounced , but still evident , as three of the nine sera mediated greater inhibition of hamatched h3n2 than hamismatched h6n2 neuraminidase activity .
results of these tests are consistent with a moderate exaggeration of ni titers in assays against viruses with matched ha subtypes , because of ha antibodymediated interference , as previously reported .
,
,
neuraminidase inhibition assay comparison using antigens with native viral ha versus ha novel to host ni , neuraminidase inhibition ; ha , hemagglutinin . * tested against wildtype a / new caledonia/20/1999 . * * tested against reverse geneticsderived virus with h6 ha and n1newcal/99 genes . * * * tested against a / wisconsin/67/2005 161b
we analyzed the intraassay variability of ni readings in the miniaturized assay by performing 12 replicate titrations of one human serum sample , each of these in duplicate .
to generate appropriately distributed data sets for analysis of variance , the dilution factors were transformed ( log2 ) and 50% endpoint titers were determined using nonlinear regression .
the mean ni titer against h6n1newcal/99 was 416 log2 , with sd 0182 log2 . against h6n2wisc/05 the mean titer was 555 log2 , with sd 0175 log2 .
thus , > 13fold difference in ni titers between two sera tested in the same assay is considered significant . we intend to confirm this analysis of intraassay variability using multiple samples during interlaboratory validation studies . finally ,
using the miniaturized ni assay with hamismatched viruses , ni titers against n1newcal/99 and n2wis/05 homologous to the vaccine antigens were determined in sera from human volunteers , before and after immunization with tiv or laiv vaccines ( table 3 ) .
prior to vaccination , ni titers against n1 ranged from < 5 to 160 , whereas titers against n2 ranged from < 5 to 80 .
increases in ni antibody titers against n1 were detected in five of 16 laiv recipients and six of 16 tiv recipients .
titers against n2 were increased in six of 16 laiv recipients and seven of 16 tiv recipients . in the two groups combined , there were six individuals with rises in titer against both n1 and n2 , five with a rise in titer against only n1 , and seven with a rise in titer against only n2 .
there were 14 individuals ( 44% ) in this study with no rise in titer against either na . despite the considerable range in ni titers detected among individuals , most of the responders to either antigen had only twofold increases in ni titer , with a few instances of fourfold increases ( three of 64 total comparisons ) .
there were also three instances in which an ni titer in postvaccination serum was twofold lower than the titer in prevaccination serum .
subtypespecific ni titers in human volunteers pre and postimmunization with seasonal trivalent influenza vaccines * laiv , liveattenuated influenza vaccine ; tiv , trivalent inactivated vaccine ; ni , neuraminidase inhibition ; gmt , geometric mean titer . * sera assayed against h6n1newcal/99 and h6n2wis/05 antigens .
influenza vaccine evaluation could be enhanced by monitoring functional antibody responses to na , in tandem with haspecific antibody analysis .
one hindrance to the widespread adoption of na antibody monitoring is the lack of suitable highthroughput serological assays . in this study , we have successfully reduced the scale of the traditional ni assay in which sialic acid molecules cleaved from fetuin substrate are measured using periodatetba chemical reactions .
there have been no fundamental changes in the nature or theory underlying the miniassay procedure .
we have shown that the miniaturized assay retains the na subtype specificity of the conventional format , and consistent , robust signals are obtained using proportionally less viral antigen .
consequently , the miniaturized assay is generally more sensitive to antibodymediated inhibition . in the event that speed of assay completion
is a top priority it is possible to perform the miniaturized assay with a 2hour virusfetuin incubation , rather than overnight .
when using the shorter incubation time , a greater concentration of viral antigen is required for robust signal readings , and this reduces the assay s sensitivity .
practical advantages for our miniaturized ni assay format compared with the conventional format include a marked increase in sample throughput , a 10fold reduction in the volume of serum required for ni titration , and greater safety in handling samples in 96well plates rather than racks of open tubes .
the small reaction volume is conducive to handling chemical reagents under the protection of a standard fume hood , and incubations outside of the fume hood can be contained by disposable plate sealers or cap strips .
furthermore , the volume of chemical waste generated per sample analyzed is reduced by approximately 20fold . the need for a large capacity boiling water bath
is eliminated , and the equipment necessary for the miniaturized assay format , including a pcr thermocycler ( or simple heat block ) for heating and a photometric plate reader , are generally available .
neuraminidase inhibition assay results can be distorted by haspecific antibodies interfering with substrate cleavage by na .
we therefore cloned ha of an h6 virus for cotransfection with the contemporary n1 or n2 na genes in construction of reassortant viruses to serve as antigens in the ni assay .
given the general absence of human immunity to h6 influenza viruses , human serological studies performed with these constructs are unlikely to be affected by haspecific antibodies .
these , or other reverse geneticsderived viruses designed with alternate ha genes , offer the same utility for quantification of ni antibody responses in laboratory animals following vaccination or challenge .
we utilized the miniaturized assay and reverse geneticsderived antigen reagents to assay ni titers against n1newcal/99 and n2wis/05 in pre and postvaccination sera of tiv and laiv recipients in a small clinical trial .
the na antigens were homologous to the h1n1 and h3n2 strains represented in the vaccines .
most individuals had positive ni titers against both na subtypes prior to vaccination , but titers varied substantially . whether examining n1newcal/99 or n2wis/05specific ni titers , both vaccine formulations elicited rises in titer in 3045% of the recipients , and similar response rates were associated with tiv and laiv . among the five individuals without initially
instances of twofold rises in titer against either na subtype far outnumbered fourfold rises , and none were greater than fourfold , despite the assay s capacity to detect much wider differences between individuals .
thus , both vaccines showed the capacity to induce ni antibodies , but it does not appear that either vaccine elicited particularly robust ni responses in this small trial .
the percentages of volunteers with antih1 and antih3 antibody responses to vaccination using the conventionally defined parameter of a fourfold rise in hai titer were comparable to ni response rates . probably reflecting preexisting titers , both vaccines induced fourfold hai titer increases in fewer than onethird of recipients , with respect to both h1 and h3 ( hassantoufighi and eichelberger , unpublished data ) .
the lower magnitude of ni titers in most human volunteers , even after tiv vaccination , may result from a low quantity of conformationally intact na protein in the vaccine formulation .
this parameter is not standardized or routinely monitored for stability . in the case of laiv , enzymatically active na should be expressed by virus replicating in vivo , but the amount of expression is not known .
there were isolated instances of twofold lower ni antibody titers in postvaccination serum compared with prevaccination serum .
however , calculating 50% endpoint titers for these sera by nonlinear regression showed that the difference in titer was only statistically significant in one of these three pairs .
assigning ni titers as the reciprocal of the highest dilution observed to inhibit na activity by at least 50% has the advantage of simplicity , but a drawback is that two samples which both reach 50% inhibition very near one of the dilutions may be assigned twofold different titers .
conversely , a pair of samples with a small difference in ni activity may be assigned the same titer .
the alternative approach of calculating 50% endpoint titers by nonlinear curve fitting precludes these errors .
however , high accuracy with this approach requires assaying across a wide range of dilutions , which restricts the output of the assay . the size and variability of a data set and
the aims of a study may be important considerations in the choice of method to assign ni titers .
development of improved methodologies for evaluation of the immune responses elicited by modern influenza vaccines is clearly a desirable objective .
ni antibody level has been shown to correlate with protection against seasonal influenza in clinical trials ,
,
which points to the potential value of monitoring ni titers as part of seasonal and prepandemic influenza vaccine evaluation
. it may be worth particular consideration in the context of prepandemic vaccines because the antigenic structure of the ha contained within a stockpiled prepandemic vaccine may differ from the strain that becomes transmissible in the human population , reducing the capacity of haspecific antibodies alone to mediate protection . because it measures functional inhibition , the conventional tba assay for antibodies that inhibit na has clear relevance to immunity in vivo .
,
,
however , the inefficiency of the standard method has been a serious hindrance to its widespread use . by miniaturizing the method to a microplate format and in the process enhancing its sensitivity to serum ni activity
in addition , this provides an effective means for comparing new methods to quantify naspecific antibody responses with the traditional assessment of na inhibition .
Output:
| background antibodies to neuraminidase ( na ) contribute to protection during influenza virus infection , but na inhibition ( ni ) titers are not routinely analyzed in vaccine trials .
one reason is the cumbersome nature of the conventional thiobarbituric acid ( tba ) ni assay , which uses chemical methods to quantify free sialic acid following incubation of na with substrate in the presence of serum .
in addition , the assay is complicated by the need to use virus of a hemagglutinin ( ha ) subtype novel to the host to detect naspecific antibodies only .
objectives our primary objectives were to miniaturize the colorimetric ni assay to a format suitable for quantitative analysis of large numbers of samples , and validate the specificity and sensitivity of the miniaturized format with ferret and human sera .
an additional aim was to use reverse genetics to construct hamismatched viral reagents bearing na of recent influenza a vaccine strains and h6 ha .
results analysis of ferret antisera by the miniaturized assay demonstrated sensitivity and specificity comparable with the conventional assay .
similar increases in the ni titers in sera from vaccinated human volunteers were measured in miniaturized and conventional assays . inactivated and liveattenuated vaccines increased ni titers against a given subtype at approximately the same rate .
conclusions the reagents and miniaturized format of the tba method described here provide a platform for practical serological monitoring of functional antibodies against na . |
PubmedSumm4816 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the somatosensory amplification scale ( ssas ) is a 10-item self - report instrument designed to assess a tendency to experience normal somatic and visceral sensations as intense , noxious , and disturbing ( 1 ) .
the concept of somatosensory amplification involves self - examination , increased attention , and vigilance to unpleasant somatic sensations , a predisposition to observe weak and rare somatic sensations and a tendency to interpret them as dangerous signs of disease without any rational cause ( 2 ) .
therefore , somatosensory amplification may have 3 main components : 1 ) hyper vigilance towards unpleasant bodily sensations ; 2 ) tendency to select and focus on certain relatively weak or infrequent sensations ; and 3 ) tendency to appraise ambiguous or vague visceral and somatic sensations as abnormal and symptomatic of disease , rather than considering them to be normal ( 3 ) .
the construct of somatic amplification is useful for the comprehension of functional somatic symptoms such as those seen in somatoform disorders , especially hypochondriasis ( 2 , 4 , 5 ) .
somatosensory amplification is important even in the organic symptoms of serious medical diseases because it may explain the variability of the symptom reports in different individuals with the same organ pathology ( 6 ) such as chronic pain ( 7 , 8) , upper respiratory tract infections ( 9 ) , migraine ( 10 ) , and inflammatory bowel diseases ( 11 ) .
moreover , amplification may be a pathogenic mechanism in amplification disorders such as fibromyalgia ( 1 ) and functional gastrointestinal disorders such as irritable bowel syndrome ( 1 ) and functional dyspepsia ( 12 , 13 ) .
therefore , the concept of somatosensory amplification is noticeable since it gives a clearer understanding of why somatic symptoms are disproportionate to certain organ pathology ( 14 ) .
moreover , it can highlight the pathogenic role of somatosensory amplification in somatization ( 15 , 16 ) and currently , health anxiety process ( 17 ) .
there are versions of the ssas in several languages such as spanish , korean , japanese , italian , turkish , hungarian , and french ( 14 ) , and the reliability and validity of these versions have been previously demonstrated .
( 1 ) , and it had good internal consistency ( cronbach s = 0.82 ) . while the test - retest reliability for the 10-item scale was 0.79 , its item - to - scale correlations varied between 0.31 and 0.66 and all were highly significant . also ,
its item - to - item correlations varied from between not significant to 0.60 , but most were in the range of 0.35 and were highly significant ( 18 ) .
( 2 ) specified that the ssas is only suitable for the samples of medical outpatients ( 2 ) , more recently , an assessment of the validity and reliability of the french adaptation of the ssas showed good internal consistency ( cronbach s = 0.81 ) in a non - clinical population ( 14 ) .
furthermore , the turkish version of the ssas was valid both for healthy individuals and patients and just reliable for healthy individuals ( 19 ) .
spinhoven and van der does ( 19 ) observed that the ssas is correlated with somatization ( subscale of the symptom checklist 90 revised [ scl-90-r som ] ) and that this correlation is not dependent on gender , presence of physical illness , and depression scores .
( 9 ) demonstrated that the ssas is significantly associated with all somatic symptoms . according to aronson et al .
( 15 ) , the ssas is not a measure for the evaluation of somatic sensitivity as an index of negative emotionality or general distress .
also , wise and mann ( 20 ) explained that the ssas focuses particularly upon a perceptual style as a strong predictor of neuroticism .
however , there are conflicts in the convergent and discriminant validity of this instrument , especially in somatization tendency .
also , the ssas has been employed in more investigations as an instrument that assesses a single construct ( i.e. the items are summed ) , and there has been little effort to investigate the factorial solution of the instrument .
bridou and aguerre ( 14 ) assessed the principal component and confirmatory factor analyses of the ssas and suggested that the french version of the ssas evaluates essentially a single and robust factor ( somatosensory amplification ) .
we hypothesized that somatosensory amplification is an appropriate index of somatization propensity ( convergent validity ) and this construct is different between patients with functional somatic syndrome and healthy groups ( discriminant validity ) .
the present study aimed to evaluate the validity and reliability and especially the factorial solution of the farsi version of the ssas among patients with functional gastroenterological disorders .
a forward and backward translation procedure was used for adapting the original american version of the ssas in an iranian patient population .
first , one bilingual gastroenterologist ( one of the authors of this article ) translated the ssas from english into persian .
this preliminary version was evaluated by 2 psychologists ( the authors of this article ) , who discussed and corrected discrepancies and cultural adaptations .
then , a back - translation was carried out by a second professional translator to verify that our version matched the original version .
finally , the face validity of the ssas was confirmed by 5 specialists ( one gastroenterologist , one psychiatrist , and 3 psychologists , who work in the health psychology context ) .
the study was carried out on patients with functional gastrointestinal disorders diagnosed based on the rom - iii criteria referring to the outpatient psychosomatic clinic of isfahan medical university and the gastroenterologist s office ( participating in this study ) during a 10-month period from may 2013 to march 2014 .
totally , 240 patients with functional gastrointestinal disorders by filling 3 questionnaires ( i.e. the ssas , scl-90-r som , and modified somatic perception questionnaire [ mspq ] ) , and 30 healthy persons by filling only one questionnaire ( the ssas ) participated in the study .
the exclusion criteria were comprised of : 1 ) having serious medical diseases , 2 ) age less than 18 and more than 60 years , 3 ) not being fluent in the persian language , 4 ) education less than high school , and 5 ) not giving informed consent .
the protocol of the study was approved by the ethics committee of isfahan university medical sciences and was clarified for all the participants .
respondents are asked to rate the degree to which each assertion is characteristic of them in general on an ordinal scale from 1 ( not at all true ) to 5 ( extremely true ) . in the original version ,
a total amplification score is obtained by adding the scores ( ranging from 10 to 50 ) .
each self - reported item was rated on a scale of 0 ( not at all distressed by the item ) to 4 ( extremely distressed by the item ) .
the participants were asked to describe the intensity of symptoms experienced during the previous week , with a higher score denoting a greater somatization propensity .
the reliability and validity of the farsi version of the scl-90-r som have been previously validated in many investigations ( 21 ) .
the mspq was administered to measure somatic arousal ( heightened autonomic or somatic awareness ) .
it can help identify somatic complaints that may be associated with psychological responses such as anxiety or depression .
the mspq is a self - rating scale in which 13 somatic symptoms are rated on 4-point scales ( 0 not all ; 3 extremely ) .
the total score ranges from 0 to 39 , with higher scores indicating a greater risk of somatization .
the participant is asked to rate how often he or she has experienced somatic symptoms during the past week .
investigations have shown that the mspq is psychometrically an instrument with adequate validity and reliability ( 22 - 24 ) . recently ,
good internal consistency ( cronbach s = 0.80 ) of the farsi version the mspq has been demonstrated ( 25 ) .
an exploratory factor analysis was used to reveal any latent variables within the ssas that caused the manifest variables to covary . to ensure that the characteristics of the data set were suitable for the factor analysis to be conducted on the functional gastrointestinal disorders sample , the kaiser - meyer - olkin ( kmo ) measure of sampling adequacy and the bartlett test of sphericity ( bts )
a maximum likelihood factor extraction procedure with varimax rotation was employed since this approach is particularly useful in extracting psychologically meaningful factors and because of the possibility that the extracted factors may be correlated . the screen test and multiple test runs were used to decide the number of meaningful factors that might be in the data set .
cronbach s was used to investigate internal reliability , and 0.70 was considered as the minimum acceptable criterion of the instrument s internal reliability . the scale was given to 30 of the same functional gastrointestinal patients after one month to assess the test - retest consistency .
the pearson correlations were calculated to analyze the test - retest reliability and the relationships between somatosensory amplification and somatization in order to test the convergent validity .
the analysis of variance ( anova ) was used to measure the total scale of the discriminant validity for the groups in the study ( patients and the healthy group ) .
chicago , il , usa ) was used for the statistical analyses of the study data .
a forward and backward translation procedure was used for adapting the original american version of the ssas in an iranian patient population .
first , one bilingual gastroenterologist ( one of the authors of this article ) translated the ssas from english into persian .
this preliminary version was evaluated by 2 psychologists ( the authors of this article ) , who discussed and corrected discrepancies and cultural adaptations .
then , a back - translation was carried out by a second professional translator to verify that our version matched the original version .
finally , the face validity of the ssas was confirmed by 5 specialists ( one gastroenterologist , one psychiatrist , and 3 psychologists , who work in the health psychology context ) .
the study was carried out on patients with functional gastrointestinal disorders diagnosed based on the rom - iii criteria referring to the outpatient psychosomatic clinic of isfahan medical university and the gastroenterologist s office ( participating in this study ) during a 10-month period from may 2013 to march 2014 .
totally , 240 patients with functional gastrointestinal disorders by filling 3 questionnaires ( i.e. the ssas , scl-90-r som , and modified somatic perception questionnaire [ mspq ] ) , and 30 healthy persons by filling only one questionnaire ( the ssas ) participated in the study .
the exclusion criteria were comprised of : 1 ) having serious medical diseases , 2 ) age less than 18 and more than 60 years , 3 ) not being fluent in the persian language , 4 ) education less than high school , and 5 ) not giving informed consent .
the protocol of the study was approved by the ethics committee of isfahan university medical sciences and was clarified for all the participants .
the ssas is a 10-item scale developed by barsky et al . ( 1 ) , and its validity and reliability have been previously demonstrated .
respondents are asked to rate the degree to which each assertion is characteristic of them in general on an ordinal scale from 1 ( not at all true ) to 5 ( extremely true ) . in the original version ,
a total amplification score is obtained by adding the scores ( ranging from 10 to 50 ) .
each self - reported item was rated on a scale of 0 ( not at all distressed by the item ) to 4 ( extremely distressed by the item ) .
the participants were asked to describe the intensity of symptoms experienced during the previous week , with a higher score denoting a greater somatization propensity .
the reliability and validity of the farsi version of the scl-90-r som have been previously validated in many investigations ( 21 ) .
the mspq was administered to measure somatic arousal ( heightened autonomic or somatic awareness ) .
it can help identify somatic complaints that may be associated with psychological responses such as anxiety or depression .
the mspq is a self - rating scale in which 13 somatic symptoms are rated on 4-point scales ( 0 not all ; 3 extremely ) .
the total score ranges from 0 to 39 , with higher scores indicating a greater risk of somatization .
the participant is asked to rate how often he or she has experienced somatic symptoms during the past week .
investigations have shown that the mspq is psychometrically an instrument with adequate validity and reliability ( 22 - 24 ) . recently ,
good internal consistency ( cronbach s = 0.80 ) of the farsi version the mspq has been demonstrated ( 25 ) .
an exploratory factor analysis was used to reveal any latent variables within the ssas that caused the manifest variables to covary . to ensure that the characteristics of the data set were suitable for the factor analysis to be conducted on the functional gastrointestinal disorders sample , the kaiser - meyer - olkin ( kmo ) measure of sampling adequacy and the bartlett test of sphericity ( bts ) were conducted on the data . a maximum likelihood factor extraction procedure with varimax rotation
was employed since this approach is particularly useful in extracting psychologically meaningful factors and because of the possibility that the extracted factors may be correlated . the screen test and multiple test runs were used to decide the number of meaningful factors that might be in the data set .
cronbach s was used to investigate internal reliability , and 0.70 was considered as the minimum acceptable criterion of the instrument s internal reliability . the scale was given to 30 of the same functional gastrointestinal patients after one month to assess the test - retest consistency .
the pearson correlations were calculated to analyze the test - retest reliability and the relationships between somatosensory amplification and somatization in order to test the convergent validity .
the analysis of variance ( anova ) was used to measure the total scale of the discriminant validity for the groups in the study ( patients and the healthy group ) .
, chicago , il , usa ) was used for the statistical analyses of the study data .
the study was carried out on 240 patients with functional gastrointestinal disorders and 30 healthy persons .
the gender distribution was 81.7% female and 17.3% male in the patient group and 86% female and 14% male in the healthy group .
the age range of the patients was between 18 and 60 years , and the mean age was 35.14 11.72 years . in the healthy group ,
the age range was between 21 and 54 years , and the mean age was 35.50 5.44 years .
most of the subjects in both groups were college educated ( 58.3% of the patients and 64% of the healthy persons ) .
the diagnosis was irritable bowel syndrome in 87.5% of the patients and functional dyspepsia in 24% .
the descriptive statistics of the ssas scores in the patient group showed that mean and standard deviation of the ssas scores were 34.68 and 5.82 , respectively .
the kaiser measure of sampling adequacy yielded an index of 0.77 , and the bts was significant ( = 372.5 , df = 45 , p < 0.001 ) .
this preparatory analysis confirmed that the data distribution satisfied the psychometric criteria for the factor analysis to be performed . to assess the underlying structure for the 10 items of the ssas , factor extraction with maximum likelihood and varimax rotation were employed .
the results of these analyses showed that the one - factor solution accounted for accumulatively 29.42% of the variance . in this model ,
the factor loadings of all the items except item 2 ( i am often aware of various things happening within my body ) were significant and ranged from 0.35 to 0.68 .
the 2-factor solution accounted for accumulatively 41.20% of the variance and the 3-factor solution , 51.77% of the variance .
however , both model contained one low - loading and one factor with only 2 items .
the one - factor model denoted that the ssas items were represented by one global dimension called somatosensory amplification .
the reliability of the ssas was evaluated by internal consistency ( cronbach s ) and test - retest consistency .
the internal consistency , item total correlation , if item deleted , and test - retest consistency values are given in table 2 .
cronbach s value of the ssas for the patients with functional gastrointestinal disorders was calculated to be 0.78
. when each item was considered , the item - to - scale correlations varied from 0.17 to 0.55 .
it was notable that the correlation for item 2 was low ( r = 0.17 ) .
furthermore , the test - retest reliability for the total scale of the ssas , after an interval of one month , was assessed in 30 of the same patients . according to the results in table 2 , the farsi version of the ssas
was noted to be strongly correlated at a level of 0.80 and established to be consistent .
the convergent validity of the ssas with somatization was examined using 2 instruments ( i.e. the somatization subscale of the scl-90-r som and the mspq ) in the patient group ( table 3 ) . as was anticipated , the correlations between somatosensory amplification and somatization by the scl-90-r som ( r = o.360 , p = 0.049 ) , and mspq ( r = 0.522 , p = 0.003 ) were positively significant at a moderate level .
abbreviations : mspq , modified somatic perception questionnaire ; scl , symptom checklist ; ssas , somatosensory amplification scale . for the discriminant validity
, the total sores of the ssas were compared between the patient and healthy groups .
the results of the anova analysis showed no significant difference between the two groups ( table 4 ) .
the study was carried out on 240 patients with functional gastrointestinal disorders and 30 healthy persons .
the gender distribution was 81.7% female and 17.3% male in the patient group and 86% female and 14% male in the healthy group .
the age range of the patients was between 18 and 60 years , and the mean age was 35.14 11.72 years . in the healthy group ,
the age range was between 21 and 54 years , and the mean age was 35.50 5.44 years .
most of the subjects in both groups were college educated ( 58.3% of the patients and 64% of the healthy persons ) .
the diagnosis was irritable bowel syndrome in 87.5% of the patients and functional dyspepsia in 24% .
the descriptive statistics of the ssas scores in the patient group showed that mean and standard deviation of the ssas scores were 34.68 and 5.82 , respectively .
the kaiser measure of sampling adequacy yielded an index of 0.77 , and the bts was significant ( = 372.5 , df = 45 , p < 0.001 ) .
this preparatory analysis confirmed that the data distribution satisfied the psychometric criteria for the factor analysis to be performed . to assess the underlying structure for the 10 items of the ssas , factor extraction with maximum likelihood and varimax rotation were employed .
the results of these analyses showed that the one - factor solution accounted for accumulatively 29.42% of the variance . in this model ,
the factor loadings of all the items except item 2 ( i am often aware of various things happening within my body ) were significant and ranged from 0.35 to 0.68 .
the 2-factor solution accounted for accumulatively 41.20% of the variance and the 3-factor solution , 51.77% of the variance .
however , both model contained one low - loading and one factor with only 2 items .
the one - factor model denoted that the ssas items were represented by one global dimension called somatosensory amplification .
the reliability of the ssas was evaluated by internal consistency ( cronbach s ) and test - retest consistency . the internal consistency ,
item total correlation , if item deleted , and test - retest consistency values are given in table 2 .
cronbach s value of the ssas for the patients with functional gastrointestinal disorders was calculated to be 0.78
. when each item was considered , the item - to - scale correlations varied from 0.17 to 0.55 .
it was notable that the correlation for item 2 was low ( r = 0.17 ) .
furthermore , the test - retest reliability for the total scale of the ssas , after an interval of one month , was assessed in 30 of the same patients . according to the results in table 2 ,
the farsi version of the ssas was noted to be strongly correlated at a level of 0.80 and established to be consistent .
the convergent validity of the ssas with somatization was examined using 2 instruments ( i.e. the somatization subscale of the scl-90-r som and the mspq ) in the patient group ( table 3 ) . as was anticipated , the correlations between somatosensory amplification and somatization by the scl-90-r som ( r = o.360 , p = 0.049 ) , and mspq ( r = 0.522 , p = 0.003 ) were positively significant at a moderate level .
abbreviations : mspq , modified somatic perception questionnaire ; scl , symptom checklist ; ssas , somatosensory amplification scale .
for the discriminant validity , the total sores of the ssas were compared between the patient and healthy groups .
the results of the anova analysis showed no significant difference between the two groups ( table 4 ) .
the exploratory factor analysis of the ssas demonstrated that a one - factor solution had the best fit for the data , accounting for approximately 29.42% of the variance .
our results support the hypothesis that the ssas has a single dimension representing somatosensory amplification .
furthermore , it could be used to measure somatosensory amplification in patients with functional gastrointestinal disorders .
the findings are consistent with the original version of the ssas , designed for the measurement of one factor , i.e. somatosensory amplification , in medical outpatients ( 2 ) . only a few studies have hitherto been conducted for the factor analysis of the ssas , and most studies have used the scale as a one construct ( 3 , 5 - 7 , 9 , 10 , 13 , 18 ) .
the exploratory and conformity factor analysis of the french version of the ssas suggested that this scale evaluates essentially a single and robust factor ( somatosensory amplification ) and 2 kinds of somatic sensitivity ( i.e. exteroceptive sensitivity and interoceptive sensitivity ) ( 14 ) .
therefore , the farsi version of the ssas also evaluates one factor as somatosensory amplification . to test the reliability of the ssas ,
cronbach s coefficient for internal consistency analysis was calculated to be 0.78 for the patients with functional gastrointestinal disorders . while barsky et al .
( 2 ) established cronbach s to be 0.82 in medical outpatients , often studies have reported the similar internal consistency .
( 26 ) demonstrated the coefficient to be 0.77 in a hospital sample , 0.64 in patients in primary care , and 0.71 in the general population .
elsewhere , gulec and sayar ( 18 ) reported the coefficient to be 0.76 in an outpatient group and 0.62 in a healthy group .
although the internal consistency in the present study was not very good , it can be considered acceptable .
the item total correlations were 0.17 - 0.55 in the patient group . it was also noted that item number 2 had the lowest correlation with the scale ( r = 0.17 ) and the coefficient of the ssas increased when this item was deleted .
this may be due to cultural differences or translation problems inasmuch as this item may have been incomprehensible to iranian subjects .
therefore , it seems advisable that this item be removed from the farsi version of the ssas .
the test - retest consistency of the 10-item ssas was evaluated by giving the scale to 30 of the same patients with functional gastrointestinal disorders after an interval of one month .
there was a positive correlation of 0.80 between the total scores of the 2 tests .
this finding is consistent with the results of an original study by barsky et al .
the authors reported the test - retest reliability after an interval of between one and 6 weeks ( r = 0.79 ) . in another study , gulec and sayar ( 18 ) reported a test - retest correlation of 0.73 in healthy university students after an interval of one month . based on these findings
the evaluation of the convergent validity with somatization was conducted by giving the patients the mspq and the scl-90-r som subscale . as was expected
, there were correlations between the total scores on the mspq , the scl-90-r som subscale , and the total scores on the ssas .
the results indicated that these correlations were moderate by the scl-90-r som ( r = o.360 , p < 0.05 ) and mspq ( r = 0.522 , p < 0.001 ) . while wise and mann ( 20 ) posited that there is a link between somatization and amplification independent of depression and anxiety , aronson et al .
( 15 ) demonstrated that the ssas is more likely to be an index of negative emotionality and general distress than a valid measure of somatic sensitivity . in the present study ,
we also evaluated somatization using a different questionnaire ( i.e. the mspq ) , which measures somatic arousal allied to psychological responses such as anxiety or depression .
the positive correlation between the ssas and the mspq in our study suggests that the ssas is not independent of psychological responses , although it is a reliable indicator of somatization .
finally , our assessment of the discriminant validity showed no significant difference between the patients and the control group . while barsky et al .
( 2 ) specified that the ssas is only suitable for medical outpatients , some studies have demonstrated the validity and reliability of the ssas in non - clinical populations ( 14 , 15 , 18 ) .
our results suggest that the ssas is not specific to patient populations , although we did not examine its psychometric properties in our healthy group .
several limitations in the current study need to be addressed . first , with respect to the discriminant validity
second , the validity and reliability of the ssas were not evaluated in the healthy group for comparison with the patients .
third , the test - retest reliability of the ssas was examined in a limited population of patients with functional gastrointestinal disorders .
further research is needed to examine cross - cultural differences and to compare men and women in their amplification of somatic information .
also , the ssas should be evaluated in various clinical populations such as people suffering from psychological problems ( e.g. depression , anxiety , and somatoform disorders ) , patients with various functional somatic syndromes , and patients with serious medical diseases ( e.g. chronic pains and infections ) as well as in non - clinical populations in iran .
our results demonstrated that the ssas is valid and reliable for patients with functional gastrointestinal disorders in the iranian population .
a single factor model is the best model for the evaluation of somatosensory amplification and the farsi version of the ssas seems to assess the same construct as the original scale .
this scale is an appropriate indicator of somatization and is not specific to patient populations .
Output:
| background : the somatosensory amplification scale ( ssas ) is a 10-item self - report instrument designed to assess a tendency to experience normal somatic and visceral sensations as intense , noxious , and disturbing.objectives:the present study investigated the reliability and validity of the ssas , developed by barsky et al . ( 1988 ) , in the iranian population.materials and methods : the study was carried out on 240 patients with functional gastrointestinal disorders and 30 healthy persons selected by convenience sampling from 2013 to 2014 .
the patients completed the ssas , the somatization subscale of the symptom checklist-90-revised ( scl-90-r som ) , and the modified somatic perception questionnaire ( mspq ) , whereas the healthy persons completed just the ssas.results:exploratory factor analysis indicated that the one - factor solution , accounting for 29.42% of the variance , explained that the ssas items were represented by one global dimension .
the ssas had acceptable internal consistency ( = 0.78 ) and good test - retest reliability ( r = 0.80 ) .
the item - to - scale correlations varied from 0.17 to 0.55 .
item 2 had the lowest item - total score correlation ( r = 0.17 ) , and the coefficient for the ssas exceeded when this item was deleted .
the convergent validity of the ssas with somatization was shown with a significant correlation between the ssas , scl-90-r som ( r = 0.36 ) , and mspq scores ( r = 0.52 ) .
discriminant validity analysis showed no significant difference in the ssas between the patient and control groups ( p > 0.05 ) and non - specificity of the ssas for patients.conclusions:in sum , the ssas has acceptable reliability and validity for the iranian population and the scale measures the same the original scale , namely somatosensory amplification . |
PubmedSumm4817 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: acute brain injury is a major cause of morbidity and mortality which correlates partly to the initial cerebral insult ( 1 ) .
following traumatic brain injury ( tbi ) , the function of some organs is impaired , contributing to a worse outcome .
systemic inflammatory response syndrome ( sirs ) is commonly encountered following acute brain injury . the gastrointestinal tract is frequently affected within sirs .
distorted motility , gastrointestinal bleeding , splanchnic ischemia , gut hyperpermeability and bacterial translocation have been described as the acute brain injury consequences ( 2 ) .
nonsteroidal anti - inflammatory drugs ( nsaids ) are the most frequently used drugs in inflammatory diseases , since they are helpful in management of the pain , fever , redness , and edema arising as a result of inflammatory mediator liberation ( 3 ) .
studies have shown that both therapeutic and side effects of nsaids are dependent on cyclooxygenase ( cox ) inhibition ( 4 ) .
it has been proposed that cox-2 inhibition is responsible for the therapeutic effects of nsaids , while cox-1 inhibition causes the gastrointestinal and renal side effects ( 5 ) . in spite of , similar amino acid sequence and catalytic activity of two cox isoforms , they were demonstrated to have different roles .
cox-1 catalyzes the construction of cyto - protective prostaglandins ( pgs ) in thrombocytes , vascular endothelium , stomach mucosa , kidneys , pancreas , langerhans islets , and brain .
cox-1 products ( prostaglandins ( pgi2 and pge2 ) ) , keeps integrity of gastrointestinal tract by reducing gastric acid secretion , increasing the thickness of mucus layer , stimulating bicarbonate secretion , and enhancing mucosal blood flow ( 7 , 8)
. drugs , which inhibit cox-1 more than cox-2 , such as indomethacin , naproxen , and ibuprofen , cause more severe damage to the gastric tissues . as a result of studies focused on reduction of the adverse effects of nsaids , selective cox-2 inhibitors , such as celecoxib and rofecoxib , have been developed ( 9 ) .
selective inhibitors of cox-2 are drugs in which therapeutic effects are as strong as conventional nsaids but would lead to fewer side effects ( 10 ) .
they possess analgesic , antipyretic and anti - inflammatory effects as potent as traditional antiinflammatory drugs .
it has been reported that these drugs do not induce any damage to the stomach tissue ( 12 ) .
while the effects of selective and non - selective cox inhibitors on gastric mucosal integrity are the subject of continued investigation , there is little information about the specific effect of cox-1 and cox-2 inhibitors on gastrointestinal motility following traumatic brain injury . in the present study
, we evaluated the effects of cox-2 selective inhibitor ( celecoxib ) or non - selective cox inhibitor ( ibuprofen ) on gastrointestinal motility , using gastric emptying and intestinal transit model after the induction of traumatic brain injury .
male wistar rats ( 250 to 300 g ) were purchased from animal center of kerman university of medical sciences , iran .
the rats were housed in temperature and humidity controlled animal quarters with a 12 hr light / dark cycle .
all procedures were approved by the institutional animal care committee of kerman university and were in accordance with the guidelines of the national institutes of health on the care and use of animals surgery .
the rats were randomly divided into five groups ( 7 rats in each group ) : 1 ) intact group : the animals that were not given any drugs ; 2 ) sham group : sham operated rats , but without actual induction of tbi ; 3)tbi group : intact rats injured using the traumatic brain injury device ; 4 ) celecoxib group : gavaged with celecoxib ( 10 mg / kg ) at 1 hr before the tbi induction ( 13 ) ; 5 ) iboprofen group : gavaged with ibuprofen ( 10 mg / kg ) at 1 hr before the tbi induction ( 14 ) .
the process of the tbi induction ( made by department of physiology , kerman university of medical sciences ) was as follows : a 250 g weight was dropped from a 2 meter height on the head of the anesthetized rat ( with halothane in an mixture of 70% n2o / 30% o2 gas ) when a metal disc ( stainless steel ) 10 mm in diameter and 3 mm thick is attached on the animals skull .
after the induction of trauma , the rats were immediately connected to animals respiratory pump ( tsa animal respiratory compact , germany ) .
phenol red indicator ( 25 mg ) was dissolved in 50 ml of distilled water and filtered .
the filtrate was heated to 70c and methylcellulose ( 0.75 g ) was added to it with continuous stirring .
the standard method of phenol red marker meal accomplished by earlier workers , was used .
rats were deprived of food for 24 hr prior to experimentation but had free access to water , and 0.5 ml of phenol red meal was administered by the aid of the oral feeding syringe .
animals were killed by cervical dislocation under intravenous thiopentone sodium anesthesia 15 min after the administration of the meal .
abdomen was opened and stomach was dissected out after careful ligation at the cardiac and pyloric ends , and was washed with normal saline .
then , 0.5 ml of trichloroacetic acid ( 20 % w / v ) was added to 5 ml homogenate and centrifuged at 3000 rpm for 20 min .
this correlates with the concentration of phenol red in the stomach , which in turn depends upon the gastric emptying .
the percentage gastric emptying is derived as ( 1-x / y ) 100 where , x is absorbance of phenol red recovered from the stomach of animals sacrificed 15 min after test meal .
y is mean ( n=5 ) absorbance of phenol red recovered from the stomachs of control animals ( killed at 0 min following test meal ) ( 16 ) .
the small intestine was dissected out from the pylorus and ileocaecal junction and the point to which meal had traversed was secured with thread to avoid change in the length of the transit due to handling .
the total length of the small intestine and distance traveled by phenol red meal was measured .
the small intestinal transit ( sit ) was calculated considering the distance traveled by phenol red meal divided by total length of the small intestine , multiplied by 100 .
each parameter was expressed as mean sem , and compared using one - way analysis of variance ( anova ) , followed by least significant difference ( lsd ) test .
male wistar rats ( 250 to 300 g ) were purchased from animal center of kerman university of medical sciences , iran .
the rats were housed in temperature and humidity controlled animal quarters with a 12 hr light / dark cycle .
all procedures were approved by the institutional animal care committee of kerman university and were in accordance with the guidelines of the national institutes of health on the care and use of animals surgery .
the rats were randomly divided into five groups ( 7 rats in each group ) : 1 ) intact group : the animals that were not given any drugs ; 2 ) sham group : sham operated rats , but without actual induction of tbi ; 3)tbi group : intact rats injured using the traumatic brain injury device ; 4 ) celecoxib group : gavaged with celecoxib ( 10 mg / kg ) at 1 hr before the tbi induction ( 13 ) ; 5 ) iboprofen group : gavaged with ibuprofen ( 10 mg / kg ) at 1 hr before the tbi induction ( 14 ) .
all animals were intubated before the tbi induction . the tbi was moderate and diffused using the marmarou method .
the process of the tbi induction ( made by department of physiology , kerman university of medical sciences ) was as follows : a 250 g weight was dropped from a 2 meter height on the head of the anesthetized rat ( with halothane in an mixture of 70% n2o / 30% o2 gas ) when a metal disc ( stainless steel ) 10 mm in diameter and 3 mm thick is attached on the animals skull . after the induction of trauma , the rats were immediately connected to animals respiratory pump ( tsa animal respiratory compact , germany ) .
phenol red indicator ( 25 mg ) was dissolved in 50 ml of distilled water and filtered .
the filtrate was heated to 70c and methylcellulose ( 0.75 g ) was added to it with continuous stirring .
the standard method of phenol red marker meal accomplished by earlier workers , was used .
rats were deprived of food for 24 hr prior to experimentation but had free access to water , and 0.5 ml of phenol red meal was administered by the aid of the oral feeding syringe .
animals were killed by cervical dislocation under intravenous thiopentone sodium anesthesia 15 min after the administration of the meal .
abdomen was opened and stomach was dissected out after careful ligation at the cardiac and pyloric ends , and was washed with normal saline .
then , 0.5 ml of trichloroacetic acid ( 20 % w / v ) was added to 5 ml homogenate and centrifuged at 3000 rpm for 20 min .
this correlates with the concentration of phenol red in the stomach , which in turn depends upon the gastric emptying .
the percentage gastric emptying is derived as ( 1-x / y ) 100 where , x is absorbance of phenol red recovered from the stomach of animals sacrificed 15 min after test meal .
y is mean ( n=5 ) absorbance of phenol red recovered from the stomachs of control animals ( killed at 0 min following test meal ) ( 16 ) .
the small intestine was dissected out from the pylorus and ileocaecal junction and the point to which meal had traversed was secured with thread to avoid change in the length of the transit due to handling .
the total length of the small intestine and distance traveled by phenol red meal was measured .
the small intestinal transit ( sit ) was calculated considering the distance traveled by phenol red meal divided by total length of the small intestine , multiplied by 100 .
each parameter was expressed as mean sem , and compared using one - way analysis of variance ( anova ) , followed by least significant difference ( lsd ) test .
as shown in figure 1 , the gastric emptying did nt change in tbi group ( 95.42 1.2 ) compared to intact group ( 95 0.61 ) .
also , the consumption of iboprophen ( 94 1 ) or celecoxib ( 95 1.2 ) did nt have any effect on gastric emptying compared to sham group .
gastric emptying in different groups ( n= 7 in each group ) after traumatic brain injury .
abbreviation : tbi : traumatic brain injury as shown in table 1 , tbi induction did nt have any effect on the intestinal transit . also , there is no significant difference between ibuprofen or celecoxib consumption compared to sham group ( p > 0.05 ) .
small intestinal transit in different groups ( n= 7 in each group ) after traumatic brain injury .
as shown in figure 1 , the gastric emptying did nt change in tbi group ( 95.42 1.2 ) compared to intact group ( 95 0.61 ) .
also , the consumption of iboprophen ( 94 1 ) or celecoxib ( 95 1.2 ) did nt have any effect on gastric emptying compared to sham group .
gastric emptying in different groups ( n= 7 in each group ) after traumatic brain injury .
as shown in table 1 , tbi induction did nt have any effect on the intestinal transit . also , there is no significant difference between ibuprofen or celecoxib consumption compared to sham group ( p > 0.05 ) . small intestinal transit in different groups ( n= 7 in each group ) after traumatic brain injury .
this study describes a model of tbi in rat and the effects of a cox-2 selective inhibitor ( celecoxib ) or non - selective cox inhibitor ( ibuprofen ) on gastrointestinal motility . in the present study
it was found that gastric and intestinal transit did nt change following brain trauma . in consistent with our results ,
melro et al reported that gastric emptying did not change following mild to moderate ischemic brain injury ( 17 ) .
however , the presence of vomiting , abdominal distension , and increased gastric remnants after neurological trauma suggests abnormal gastric movements in some studies .
it has been observed that gastric movements were inhibited during the first min by bilateral carotid artery ligation and cerebral ischemia ( 18 ) .
also , increased intracranial pressure caused reversible inhibition of duodenal and gastric motor function immediately ( 19 ) .
possible reasons for this controversy could be explained by ischemic brain injury type , time , and method of gastric motility measurement .
the current study also showed that gastric motility and intestinal transit did nt change following treatment with ibuprofen or celecoxib .
arachidonic acid is released from cell membranes following tbi and converted to prostaglandins by cyclooxygenases ( 20 ) .
cyclooxygenase-2 ( cox-2 ) is a primary inflammatory mediator that converts arachidonic acid from damaged membranes into vasoactive prostaglandins , producing reactive oxygen species in the process ( 21 ) .
also , cox-1 and cox-2 are expressed in the gastrointestinal neuromuscular tissue , and that the mechanical activities of gastrointestinal muscles are modulated by prostanoids originating from both isoforms ( 22 ) . in agreement with our results ,
bouras et al showed that cox-2 inhibitors , celecoxib or rofecoxib , had no effect on gastric emptying ofliquids and solids in humans ( 23 ) .
tanaka et al showed that a selective cox-1 inhibitor ( sc-560 ) caused marked gastric and intestinal hypermotility , whereas a selective cox-2 inhibitor ( rofecoxib ) had no effect on basal gastric or intestinal motor activities ( 24 ) .
santoz et al showed that pharmacologically selective cox-2 inhibitor delayed gastric emptying but not intestinal transit , and inhibition of cox-1 delayed intestinal transit but not gastric emptying of liquids in awake rats ( 25 ) .
however , porcher et al showed that both gr253035x ( cox-2 selective inhibitor ) and indomethacin ( non selective cox inhibitor ) reduced the fundal tone , and increased antral phasic contraction in the mouse stomach ( 22 ) .
takeuchiet et al showed that sc-560 , a cox-1 selective inhibitor , enhanced both amplitude and frequency of intestinal contractions in rats ( 26 ) . in general , the results with cox-2 inhibitors were somewhat unexpected , as previous data with prostaglandins and non - selective cox inhibitors showed motor effects in vivo . in animal studies of myoelectrical activity and gastric emptying ,
prostaglandins have variable effects on the upper gut ( 22 ) . although some studies suggest prostaglandins accelerate emptying of liquids from the human stomach , many studies have shown either no effect or a delay in gastric emptying in humans secondary to prostaglandins ( 27 ) . in the current study , one possible explanation for the lack of the effect of the studied cox - inhibitors is inadequate dosing of drugs .
the lack of the effect could also be secondary to the class of the cox inhibitors studied , based on the difference in expression of the cox isoforms ( 28 ) .
it is also possible that if we could use heavier weight , a significant inflammation might be induced . in this condition
in summary , by the applied dosages , the cox-2 selective inhibitor ( celecoxib ) or non - selective cox inhibitor ( ibuprofen ) had no effects on gastric or small bowel transit .
further works are needed to investigate the effects of non - selective cox inhibitors and their impact on gastrointestinal motility in diseases associated with inflammation .
Output:
| objective(s):this study was carried out to investigate the effects of cox-2 selective inhibitor ( celecoxib ) or non - selective cox inhibitor ( ibuprofen ) on gastrointestinal motility.materials and methods : the rats were randomly divided into five groups including : intact , sham , traumatic brain injury ( tbi ) group ( intact rats under tbi ) , celecoxib group ( 10 mg / kg ) , ibuprofen group ( 10 mg / kg ) . rats of the treatment groups received gavages at 1 hr before the tbi induction . the tbi was moderate and diffused using the marmarou method .
the gastric emptying and small intestine transit were measured by phenol red method.results:the gastric emptying did nt change following tbi induction compared to intact group .
the consumption of ibuprofen or celecoxib did nt have any effect on gastric emptying compared to sham group .
tbi induction did nt have any effect on the intestinal transit .
also , there was no significant difference between ibuprofen or celecoxib consumption vs. sham group ( p>0.05).conclusion : the cox-2 selective inhibitor ( celecoxib ) or non - selective cox inhibitor ( ibuprofen ) have no effects on gastric or small bowel transit .
further work is necessary to investigate the effects of non - selective cox inhibitors and their impact on gastrointestinal motility disorders . |
PubmedSumm4818 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: ischemic heart disease remains a leading cause of morbidity and mortality worldwide.1 borderline coronary artery lesions are responsible for about 80% of acute coronary syndromes ( acs).2 it is not uncommon during the performance of coronary angiography to identify borderline coronary stenosis ( > 40 and < 80% ) in the absence of more severe lesions.3 percutaneous coronary intervention ( pci ) of an intermediate stenosis without evidence of ischemia is often performed , but its benefit is unproven .
coronary pressure - derived fractional flow reserve ( ffr ) is an index used to identify a stenosis responsible for reversible ischemia,4 which profits from revascularization.5 uncertainty about the significance of these lesions may be augmented by the error associated with visual estimation of the severity of the stenosis .
thus , in a patient with a borderline lesion the results of an ffr can be very useful to evaluate the functional significance of coronary lesions.3 the measurement of fractional flow reserve ( ffr ) is commonly used in clinical practice to assess the hemodynamic significance of epicardial coronary stenosis and an ffr value of 0.75 is accepted as a physiologically significant stenosis .
however , an ffr between 0.75 and 0.80 is considered to be a borderline and represents a gray zone of functional significance for coronary stenosis.6 achievement of maximal hyperemia of coronary microcirculation is the prerequisite for the exact assessment of ffr in order to minimize the effect of microvascular resistance . with suboptimal coronary hyperemia
, ffr will be artificially high , resulting in a potentially significant underestimation of the functional severity of coronary stenosis.7 to achieve maximal hyperemia , iv adenosine is considered the standard method , but its use in the catheterization laboratory is time consuming and expensive compared with intracoronary adenosine.8 therefore , this study compared intracoronary adenosine for the potential to achieve a maximal hyperemia equivalent to the standard intravenous route .
the study sample was comprised of 22 patients who underwent elective coronary angiography and were found to suffer from 30 borderline lesions in the period from january 2012 to august 2012 .
this study is a prospective study designed to compare different strategies to induce coronary vasodilation for ffr measurements .
22 consecutive patients undergoing diagnostic cardiac catheterization for suspected coronary artery disease showing 30 angiographically intermediate lesions ( diameter stenosis 50% to 70% at visual estimation ) in at least 1 main coronary artery were consecutively and prospectively enrolled .
intermediate lesions in a vessel with thrombus , moderate or severe calcification , angulation , or tortuosity was excluded .
pci may have been performed in such non - target vessels or lesions prior to study enrollment , however , as long as it was successful and uncomplicated .
clinical exclusion criteria were recent myocardial infarction ( within 7 days ) or prior myocardial infarction in the territory supplied by the target vessel , severe valvular heart disease , acutely decompensated chronic heart failure , or advanced renal failure ( estimated glomerular filtration rate < 30 ml / min ) .
the study was approved by the local ethical committee and conformed to the declaration of helsinki on human research , and informed consent was obtained after complete explanation of the protocol and potential risks .
coronary angiography was performed using standard techniques ( innova 2000 ge , general electric ) along with a quantitative estimation of the coronary artery diameter .
quantitative coronary angiography ( qca ) was evaluated and performed with ge qca software ( ge innova 2000 , fairfield , ct , usa ) .
heparin was administered at the beginning of the procedure ( 60 u / kg ) .
pressure measurements were obtained using a volcano s5i imaging system and prime wire pressure guide wire . the pressure guide wire was calibrated and introduced into the guiding catheter .
the pressure transducer was advanced just outside the tip of the guiding catheter , and the pressure measured by the sensor was then equalized to that of the guiding catheter .
special attention was paid to avoid arterial pressure wave damping , unselective catheterization of coronary ostia and variation in the position of the pressure wire .
ffr was calculated as the ratio of distal coronary pressure divided by aortic pressure obtained after achievement of maximal hyperemia .
after checking the correct position of both the guiding catheter and the pressure wire ntg ( 200 g ) was administered ( in order to reduce vasospasm ) . the study procedure consisted of 2 sequential steps : ic bolus injection at the dose of 150 g and rapidly flushed with saline solution then ffr , arterial blood pressure ( abp ) and heart rate ( hr ) readings recorded after 3 seconds .
hr and bp were recorded in order to indicate the hyperemic state , evidenced by a 1020% decrease in bp and a similar increase in hr .
the same process was repeated using iv adenosine infusion at the dose of 140 g / kg / min . after reaching the steady state of hyperemia
is determined by coronary auto - regulatory mechanisms ( causing vasoconstriction ) and the systemic blood pressure ( driving pressure ) .
so , maximal hyperemia was induced to abolish auto - regulatory mechanisms and cbf became directly related to the driving pressure .
heart rate , aortic pressure , and distal coronary pressure were continuously recorded and digitally stored throughout all the phases of the study .
patient symptoms ( namely an angina - like sensation , dyspnea , or flushing ) , development of complete atrioventricular - nodal block ( avb ) , or any other complication were carefully recorded .
the qualitative data are presented using numbers and percentages while the quantitative data are presented using range and mean sd .
an independent samples t - test was used to compare two groups with normal distribution , and a with wilcoxon - rank test was used as a non parametric test .
coronary angiography was performed using standard techniques ( innova 2000 ge , general electric ) along with a quantitative estimation of the coronary artery diameter . quantitative coronary angiography ( qca )
was evaluated and performed with ge qca software ( ge innova 2000 , fairfield , ct , usa ) .
heparin was administered at the beginning of the procedure ( 60 u / kg ) .
pressure measurements were obtained using a volcano s5i imaging system and prime wire pressure guide wire . the pressure guide wire was calibrated and introduced into the guiding catheter .
the pressure transducer was advanced just outside the tip of the guiding catheter , and the pressure measured by the sensor was then equalized to that of the guiding catheter .
special attention was paid to avoid arterial pressure wave damping , unselective catheterization of coronary ostia and variation in the position of the pressure wire .
ffr was calculated as the ratio of distal coronary pressure divided by aortic pressure obtained after achievement of maximal hyperemia .
after checking the correct position of both the guiding catheter and the pressure wire ntg ( 200 g ) was administered ( in order to reduce vasospasm ) . the study procedure consisted of 2 sequential steps : ic bolus injection at the dose of 150 g and rapidly flushed with saline solution then ffr , arterial blood pressure ( abp ) and heart rate ( hr ) readings recorded after 3 seconds .
hr and bp were recorded in order to indicate the hyperemic state , evidenced by a 1020% decrease in bp and a similar increase in hr .
the same process was repeated using iv adenosine infusion at the dose of 140 g / kg / min . after reaching the steady state of hyperemia
is determined by coronary auto - regulatory mechanisms ( causing vasoconstriction ) and the systemic blood pressure ( driving pressure ) .
so , maximal hyperemia was induced to abolish auto - regulatory mechanisms and cbf became directly related to the driving pressure .
heart rate , aortic pressure , and distal coronary pressure were continuously recorded and digitally stored throughout all the phases of the study .
patient symptoms ( namely an angina - like sensation , dyspnea , or flushing ) , development of complete atrioventricular - nodal block ( avb ) , or any other complication were carefully recorded .
the qualitative data are presented using numbers and percentages while the quantitative data are presented using range and mean sd .
an independent samples t - test was used to compare two groups with normal distribution , and a with wilcoxon - rank test was used as a non parametric test .
all incidences of side effects were higher during iv infusion than during all ic infusions .
mean ffr ( mffr ) measurements were recorded only in the vessels with borderline lesion at baseline , after the injection of iv adenosine , and after ic bolus adenosine .
ic adenosine dose induced a significant decrease in ffr compared with baseline distal coronary pressure / aortic pressure ( p < 0.05 ) , ( mean baseline ffr 0.94 0.05 , mean ivadn 0.85 0.08 , and mean icadn 0.84 0.09 ) with mean values illustrated in table 3 and figure 1 .
the primary endpoint of the present study was to test the non - inferiority of icadn in comparison with ivadn in inducing maximal hyperemia measured as the lowest possible ffr value .
we considered the non - inferiority threshold to be a difference of < 0.02 0.05 in the ffr value between those calculated inducing maximal hyperemia with ivadn and those with icadn , assuming the ffr value obtained by ivadn to be the standard reference , and hypothesizing that this value was the lowest possible to detect small differences.8 a total of 6 lesions were identified with a positive ffr ( ffr < 0.75 ) by ivand ( the standard protocol ) .
notably , as regards to the primary endpoint of the study , icadn was associated with an ffr value not significantly different from ivadn ( p = 0.811 for noninferiority ) .
hemodynamic effect of iv adenosine protocol and ic adenosine protocol were recorded , it is summarized in table ( 2 ) . during the ic protocol ,
meanwhile , during the iv protocol , 6 patients developed chest pain and 4 patients developed transient a - v block .
importantly , avb was always transient and spontaneously reversible , thus never requiring atropine administration or temporary pacemaker implantation .
all incidences of side effects were higher during iv infusion than during all ic infusions .
mean ffr ( mffr ) measurements were recorded only in the vessels with borderline lesion at baseline , after the injection of iv adenosine , and after ic bolus adenosine .
ic adenosine dose induced a significant decrease in ffr compared with baseline distal coronary pressure / aortic pressure ( p < 0.05 ) , ( mean baseline ffr 0.94 0.05 , mean ivadn 0.85 0.08 , and mean icadn 0.84 0.09 ) with mean values illustrated in table 3 and figure 1 .
the primary endpoint of the present study was to test the non - inferiority of icadn in comparison with ivadn in inducing maximal hyperemia measured as the lowest possible ffr value .
we considered the non - inferiority threshold to be a difference of < 0.02 0.05 in the ffr value between those calculated inducing maximal hyperemia with ivadn and those with icadn , assuming the ffr value obtained by ivadn to be the standard reference , and hypothesizing that this value was the lowest possible to detect small differences.8 a total of 6 lesions were identified with a positive ffr ( ffr < 0.75 ) by ivand ( the standard protocol ) .
notably , as regards to the primary endpoint of the study , icadn was associated with an ffr value not significantly different from ivadn ( p = 0.811 for noninferiority ) .
hemodynamic effect of iv adenosine protocol and ic adenosine protocol were recorded , it is summarized in table ( 2 ) . during the ic protocol , none of the patients developed nether chest pain or transient a - v block . meanwhile , during the iv protocol , 6 patients developed chest pain and 4 patients developed transient a - v block .
importantly , avb was always transient and spontaneously reversible , thus never requiring atropine administration or temporary pacemaker implantation .
the induction of maximal coronary hyperemia represents a critical prerequisite to correctly assess ffr.9,10 with this aim , although iv adenosine is currently considered the gold standard approach , in everyday practice , ic adenosine administration is frequently used as a cheaper , simpler , and more rapid alternative . in the present study ,
we thus compared safety and efficacy of high - dose ic adenosine ( 150 g ) . of note ,
intravenous administration of adenosine at a dose of 140 g / kg / min represents the gold standard for ffr assessment.11 indeed , the iv route provides several practical advantages , such as an effective and safe protocol , the induction of a prolonged vasodilator stimulus allowing the achievement of a stabilization of pressure traces , and the possibility to perform a pressure wire pullback in cases of multiple lesions or diffusely diseased coronary arteries.12 however , iv adenosine administration is a time - consuming and costly procedure .
furthermore , patients often experience the typical known side effects related to systemic adenosine infusion .
conversely , ic adenosine administration allows an easy , feasible and rapid procedure that requires a much lower amount of adenosine , thus also reducing costs .
although commonly used in clinical practice in a large number of catheterization laboratories worldwide , ic adenosine administration has the major drawback of a possible suboptimal induction of maximal hyperemia.13,14 this is mainly due , on the one hand , to possible nonselective drug administration into the target coronary artery and , by contrast , to the uncertainty regarding the dose needed to achieve maximal coronary vasodilation .
1315 the former issue might be addressed by selective ic injection by microcatheter . using this technique , yoon et al.7
have demonstrated that , compared with iv or ic ( in bolus ) adenosine at commonly - suggested doses , a dose of 240 g to 360 g administered via ic in 1 min ( and not in bolus ) was more effective at inducing maximal coronary hyperemia .
however , this procedure is more invasive than the standard technique and the issue of safety might limit its widespread use . with regard to the second issue , doses lower than 50 g have been used in several previous studies , although they allow physicians to reliably measure ffr value in less than 1/4 of patients.13,14 casella et al.8 have shown that a 150 g bolus resulted in mean ffr values comparable to those obtained after iv adenosine.12 while designing this study , we selected the dose of 150 g to test the feasibility and the effect of a very high dose of ic adenosine on ffr . of note ,
the use of these high ic dose of adenosine is not uncommon in daily practice , especially in the setting of primary pci for the pharmacological treatment of no - reflow , where even higher doses have been safely administered.9,16,17 our study demonstrates that high - dose ( 150 g ) ic adenosine is sufficient to induce maximal hyperemia and was not inferior to iv adenosine .
however , the iv approach was associated with the lowest value in most cases , as compared with the ic dose . using the cutoff of the fame study5 ; however , iv adenosine was associated with a lower ffr value in a higher percentage of cases than of those using the ic strategy .
although technical pitfalls due to catheter dislodgement and unselective administration of adenosine might have played a role , this might indicate that the iv approach is superior in inducing maximal hyperemia , and finally , in identifying functionally significant stenosis .
in this view , the iv route might represent an alternative to ic administration only in those cases where the ffr value approaches 0.80 ( 0.81 to 0.83 ) .
intravenous administration of adenosine at a dose of 140 g / kg / min represents the gold standard for ffr assessment.11 indeed , the iv route provides several practical advantages , such as an effective and safe protocol , the induction of a prolonged vasodilator stimulus allowing the achievement of a stabilization of pressure traces , and the possibility to perform a pressure wire pullback in cases of multiple lesions or diffusely diseased coronary arteries.12 however , iv adenosine administration is a time - consuming and costly procedure .
furthermore , patients often experience the typical known side effects related to systemic adenosine infusion .
conversely , ic adenosine administration allows an easy , feasible and rapid procedure that requires a much lower amount of adenosine , thus also reducing costs .
although commonly used in clinical practice in a large number of catheterization laboratories worldwide , ic adenosine administration has the major drawback of a possible suboptimal induction of maximal hyperemia.13,14 this is mainly due , on the one hand , to possible nonselective drug administration into the target coronary artery and , by contrast , to the uncertainty regarding the dose needed to achieve maximal coronary vasodilation .
1315 the former issue might be addressed by selective ic injection by microcatheter . using this technique , yoon et al.7
have demonstrated that , compared with iv or ic ( in bolus ) adenosine at commonly - suggested doses , a dose of 240 g to 360 g administered via ic in 1 min ( and not in bolus ) was more effective at inducing maximal coronary hyperemia . however , this procedure is more invasive than the standard technique and the issue of safety might limit its widespread use . with regard to the second issue , doses lower than 50 g have been used in several previous studies
, although they allow physicians to reliably measure ffr value in less than 1/4 of patients.13,14 casella et al.8 have shown that a 150 g bolus resulted in mean ffr values comparable to those obtained after iv adenosine.12 while designing this study , we selected the dose of 150 g to test the feasibility and the effect of a very high dose of ic adenosine on ffr . of note ,
the use of these high ic dose of adenosine is not uncommon in daily practice , especially in the setting of primary pci for the pharmacological treatment of no - reflow , where even higher doses have been safely administered.9,16,17 our study demonstrates that high - dose ( 150 g ) ic adenosine is sufficient to induce maximal hyperemia and was not inferior to iv adenosine .
however , the iv approach was associated with the lowest value in most cases , as compared with the ic dose . using the cutoff of the fame study5 ; however , iv adenosine was associated with a lower ffr value in a higher percentage of cases than of those using the ic strategy .
although technical pitfalls due to catheter dislodgement and unselective administration of adenosine might have played a role , this might indicate that the iv approach is superior in inducing maximal hyperemia , and finally , in identifying functionally significant stenosis .
in this view , the iv route might represent an alternative to ic administration only in those cases where the ffr value approaches 0.80 ( 0.81 to 0.83 ) .
on the basis of the results of this study , we suggest using ic adenosine at the tested dose to perform a safe and cost - effective functional evaluation of intermediate stenosis with ffr .
conversely , if ffr is equivocal , that is , the ffr value is between 0.83 and 0.81 , ffr evaluation should be repeated with iv adenosine and then a decision should be made on the basis of the cutoff value of 0.75 . in conclusion , our study clearly demonstrates that high doses of ic adenosine can be relatively safely administered to most patients , and allows for obtainment of the minimum ffr value in a similar proportion of patients to the gold standard iv route .
thus the iv route might be reserved for those cases of equivocal ffr after ic adenosine .
this is a pilot trial , indicating that ffr after ic and iv administration seems to be comparable .
the next step would be a study with extended sample size with a higher proportion of positive ffr < 0.75 to increase the negative and positive icadn protocol specificity and sensitivity . it is speculated that higher doses of adenosine may be needed to yield a near - maximal hyperemic response in patients with microvascular disorders and other conditions possibly accompanied by decreased sensitivity of the vascular system to adenosine .
arterial hypertension , diabetes mellitus , and myocardial infarction impair vasodilatation of the peripheral microvasculature .
these pathologies affect a well - represented population in the real world , as suggested from the extremely high prevalence of hypertension and diabetes mellitus in this study .
in addition , although high intracoronary adenosine bolus could be an acceptable alternative to intravenous adenosine , intracoronary adenosine produces a plateau hyperemic phase of approximately 4 seconds , which corresponds to 3 to 6 beats , but not to a true steady state .
this absence of a prolonged hyperemic state is a strong limitation to the ic approach in cases of mild to moderate tandem stenoses or in cases of diffuse disease , when a pullback maneuver of the pressure wire is necessary to detect the exact location of the critical lesion .
Output:
| backgroundmaximal hyperemia is the critical prerequisite for fractional flow reserve ( ffr ) assessment . despite intravenous
( iv ) adenosine currently being the recommended approach , intracoronary ( ic ) administration of adenosine constitutes a valuable alternative in everyday practice .
however , it is surprisingly unclear which ic strategy allows the achievement of ffr values that are comparable to iv adenosine.objectivesthis study sought to compare increasing doses of ic adenosine versus iv adenosine for ffr.methods30 intermediate coronary stenoses undergoing ffr measurement were prospectively and consecutively enrolled .
hyperemia was sequentially induced by bolus of ic adenosine ( adn ; 150 g ) followed by iv adenosine ( ivadn ) infusion over 3 minutes at dose of ( 140 g / kg / min ) .
ffr values , symptoms , and development of atrioventricular block were recorded.results150 g doses of ic adenosine were well tolerated and associated with fewer symptoms than iv adenosine .
intracoronary adenosine doses induced a significant decrease of ffr compared with baseline levels ( p < 0.01 ) . among the 6 patients with ffr values less than 0.80 identified by ivadn ,
4 were correctly identified also by 150 g bolus ic adenosine .
larger randomized studies with cross - over design are necessary to verify the results.conclusionsthis small pilot study suggests that ic adenosine might be an alternative to iv adenosine .
larger randomized studies with a cross - over design are necessary . |
PubmedSumm4819 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: a major goal in pediatric dentistry is to maintain primary dentition in an intact state until permanent successors erupt .
primary dentition is essential for maintenance of arch length , mastication , speech and esthetics and prevention of abnormal oral habits .
this does not mean that tooth needs removal ; it can be retained in oral cavity in a functional state with appropriate treatment .
this is accomplished through various procedures which include indirect pulp capping , direct pulp capping , pulpotomy , pulpectomy and apexification .
pulpotomy is a procedure performed in a tooth with deep carious lesion adjacent to pulp , where coronal pulp is amputated to preserve the vitality of radicular pulp .
a wide range of materials such as formocresol ( fc ) , glutaraldehyde , ferric sulfate , zinc oxide eugenol and calcium hydroxide have been used over the years for pulpotomy .
fc has been a popular pulpotomy medicament in primary dentition for the past 60 years .
concerns have been raised about the toxicity and potential carcinogenicity of fc in humans.[46 ] studies have demonstrated systemic uptake of fc from pulpotomized teeth and have also shown fc to produce defects in succedaneous teeth . alternative technique and pulp therapy agents have been proposed to maintain partial pulp vitality .
these include glutaraldehyde , electrosurgery , laser , freeze - dried bone , bone morphogenic protein , osteogenic protein and mineral trioxide aggregate ( mta ) . in recent times , with the introduction of new materials , which are not only biocompatible but also bioinductive , the emphasis has shifted from mere preservation to regeneration .
mta attracted attention in the field of endodontics with its excellent sealing ability , biocompatibility , and ability to form dentinal bridge , and cementum and periodontal ligament regeneration .
mta has the ability to stimulate cytokine release from bone cells , indicating that it actively promotes hard tissue formation .
it has also been proved that mta has antimicrobial properties similar to zinc oxide eugenol ( zoe ) and has no cytotoxic effect .
mta has been proposed as a potential medicament for pulpotomy procedure , capping of pulps with reversible pulpitis , apexification , repair of root perforation and repair of resorptive defects .
hence , the present study was conducted with an aim to assess clinically and radiographically the effects of mta as a pulp dressing after coronal pulp amputation in human primary molars and compare them to those of fc .
the procedure , possible discomfort and benefits were explained fully to parents of the children involved and their written consent was obtained prior to the treatment .
normal , healthy and cooperative children for the study were selected from the patients attending the department of pedodontics and preventive dentistry , i. t. s.
a total of 50 maxillary and mandibular primary molar teeth were selected from 33 children requiring pulp therapy and aged between 5 and 8 years , who were selected after clinical and radiographic assessment .
the criteria for selection of teeth to be included in the study are given in table 1 .
the teeth were divided into two equal groups : in group a , fc ( pharmadent remedies pvt . ltd . , gundlav , india )
was used as the pulp dressing agent and gray mta ( proroot mta , dentsply , tulsa dental , tulsa ok , usa ) was used in group b. cases which came under the exclusion criteria were eliminated and they are not represented in the study . in case a child had two molars needing pulpotomy , the second tooth was assigned to alternative group .
the teeth treated were assessed postoperatively after 1 , 3 , 6 and 12 months .
the criteria for the selection of teeth to be included in the study the conventional pulpotomy procedure was carried out step - by - step in one visit using local anesthesia and isolating the teeth with rubber dam .
after caries removal with round bur , coronal access was obtained using a # 330 high - speed bur with water spray to expose the pulp chamber .
de - roofing of pulp chamber was done by connecting the pulp horns by a non - end cutting bur .
the coronal pulp was excised until root canal orifices could be seen , with no tags remaining on the pulpal floor , by using hu - friedy sharp spoon excavator .
after the pulp was amputated , the pulp chamber was irrigated with saline to wash away dentin debris .
following irrigation , sterile , saline - wetted cotton pellets were applied for 5 minutes on the amputated pulp stumps to achieve hemostasis .
after the standardized technique was completed , the teeth assigned for group a were treated with sterile cotton pellet moistened with fc squeezed twice , which was placed over the radicular pulp for 5 minutes and then removed .
a thick mix of zinc oxide eugenol paste was placed over the fc fixed tissue .
intermediate restorative material ( irm ) was placed over the zinc oxide eugenol layer at the same appointment . within 1 week
b , pulp stumps were covered with mta paste , obtained by mixing mta powder with distilled water provided by the manufacturer in 3:1 ( powder : liquid ) ratio , which was placed over the exposure site with a plastic instrument .
then , the mixture was compressed against the exposure site with a moist cotton pellet .
wet cotton pellet was placed in pulp chamber and the cavity was covered with irm . in the second session ( after 1 day ) , the patient was recalled , cotton pellet was removed and the cavity was restored with irm . within 1 week , the tooth was restored with a preformed stainless steel crown . in both the groups ,
the children were recalled for clinical and radiographic examination postoperatively after 1 , 3 , 6 and 12 months .
the children were examined at follow - up clinically for the signs and symptoms like pain , swelling and sinus / fistula and radiographically for periapical changes , furcation radiolucency and internal resorption .
the treatment was regarded as a failure when one or more of the above - mentioned signs and symptoms were present , but pulp canal obliteration ( pco ) was not regarded as a failure .
all data were entered in ms excel sheet and analyzed by epi - info 2002 software to assess the success rate of the treatment with mta and fc after 12 months .
the difference between the effects of two materials was statistically analyzed by fisher 's exact test and p < 0.05 was considered statistically significant .
all 50 teeth in 33 children were available for analysis of success / failure rate .
the age of the subjects ranged from 5 to 8 years , with a mean ( sd ) age of 6.04 ( + 0.84 ) years in fc group and 6.44 ( 1.12 ) years in mta group .
the distribution of teeth by type of tooth and material used is shown in table 2 .
distribution of assessed teeth according to type of material a total of 12 first primary molars and 38 second primary molars were treated by conventional pulpotomy technique .
the follow - up evaluation revealed 100% success with regard to the clinical signs and symptoms for both the groups .
none of the teeth in either group showed any clinical pathology at the end of 12 months when observed by the same observer .
fisher 's exact test was not necessary for the clinical signs as none of the samples showed signs of clinical evidence of failure , giving 100% success .
the radiographic evaluation at 3 , 6 and 12 months follow - up period for both the groups is shown in table 3 .
the cases which showed furcation radiolucency and internal resorption with fc pulpotomy and regarded as failure are shown in figures 1 and 2 . the case which showed internal resorption with mta pulpotomy
is shown in figure 3 . however , both the groups did not show any periapical changes at the above intervals .
pulp canal obliteration ( calcific metamorphosis ) was found in the three cases in mta treated teeth ( group b ) and was not considered as failure . out of 25 teeth treated in each group , 22 in group a and 24 in group b did not show any radiographic changes , giving 88% and 96% success , respectively .
assessment of radiographic signs at 3 , 6 and 12 months preoperative and postoperative radiographs of mandibular second primary molar treated with formocresol pulpotomy revealed internal resorption and furcation radiolucency .
( a ) preoperative radiograph ; ( b ) radiograph taken 3 months postoperatively showing features of failure in pulpotomy ; ( c ) radiograph taken 6 months postoperatively showing features of failure in pulpotomy ; ( d ) radiograph taken 12 months postoperatively showing features of failure in pulpotomy preoperative and postoperative radiographs of mandibular second primary molar treated with formocresol pulpotomy revealed furcation radiolucency .
( a ) preoperative radiograph ; ( b ) postoperative radiograph taken immediately after formocresol pulpotomy and restored with stainless steel crown ; ( c ) radiograph taken 6 months postoperatively showing feature of failure in pulpotomy ; ( d ) radiograph taken 12 months postoperatively showing feature of failure in pulpotomy preoperative and postoperative radiographs of mandibular second primary molar treated with mta pulpotomy revealed internal resorption .
( a ) preoperative radiograph ; ( b ) postoperative radiograph taken immediately after mta pulpotomy and restored with stainless steel crown ; ( c ) radiograph taken 3 months postoperatively showing feature of failure in pulpotomy ; ( d ) radiograph taken 6 months postoperatively showing feature of failure in pulpotomy the statistical analysis was carried out by fisher 's exact test pertaining to radiographic findings in both the groups .
there was no significant difference found between the two groups after 12 months of radiographic evaluation ( p = 0.61 ) .
the objective of pulp therapy in a child patient is the successful treatment of a pulpally involved tooth and to retain the tooth in a healthy condition so that it may fulfil its role as a useful component of a primary and young permanent dentition .
this report intended to examine the clinical and radiographic success rates of pulpotomies with mta , a material with evidence - based success in many endodontic procedures .
several in vitro and in vivo studies have shown that mta prevents microleakage , is biocompatible , and promotes regeneration of the original tissues when it is placed in contact with the pulp or periradicular tissues .
fc was selected as it is still considered gold standard in pediatric dentistry , may be mainly because of its ease in use and excellent clinical success . the estimated dose associated with one pulpotomy procedure , assuming a 1:5 dilution of fc placed on a no .
4 cotton pellet that has been squeezed dry , is approximately 0.020.10 mg .. children from 5 to 8 years of age were selected as per the inclusion and exclusion criteria for the study , irrespective of their sex .
the age group was selected taking into consideration the lack of cooperation of children less than 5 years of age and physiologic root resorption ( > 3/4 of root ) above 8 years of age .
the first and second primary molars of both arches were included in the present study .
clinically , the success rate was 100% with both the groups at all observation periods .
the results are in agreement with the results of various previous studies.[4151820 ] the clinical success of fc pulpotomy in this study could be attributed to proper case selection , high aseptic standards , proper technique protocol and appropriate use of medicament .
in addition to this , the germicidal and bactericidal action of fc , and also its fixative qualities , might have contributed to the success .
the clinical success of mta in this study could also be considered to be due to the above - mentioned factors and also its excellent sealing ability , biocompatibility , alkalinity and ability to regenerate the hard tissues .
effects of mta on amputated pulpal tissue seem to suggest that the material preserves the pulp tissue and promotes the regeneration of hard tissues .
radiographically , in group a , at 3 months , internal resorption and furcal changes were seen in one tooth and furcal changes alone in another tooth . at 6 months follow - up
, furcal changes were seen in one more tooth , similar to the results of a previous study .
internal resorption is the result of odontoclastic activity and suggests that the tooth is retaining some degree of vitality and function over time .
although the cause of internal resorption is unknown , there is a speculation that whatever the precipitating factor , it produces a vascular change in the pulp that involves an inflammation and formation of granulation tissue .
the reason for internal resorption following pulpotomy is believed to be the irritating effects of the medicaments present in the paste .
previous investigation of zoe as a pulpotomy agent or as a base for pulpotomies suggests that zoe can cause pulp inflammation , with a risk for subsequent internal resorption .
zoe , when used as a base in pulpotomies , comes in contact with highly perfused environment of pulp and undergoes hydrolysis of the zinc eugenolate to yield free eugenol and zinc hydroxide .
this eugenol comes in direct contact with the vital tissue and causes moderate to severe inflammatory response , resulting in chronic inflammation and necrosis .
this , however , can not explain the internal resorption in the present study because zoe paste was placed as a sub - base on fc fixed tissue .
cotes et al . claimed that if the pulp tissue is fixed by fc it will not be affected by eugenol , and smith et al . also claimed that application of fc on pulp serves as a barrier to eugenol . in the present study ,
it is more likely that internal resorption was the result of undiagnosed chronic inflammation existing in radicular pulp prior to pulpotomy rather than due to exposure of radicular pulp to eugenol . due to this
, the recovery of pulpal tissue to the normality might have been hampered , causing a delay in the completion of technique .
increasing time of procedure leading to a certain amount of inflammation in the pulpal tissue might have led to exaggerated response in the form of internal resorption . however , since the progress of such activity was limited , such response can not be taken as failure of the procedure at microlevel .
another probable reason for internal resorption could be the reversible fixative effect of fc and its irritative ph .
furcation changes might be seen due to the presence of micro pulp remnants even after the amputation of coronal pulp tissue .
the occurrence of such changes might be dependent on the medicament concentration and application time offc . in the mta group ,
one tooth showed internal resorption at 3 months , which did not progress any further over a period of the next 9 months .
this could be more likely the result of undiagnosed chronic inflammation existing in the radicular pulp prior to pulpotomy .
a similar finding was seen at a duration of 2538 months in two cases in a study by holen et al . and at a duration of 12 months in a study by jabbarifar et al .
since mta contains highly alkaline substances , the possibility of exaggerated response of pulp can not be ruled out .
it is known from various studies that calcium hydroxide placed on primary pulp reacts by producing internal resorption .
internal resorption may result from overstimulation of primary pulp by the highly alkaline calcium hydroxide .
overstimulation induced by high alkalinity could cause metaplasia within the pulp tissue , leading to the formation of odontoclasts .
though mta does not contain calcium hydroxide , it has calcium oxide that forms calcium hydroxide when mixed with water . according to holland et al . , the reaction of calcium from calcium hydroxide with the carbon dioxide from pulpal tissue produces calcite crystals .
therefore , we believe that the mechanism of action of mta is similar to that of calcium hydroxide . in the present study , in group b ,
internal resorption was noticed at a duration of 3 months and did not progress to root perforation and osseous changes .
therefore , such internal resorption may be ignored as being a reason for the amount of inflammation at the time of pulpotomy .
pulp canal obliteration ( calcific metamorphosis ) was found in the three cases in mta treated teeth ( group b ) and was not considered as failure , but was a result of the odontoblastic activity , and this might suggest that the tooth is retaining some degree of vitality and function overtime . in the current study , radiographic success rates of fc and mta were 88% and 96% , respectively , at 12 months follow - up . however , this difference in success rates was not statistically significant ( p = 0.061 ) as reported in previous studies .
the mummification of the pulp induced by fc only treats the symptoms , but does not have any healing capacity .
the objectives of fc pulpotomy are solely clinical , that is , maintaining the tooth in an asymptomatic condition until normal exfoliation .
enough evidence is present to suggest that the objective should no longer be complete mummification .
stated in modern terms , the rationale of the fc pulpotomy is to fix the radicular tissue while allowing recovery of cells and possible replacement of fixed tissue .
there is also a reported case of dentigerous cyst and necrosis of crestal bone associated with the use of fc in pulpotomy .
fc has recently come to critical review and three concerns about the material should be under immediate inspection : firstly local toxicity , secondly the effects of the material systemically and lastly its effects of mutagenicity and carcinogenicity . mta appears to meet the requirements for pulp capping materials .
mta 's advantages might be related to its sealing ability to prevent bacterial penetration and to its high level of biocompatibility .
mta is a technique - sensitive material and takes about 4 hours to set when in contact with moisture .
histological evaluation of pulpal tissue in animals and humans demonstrated that mta produces thicker dentin bridge formation , with less inflammation , hyperemia , and pulpal necrosis compared to calcium hydroxide .
mta also appears to induce dentin bridge at a faster rate than calcium hydroxide at amputation sites .
an important clinical advantage of mta over fc is the fact that less time is required for the procedure .
while fc requires 35 minutes application before the cotton pellet is removed , with mta the pulp chamber is filled with irm immediately after application of the dressing material .
moreover , during the removal of fc - soaked cotton pellet , there is a possibility of the cotton fibers adhering to clot , resulting in reoccurrence of bleeding .
presently one of the factors limiting the routine use of mta is the high cost of the material .
although high success rates have been reported with mta , re - entry into canal in cases further indicated for pulp therapy may not be possible in teeth with pulp canal obliteration .
mta showed clinical and radiographic success as a dressing material following pulpotomy in primary teeth after a short - term evaluation period and has a promising potential to become a replacement for fc in primary teeth .
though fc is in the center of much controversy for the past 20 years , it is still used extensively in pulpotomy procedure .
however , mta seems to have more promising potential to become a replacement for fc in primary teeth except for the cost factor and technique sensitivity .
further histological studies using larger sample size and longer observational period should be carried out in future .
Output:
| background : preservation of pulp vitality is of utmost importance to the normal physiological functioning of tooth in situ and physiological process of exfoliation in a tooth affected by disease or trauma .
pulpotomy serves such a purpose using various medicaments applied directly on vital pulp.aim:the aim of this study was to evaluate clinically and radiographically the effects of mineral trioxide aggregate ( mta ) and formocresol ( fc ) as a pulp dressing after coronal pulp amputation ( pulpotomy ) in primary molars prospectively over a period of 1 year.materials and methods : thirty - three healthy children , aged between 5 and 8 years , requiring pulp therapy were selected after clinical and radiographic assessment .
a total of 50 maxillary and mandibular primary molars were treated by the conventional pulpotomy technique .
the teeth were divided into two equal groups . in group
a , fc was used as the pulp dressing agent , and in group b , mta was used before restoration with stainless steel crowns .
the research employed was a prospective study .
the teeth treated were assessed postoperatively after 1 , 3 , 6 and 12 months .
the observations were tabulated and statistically analyzed.results:clinically , both the groups showed 100% success at 1 , 3 , 6 and 12 months . at 3 months , the radiographic success rates of fc and mta were 92% and 96% , respectively , and at 6 and 12 months , the radiographic success rates of fc and mta were 88% and 96% , respectively.conclusion:mta showed a higher success rate than fc and may be a favorable material for pulpotomy in primary molars whose pulps have been compromised by a carious or mechanical pulp exposure |
PubmedSumm4820 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: malignant pleural mesothelioma ( mpm ) is a rare malignant neoplasm that typically affects individuals occupationally exposed to asbestos through a variety of industries .
mpm is cancerous proliferation of mesothelial cells that involves a large extent of the pleural cavity and is the most common primary neoplasm of the pleura .
the patients experience an insidious onset of symptoms including dyspnea , chest pain , cough , malaise , and weight loss ( 1 ) .
metastatic pleural tumor is a type of cancer that has spread from another organ to the membrane ( pleura ) surrounding the lungs .
the pathological diagnosis of mpm is difficult and special stains or immunohistological or ultra - structural analysis may be required to differentiate mpm from metastatic carcinoma of the pleura .
the radiographic findings of mesothelioma are nonspecific and more common diseases such as benign asbestos related pleural disease and metastatic carcinoma can look radiographically identical to mesothelioma . computed tomography is the primary imaging modality used for diagnosis and staging of mpm . generally , the combination of accurate history , examination , radiology , and the acquisition of pathology is essential to diagnose mesothelioma ( 2 - 4 ) .
the aim of this study is to differentiate mpm from metastatic carcinoma of the pleura by pathological and radiological assessment in order to investigate ability and accuracy of ct scan in this regard and also to evaluate ct features of these two diseases .
we conducted a retrospective study of 55 pleural malignancy patients including mpm and metastatic pleural disease cases hospitalized from 2009 through 2012 at a chronic respiratory center in iran .
the ihc panel of antibodies for differentiating malignant mesothelioma and metastatic carcinoma were hbme7 , wt9 , 0240 , calretinin , cea , moc31 , and ck5/6 .
chest ct scans were performed in all patients with and without contrast with a single detector row ct scanner ( somatom plus ; siemens , germany ) .
a checklist of relevant findings was fulfilled for each case and the most probable diagnosis according to ct scan was made by the radiologist .
studied ct features consisted of pleural and pericardial effusion , pleural and pericardial thickening , parenchymal infiltration , fibrotic band , subpleural nodule , contralateral extension , contraction of involved hemithorax , pleural mediastinal shift , lymphadenopathy , thickening of the interlobar fissure , diaphragmatic involvement , and chest wall / hepatic / intraperitoneal invasion .
, chicago , il ) and the accuracy of radiology for differentiating mpm and metastatic carcinoma of the pleura was evaluated .
continuous variables were described by mean and standard deviation ( sd ) and categorical variables were described by frequency and percentage .
ct findings were classified according to their prevalence and their contributing role for differentiating between mesothelioma and metastatic carcinoma .
fifty - five patients including 29 males and 26 females were evaluated in this study . according to pathology reports ,
17 patients ( 11 males and 6 females ) had mesothelioma and 38 patients ( 18 males and 20 females ) were diagnosed with metastatic carcinoma of the pleura ( 30.9% mesothelioma and 69.1% metastatic carcinoma ) . on the other hand , according to radiology reports , 22 patients ( 14 males and 8 females ) had mesothelioma and 33 patients ( 15 males and 18 females ) were diagnosed with metastatic carcinoma ( 40% mesothelioma and 60% metastatic carcinoma ) . by radiology ,
82% of patients with mesothelioma and 79% of patients with metastatic carcinoma of the pleura were diagnosed correctly . among all 55 cases ,
the most common finding was pleural thickening ( 70.9% , n = 39 ) ( figure 1 ) followed by free pleural effusion ( 60% ) and parenchymal infiltration ( 56.4% ) . based on pathology
, we divided our cases into two groups of malignant mesothelioma ( 17 cases ) and metastatic carcinoma ( 38 cases ) .
twenty imaging findings were assessed and their frequencies in each group are reported in table 1 . the values are presented as % .
the most prevalent finding in the mesothelioma group was pleural thickening seen in 88.2% ( n = 15 ) followed by loculated effusion in 58.8% , and thickening of interlobar fissure in 47.1% ( figure 2 , 3 and 4 ) .
the least common finding in the mesothelioma group was hepatic invasion detected in one case .
the most common finding was free pleural effusion ( 71.7% , n = 27 ) and it mostly appeared as massive volumes rather than mild or moderate volumes ( 55.3% vs. 15.8% ) ( figure 5 ) .
parenchymal infiltration ( 65.8% ) and pleural thickening ( 63.2% ) were ranked second and third common findings , respectively , with an almost similar prevalence .
none of the metastatic cases showed hepatic invasion , but chest wall and intraperitoneal invasion each were seen in one patient ( figure 6 ) .
malignant pleural mesothelioma is a rare pleural malignancy that is diagnosed by imaging and histology assessment .
one of its important differential diagnoses is pleural metastatic carcinoma with several similar imaging findings . in this study
, we compared the radiologist and pathologist s diagnoses on 55 pleural malignancy cases and investigated their ct findings . according to chest ct scans in our study ,
14 out of 17 mesothelioma and 30 out of 38 metastatic pleural malignancy cases were diagnosed correctly .
it means that 82% of the patients with mesothelioma and 80% of the patients with metastatic carcinoma of the pleura were correctly diagnosed by the radiologist .
seely et al . in their study on 92 mesothelioma patients concluded that interobserver agreement ( pathology and radiology ) was excellent ( 5 ) .
said that the combination of radiology and acquisition of pathology is essential in the diagnosis of mesothelioma ( 6 ) .
senyigit and colleagues mentioned in their study that although ct findings of mpm vary , they may provide a valuable clue to the diagnosis , at least in patients with a history of asbestos exposure ( 7 ) . according to our results , the three most common findings of pleural malignancies were pleural thickening , free pleural effusion and parenchymal infiltration .
similarly , in an article by moore et al . , nodular pleural thickening and pleural thickening > 1 cm are named as most helpful ct findings suggesting malignant pleural disease ( 6 ) .
we noticed that tumor invasion to the chest wall , liver and peritoneum are rarely seen among all cases , but they were more common in malignant mesothelioma compared to metastatic carcinoma .
in the study performed by wang et al . , it has been mentioned that mpm is locally aggressive with frequent invasion to the chest wall , mediastinum and diaphragm ( 8) . in our study , among malignant mesothelioma cases , pleural thickening , loculated pleural effusion and thickening of the inter lobar fissure were the most prevalent ct findings and the least common ones were hepatic / chest wall invasion , massive pleural effusion , and pericardial effusion . in metastatic pleural disease cases , free pleural effusion , parenchymal infiltration , and pleural thickening were the most common ct findings and invasion to other organs , pericardial effusion , and thickening had the lowest rate in this disease .
senyigit et al . in their study in 2000 on 117 mesothelioma patients reported that pleural effusion ( 89% ) , pleural thickening ( 82% ) , mediastinal pleural involvement ( 66% ) , and thickening of the interlobar fissure ( 53% ) are the most common ct findings in mesothelioma patients ( 7 ) . in a study conducted by ng and colleagues on 70 mpm patients ,
pleural thickening ( 94% ) and pleural effusion ( 76% ) were the most common pretreatment findings ( 9 ) similar to a study carried out by sahin et al on 84 mpm patients ( 10 ) .
wang et al . named unilateral pleural effusion , nodular pleural thickening , and thickening of interlobar fissure the key ct finding of mpm ( 8) .
also , in a study on 92 mesothelioma cases in 2009 by seely and colleagues , pleural thickening was detected in all patients .
they reported 87% pleural effusion in mesothelioma patients , which is different to our result , but they also confirmed that massive pleural effusion is not common in mesothelioma(5 ) .
kawashima and lidshitz also mentioned pleural thickening ( 92% ) as the most common finding in mpm ( 11 ) .
philippe grenier wrote in his article that malignant pleural effusion is the most common manifestation of metastatic involvement , similar to our result ( 12 ) . comparing the two groups , pleural thickening ( p = 0.05 ) and thickening of the interlobar fissure ( p = 0.02 ) are more prevalent in malignant mesothelioma ; therefore
free pleural effusion is significantly more prevalent in metastatic pleural disease ( p = 0.01 ) while its prevalence is modest in malignant mesothelioma .
massive pleural effusion ( p = 0.003 ) and parenchymal infiltration ( p = 0.03 ) are significantly more common in metastatic pleural disease as well .
therefore , they should be considered as important findings to differentiate these two diseases and parameters leading to the diagnosis of metastatic carcinoma of the pleura .
a study by yilmaz et al . in 2005 demonstrated findings of malignant mesothelioma as involvement of interlobar fissure ( sensitivity of 30% , specificity of 92% ) and pleural thickening greater than 1 cm ( sensitivity of 60% , specificity of 77% ) , whereas those of metastatic pleural disease are mediastinal / hilar lymph node enlargement and lung parenchymal involvement ( 13 ) . in metintas and colleagues study which reviewed 99 mpm and 39 malignant pleural disease in 2002 ,
ring - like pleural involvement , mediastinal pleural involvement , and pleural thickness more than 1 cm were considered as independent ct findings for differentiating between mpm and malignant pleural disease with the sensitivity / specificity values of 70/85 and 59/82,respectively ( 14 ) .
generally , this data analysis manifests that ct scan is highly accurate in differentiating malignant pleural mesothelioma and metastatic pleural diseases .
comparing malignant mesothelioma and metastatic carcinoma of the pleura , pleural thickening and thickening of the interlobar fissure lead us to the diagnosis of malignant mesothelioma and massive free pleural effusion insists on metastatic carcinoma diagnosis .
Output:
| background : malignant pleural mesothelioma ( mpm ) is a rare malignant neoplasm of the pleura that typically affects individuals occupationally exposed to asbestos through a variety of industries .
mpm presents with several ct features similar to more common pleural diseases such as metastatic pleural malignancy.objectives:the aim of this study is to differentiate malignant pleural mesothelioma from metastatic carcinoma of the pleura by pathological and radiological assessment in order to investigate accuracy of ct scan in this regard and to compare ct features of these two malignancies.patients and methods : chest ct scans of 55 pleural malignancy patients including mpm and metastatic pleural malignancy were evaluated in this retrospective study .
the pathologist made the definite diagnosis based on immunohistochemistry .
a chest radiologist unaware of the pathology diagnosis observed all ct scans .
several parameters including pleural thickening , pleural effusion , thickening of inter lobar fissure , contralateral extension , contraction of involved hemithorax , parenchymal involvement ( infiltration , nodules , fibrosis ) , pleural mediastinal involvement , lymphadenopathy , extrapleural invasion ( hepatic , chest wall , diaphragm , intraperitoneal ) , and pericardial involvement were checked .
data analysis was carried out using spss version 16 , and the ability of ct scan to differentiate malignant pleural mesothelioma and metastatic pleural diseases was investigated.results:totally 29 males and 26 females were assessed in this study . based on pathology , 17 mpm and 38 metastatic pleural malignancies were diagnosed . according to ct study , about 82% of the patients with mpm and about 79% of the patients with metastatic pleural diseases
were correctly diagnosed by a radiologist .
the most common findings suggestive of mpm were pleural thickening ( 88.2% ) , loculated effusion ( 58.8% ) , and thickening of the interlobar fissure ( 47.1% ) . whereas free pleural effusion ( 71.7% ) , parenchymal infiltration ( 65.8% ) and pleural thickening ( 63.2% ) were most prevalent parameters among metastatic cases.conclusion:ct scan is highly accurate in differentiating malignant pleural mesothelioma and metastatic pleural diseases .
pleural thickening and thickening of interlobar fissure lead us to the diagnosis of mpm and massive free pleural effusion is more commonly seen in metastatic pleural malignancy . |
PubmedSumm4821 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: while the number of proteins for which the structures are known seems to increase exponentially each year ( there are now almost 72,000 structures in the research collaboratory for structural bioinformatics [ rcsb ] protein data bank ) , only a handful of intrinsic membrane proteins are among this group , despite the fact that they represent nearly 40% of all proteins .
the main reason for this is a practical one : by necessity , the portion of the protein that passes through the membrane is hydrophobic , so most methods used to extract them are tuned to maintain the protein stably in a detergent - lipid - protein micellar structure . in situ
, the associated lipid bilayer has limited the techniques that can be applied to determine structure to electron microscopy , or electron diffraction from rarely occurring two - dimensional crystals in the membrane .
x - ray crystallography remains the only general method that can yield reliable insights into the atomic structure of membrane proteins of any size , at a resolution where interatomic atom positions can be determined .
alternatively , use of lipidic phases can lead to crystallization in three dimensions within stacked planar lipid bilayers . as a result , elucidating the structures of membrane proteins presents particularly tough challenges .
this is reflected in the recent commitment of funds from the national institute of general medical sciences to support the protein structure initiative s psi : biology program aimed at membrane protein structure determination at no less than nine centers .
this is partly driven by the therapeutic possibilities since many membrane proteins are implicated in disease , and a better understanding of their structures will allow more efficient focus on development of effective drugs , seen in the context of the molecular structure of their target . despite the great technical challenges , a combination of tenacity , great patience , and ingenuity has produced a raft of technical advances that have greatly improved our ability to determine some of these structures at a resolution useful for assistance in therapeutic development .
here , i outline some of the recent achievements in advancing this most demanding of disciplines .
most membrane proteins are not expressed at high enough levels in cells of their natural environment , so determining their structures relies on inducing overexpression in cells , or by cell - free synthesis .
once expressed and inserted into the plasma membrane of cells that can be grown in quantity , membrane proteins must be solubilized from the membrane fraction , purified , and conditions optimized to maintain the protein either stably in solution over several weeks , or in lipidic environments for x - ray crystallography , electron microscopy , or nuclear magnetic resonance ( nmr ) . a further level of difficulty is associated with eukaryotic , as opposed to prokaryotic , membrane proteins that can often be expressed in the membranes of prokaryotic cells .
eukaryotic membrane proteins are normally assembled in the endoplasmic reticulum , an organelle not found in prokaryotes , and delivered to the cell surface via trafficking mechanisms and further post - translational processing in the golgi apparatus .
one of the more dramatic achievements came with the structure of the eukaryotic chloride clc transporter .
the elucidation of this structure was remarkable not only because the clc transporter is a eukaryotic membrane protein and was successfully expressed in heterologous eukaryotic cells , but for the elegant replacement of each of 30 sites by hydrophobic methionine in 20 different mutant forms of the protein .
these mutants were used because at limited resolution , which all too often is all that can be achieved , individual atoms can not be placed unambiguously .
the protein was then expressed in selenomethionine , which replaces the methionine sulfur atoms in the protein with larger selenium atoms to provide firm experimental assignment of the positions of mileposts along the protein chain .
thus this process effectively tagged the protein with visible markers at each of 30 labeled sites .
this publication also dramatically coupled visual images of the structure and explanation by rod mackinnon with music , as rimsky - korsakov s flight of the bumble bee was used as a beautiful accompaniment to the supplementary movie that illustrates the stochastic nature of chloride transport .
it is a great example of how intricate mechanisms can truly become accessible to the broad community .
cloning and expression of membrane proteins requires that they be correctly inserted into lipid bilayers or into the bacterial plasma membrane .
however , while bacteria are excellent for producing many eukaryotic proteins , they tend to not be so good at folding them . for this reason ,
it is better , if possible , in many cases to use a eukaryotic expression system .
operating in compartmentalized cells , eukaryotic membrane proteins are , however , subject to much more involved trafficking through the endoplasmic reticulum and the golgi apparatus , so protein insertion involves additional steps . a major advance has been the increasing ability to express such membrane proteins in eukaryotic cells , a key to understanding human membrane biology at the level of molecular structure .
one of the most attractive eukaryotic expression systems is in yeast saccharomyces cerevisiae , in part because there is a wealth of genetics available and it is easily grown to high volumes within a week , whereas expression in hek ( human embryonic kidney ) cells can take 1 month to establish transient expression , and around 3 months to generate stable cell lines .
rapid ways of screening expression levels by fusing a fluorescent protein to the membrane protein being tested , prior to analysis by fluorescence - detection size - exclusion chromatography to assess and eliminate misfolded and aggregated proteins , and even prior to solubilizing the membrane fraction or purification , have been instrumental in rapidly settling on satisfactory expression methods .
multiple homologous genes can be tested and screened for expression in the membranes of eukaryotic cells including insect cells , hek cells , and cos cells .
this powerful screening method for proteins that express better in certain species compared with others has resulted in several exciting breakthrough structures of membrane proteins , by first rapidly identifying the species that best expresses for crystallization .
gene redesign has become a powerful tool in controlling the expression level of membrane proteins , making structure determination possible . in a recent study ,
two redesigns of a plasmodium falciparum gene gave us low - level expression in the plasma membrane fraction of escherichia coli , whereas the wild - type gene was not expressed .
this is a common problem in expressing eukaryotic proteins in bacteria , but it can be circumvented by
in which codons that are not copied well by the bacterium are replaced by those that are , while producing the same amino acid sequence .
genes for 21 different proteins , which led to 7 of the best - expressed proteins progressing to crystallization trials . however , the rules for optimizing are still quite variable , and only about 50% of the constructs showed better expression levels than the wild - type gene , indicating that while it is a powerful tool , sometimes it requires several constructs for the same protein to find one that expresses at a higher level . of the 21 ,
codon optimization for each of these proteins was essential for adequate expression , mostly in e. coli , and for moving towards crystallization trials .
the sequence of bases is different every time the gene is designed . in attempts to calibrate effects of gene optimization and to extract algorithms that might be predictive of increased expression , two independent genes were systematically codon optimized for expression in e. coli .
the different gene variants within each set had as low as 65% dna identity with the original gene while still encoding the same wild - type amino acid sequence .
protein expression levels varied from below the level of detection to 30% of cell mass . machine learning algorithms were used to identify 12 variables of the gene and the amino acid sequence that could be used to build highly predictable and robust rule - based gene sequences that produce proteins for crystallization .
each of the important variables in e. coli was identified to be a specific codon .
the hydrophobic nature of their membrane - spanning regions makes stabilization of expressed membrane proteins more complex than soluble proteins .
the importance of lipids in interacting directly with membrane proteins has become increasingly recognized , and hence lipid mixtures are now increasingly being incorporated into crystallization cocktails .
one recipe uses buffers that contain 0.1mg / ml lipid in a 3:1:1 ratio of popc : pope : popg ( 1-palmitoyl-2-oleoyl - sn - glycero-3-phosphocholine : 1-palmitoyl-2-oleoyl - sn - glycero-3-phosphoethanolamine : 1-palmitoyl-2-oleoyl - sn - glycero-3-[phospho - rac-(1-glycerol ) ] ) , obtained from avanti polar lipids , inc . , and 5 mm of n - dodecyl -maltoside ( ddm ) as detergent .
one example of a lipid playing such a direct structural role emerged in the structure of an engineered beta-2 adrenergic receptor , where a cholesterol molecule formed the interface between the protein molecules in the physiological state of the membrane protein .
another such example is in the case of voltage - sensing domains of potassium channels , where lipid molecules are critical for correct channel conformation , and crystal structures determined without lipids show unphysiological distortions .
nmr has shown that the voltage - sensing domains interact with short - chain and long - chain phospholipids in the context of a phospholipid micelle .
the atomic description of the micelle environment and the difference in affinity for membrane lipids along the protein surface likely could not have been obtained without the use of nmr and micelles to stabilize the protein .
this nmr approach is broadly applicable and opens the door to understanding the structure , dynamics , and lipid interactions of other integral membrane proteins .
facial amphiphiles , such as cholate - based amphiphiles in which hydrophilic maltose units project from one side of the rigid and hydrophobic steroidal skeleton , are especially attractive .
particularly interesting are tandem facial amphiphiles , termed tfas , in which two deoxycholate moieties are coupled together as a covalent head - to - head dimer .
these form small , discrete micelles in water ( with a molecular weight of approximately 13 kda ) whereas ddm forms much larger micelles ( ~ 90 kda ) .
the radii of the tfas were significantly smaller ( ~19 - 30 ) , relative to ddm micelles ( ~34 ) . since the detergent micelle that surrounds the hydrophobic portions of membrane protein is essentially liquid - like
hence the smaller micelle allows proteins to pack more closely together in the crystal , and increases the amount of protein outside the smaller micelle , allowing more access to the protein for lattice formation .
three tfas showed excellent ability to maintain intrinsic membrane proteins or protein assemblies in native - like forms in aqueous solution .
affinity purification using nickel affinity tags , or antibodies to protein antigenic sites , have been developed to capture poorly expressed levels of eukaryotic membrane proteins .
size - exclusion chromatography is then used to select well - folded protein and the correct oligomeric state of protein complexes .
detergents used to stabilize membrane proteins can interfere with crystallization , so tools to assess how detergent - free a sample is are another big advance .
triple and tetra detectors that incorporate right - angle light scattering , viscosity , and the refractive index can analyze the separation of the free detergent or detergent / lipid micelles from the protein - lipid - detergent micelle and can also , in principle , determine the molecular weight of the protein - detergent - lipid complex .
x - ray crystallography is the commonest technique used to determine protein structures at a resolution high enough to provide coordinates for its atoms , and for this proteins must be crystallized .
crystallization in lipidic phases has only recently been developed but has already become an essential tool in the arsenal of membrane protein crystallization .
the method originated from ehud landau and jrg rosenbusch in 1996 and was soon followed by application to bacteriorhodopsin .
this protein had been crystallized and was the target for crystallization attempts for many years but without adequate resolution for an atomic structure determination . in the early 1980s , larry miercke , working with edward dratz and myself , had grown large - sized ( ~1 mm ) crystals of bacteriorhodopsin in the dark under dim red lights to prevent photobleaching using detergents ; hartmut michel similarly had crystallized this readily available , colored membrane protein . however , the so - called lipidic mesophase methods , a term describing lipid molecules that have properties between those of a conventional liquid and a solid crystal , proved the key to solving the structure , which eventually reached very high resolution ( 1.55 ) , with the subsequent mapping of the structural changes in the photoreaction .
this method was also applied to two other haloarchaeal rhodopsins , sensory rhodopsin and halorhodopsin , also colored membrane proteins , with success .
but until recently , it remained a boutique method readily applicable to colored proteins that could be seen inside the clear viscous phase .
the biophysics of how the method works to exclude membrane proteins into a lamellar phase where they may crystallize is still an exciting question .
these include the high - throughput robotic screening of mesophase materials for embedded crystals using x - rays that can pick out crystals of even noncolored proteins , a key step making the method routinely applicable .
another powerful approach seeks to assess the ability that membrane proteins have while in the lipidic bilayer - based mesophase and identify conditions that favor them diffusing in two dimensions as freely as possible in order to find other protein partners with which to build the two - dimensional array , which will become the nucleus for stacking up layers to form a three - dimensional crystal lattice .
a major advance is the application of fluorescence to assay the diffusion rates , seeking conditions that maximize the diffusability .
dyes such as hydrophobic 5,5-disulfato-1-ethyl-3,3,3,3-tetramethylindocarbocyanine ( cy3 ) are attached to the protein . in this method ,
labeled protein in solution ( 40% w / w ) is mixed with molten monoolein ( 1-oleoyl - rac - glycerol , sigma ) ( 60% w / w ) using a syringe lipid mixer to form lipidic cubic phase ( lcp ) .
the fluorescent dye - labeled proteins are used to assay effects of swelling agents such as butanediol on the lipid phase , and effects of cholesterol , for example , in slowing diffusion .
these methods seek to trap each membrane protein molecule within a disc of lipid bilayer of finite size .
the size of a bicelle is determined by the mass ratio of shorter chain lipids that form the rim around the disc ; the nanodisc dimension is determined by a surrounding protein .
thus the method has the advantage of bilayer - based methods of preserving integrity of the membrane protein , and the advantage of the ability to diffuse in three dimensions in the process of forming a three - dimensional lattice . in the case of bacteriorhodopsin ,
clear density for a chapso molecule inserted between protein subunits is seen within the layers indicating that an important interaction between lipid and protein has been preserved within the bicelle by the cholesterol - like detergent . the ability to grow crystals at room temperature , rather than under defined temperatures used to stabilize these heterogeneous states , significantly expands the applicability of bicelle crystallization .
bicelle lipid / amphiphile mixtures tend to form small bilayer discs at low temperature , and form a perforated lamellar phase at higher temperature .
the transition temperature depends on the lipid / amphiphile composition . in the perforated lamellar phase ,
the mixtures form gels , but at lower temperatures the mixtures are liquid and can be easily manipulated .
consequently , proteins in bicelles can be handled at low temperatures just like proteins in detergent , and crystal trials can be performed in the same manner as detergent crystallization .
thus , the bicelle approach has the advantage of convenience in handling membrane proteins within a bilayer , but in solution as opposed to being embedded in a large deformable lipid - bilayer membrane .
this allows them to diffuse freely so they can find each other and build a three - dimensional lattice while maintaining the protein in a bilayer - like environment ( as it would be in a natural membrane ) .
nanodiscs , like bicelles , are yet another template for solubilizing membrane proteins with some advantages over liposomes or detergent micelles in terms of size and stability .
the nanodisc is a noncovalent assembly of phospholipids , typically popc , dipalmitoylphosphatidylcholine ( dppc ) , dimyristoylphosphatidylcholine ( dmpc ) , and a genetically engineered membrane scaffold protein based on the sequence of human serum apolipoprotein ai .
they are formed by removing detergent from a mixture of the membrane protein , lipid , and detergents .
the phospholipid bilayer is composed of two opposed leaflets , or layers in which all lipid chains are pointed in the same direction .
the nanodisc is constrained by two molecules of membrane scaffold protein that wrap around the edges of the discoidal structure in a belt - like arrangement , such that one membrane scaffold protein coats each of the hydrophobic alkyl chains of each leaflet . to date , these bilayer - based , diffusible structures have been used to best advantage with nmr methods , or for assessing the ligand binding or native state of membrane proteins .
truncations of the hydrophilic , often flexible termini of membrane proteins have often been used as an aid to crystallization since they tend to remove a sometimes flexible region that may impede formation of an ordered three - dimensional lattice .
this can be done by truncating the gene expressed , or by mild treatment with proteolysis , as was used in the determination of the human aquaporin 4 structure .
another approach is insertion of mutations that alter the protein sequence in a manner that stabilizes one particular conformation versus others , and screening of several to find those that might rigidify otherwise flexible regions . with the beta - adrenergic receptor ,
the insertion of the mutation e122w was found to make the protein stable as detected by the raised temperature of unfolding , measured as described above .
chimeric insertions were also used to insert a small , fairly rigid soluble protein into a supposedly flexible loop of the membrane protein under the theory that more ordered and rigid components make a more ordered crystal lattice , and hence yield better resolution in the structure . the soluble protein chosen was a lysozyme , chosen because it had its n- and c- termini close to each other in the soluble protein favoring a short circuit of a short excised loop .
a powerful new strategy is to try to stabilize the membrane protein along with a screen of different engineered constructs , ligands , or lipids to assess their ability to increase the thermal stability of membrane proteins .
in a recent application , exposure and reactivity of native cysteines embedded in the protein interior were used as a sensor to determine the temperature of overall unfolding of the protein as the temperature is raised . in this case ,
a fluorescent label is used to detect thermal melting of the membrane protein by covalent attachment to cysteines that become available upon melting .
the thermal information gained by investigation of the protein stability landscape can be used to guide construct design , to select stabilizing ligands or lipids , to assess detergents , and to plan crystallization strategies based on increasing the thermal stability .
this lcp - tm protocol offers a clear quantitative method of selecting conditions that are most stabilized by the variation in conditions and therefore the most likely to crystallize since they are more likely to be in a more stable state .
the last few years have seen dramatic progress in the techniques and prospects for determining structures of membrane proteins and how they function in response to binding a natural ligand or a drug , and specifically those selected for their impact on a particular biological or biotherapeutic application . at last
, scientists can begin to approach the mechanisms of transmembrane processes involved in neurochemistry , metabolic signaling via g - protein coupled receptors , receptors that signal pain whose inhibition might assuage their debilitating effects in acute conditions , and neuroreceptors and transporters in mental illness . understanding the transmembrane processes
involved in mental illness perhaps most poignantly illustrates the potential applications for the future . today
s drugs act on membrane protein receptors and transporters , yet we often do nt know which receptors , and we know little of what effect their binding evokes , or how many other targets are also affected .
such drugs are discovered by trial and error in the only animal model that relays a sense of mental disturbance : humans .
we can now just begin to decode the action of today s drugs on each specific receptor or neurotransmitter transporter . these structures , and the purified membrane proteins that are produced even before the structures are resolved , will lead us to develop a rational approach to the treatment of schizophrenia , depression , and bipolar disorder .
the introduction of a raft of effective new tools for the membrane structural biologist reflects the ingenuity of the current generation and lays the groundwork for application to numerous diseases .
Output:
| the determination of membrane structures presents the structural biologist with many challenges ; however , the last two years have seen major advances in our ability to resolve these structures at atomic resolution .
my goal here is to summarize some of the most recent advances that have enhanced our prospects for understanding membrane proteins at the level of atomic structure . |
PubmedSumm4822 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: over 50 million women who live in areas of high malaria transmission become pregnant every year , and thousands of these women die .
women in their first and second pregnancies are at particular risk of infection with plasmodium falciparum , which is a major risk factor for maternal and foetal mortality and is implicated in 75,000200,000 infant deaths per annum [ 2 , 3 ] .
selective accumulation of parasites in the placental space results in maternal anaemia [ 46 ] and infant low birth weight ( lbw ) [ 713 ] through preterm delivery ( ptd ) [ 12 , 13 ] and intrauterine growth restriction ( iugr ) [ 7 , 10 , 12 , 13 ] .
malaria demands up to 5% of the gross domestic product in sub - saharan africa .
pregnancy - associated malaria ( pam ) infection is one example of a severe malaria syndrome , mediated by the surface expression of variant surface antigens ( vsas ) of p. falciparum parasitised red blood cells ( prbc ) that allow adherence to vascular endothelium . in non - pregnant individuals ,
vsas adhere to the ubiquitous endothelial surface proteins intercellular adhesion molecule-1 ( icam-1 ) and cd36 or to other prbc or form rosettes around non - infected rbc . under high transmission settings with favourable breeding sites for the vector anopheles mosquito ,
adults acquire natural immunity to vsas , rendering them asymptomatic [ 15 , 16 ] .
in contrast , women who are immune to these parasites also display adverse consequences of infection when they become pregnant ; this has contributed to the previous belief that pregnancy represents an immunocompromised state .
regardless of the extent of previous exposure to p. falciparum during pregnancy , all pregnant women are at increased risk of malaria and appear to be more attractive to mosquitoes [ 17 , 18 ] .
marked differences in symptoms are apparent between varying levels of transmission ; pam in areas of low transmission can result in severe infection and lead to foetal and maternal death [ 19 , 20 ] . in these symptomatic women ,
the presence of symptoms results in prompt diagnosis and management which reduces the incidence of unfavourable pregnancy outcomes .
in contrast , women living in areas endemic for malaria and hence possessing prior immunity tend to be asymptomatic in pregnancy but harbour high , undetected parasite levels in the placenta [ 16 , 23 ] .
pam affects these women in a gravidity - dependent manner : primigravid ( pg ) women are more susceptible than multigravid ( mg ) women .
after correction for age - related susceptibility , this trend has been reported consistently and is more pronounced with increasing transmission [ 25 , 26 ] .
pam is managed during pregnancy with intermittent preventive strategies using chemotherapeutic medications or insecticide - treated nets .
the world health organization recommends that insecticide - treated nets and intermittent preventive treatment ( iptp ) should be used during pregnancy [ 1 , 22 ] .
iptp consists of two doses of sulfadoxine and pyrimethamine in the second and third trimesters .
a recent systematic review demonstrates limited protection from pam in some malaria - endemic regions . while sulfadoxine - pyrimethamine treatment remains effective in west africa , and more so in three doses than two , there is a need for novel interventions .
current efforts to control the incidence of malaria infection are being hampered by rapidly increasing numbers of insecticide - resistant mosquitoes and treatment - resistant parasites .
hence , production of a vaccine to protect women in high risk areas is an urgent public health priority .
this paper aims to address our current understanding of this subject and to determine whether enough is known about the interactions between parasite and placenta to consider this a realistically attainable feat .
placental malaria ( pm ) is a subset of pam which refers to the pathological process whereby prbc and inflammatory cells accumulate within the intervillous space ( ivs ) of the placenta . at delivery
, pm can be measured by microscopic examination of stained slides of placental blood , by histopathological evaluation of placental biopsies or by semiquantitative polymerase chain reaction ( pcr ) .
examination of blood smears is rapid , cheap , and easy but does not allow assessment of past infection , whereas this is possible with both histological visualisation of parasites and pcr - assisted grading of pigment deposition .
both the latter two methods have enabled recent determinations of how long parasites may survive in the placenta : leke et al . reported that the same parasites may be detected up to 98 days before delivery through pcr examination of parasite polymorphism .
histology does not provide an accurate diagnosis ; absence of parasites or pigment at histology does not necessarily mean that infection has not occurred .
lack of effective and reliable measures to diagnose placental pathology during pregnancy limits comparisons between studies .
it is neither practical nor ethical to investigate placental parasite densities during pregnancy due to the risk of inducing foetal loss .
however , placental parasite densities at term do not appear to correlate with densities of parasites in the peripheral blood which complicates diagnosis during gestation .
observations that densities of parasites in the placenta may be far higher than the densities in peripheral blood samples suggest that parasites accumulate selectively in the ivs [ 8 , 33 ] .
the ivs forms from the lacunae between foetal - derived syncytiotrophoblastic villi , which emerge following fertilisation and implantation of the blastocyst [ 3638 ] .
placental trophoblast invades the uterine wall , gaining blood supply from the spiral arteries that pass through the endometrium .
a recent cohort study that examined the effects of timing and frequency of p. falciparum infection on pregnancy outcomes in 2,462 subjects was unable to evaluate the effects in early pregnancy because only six women in their first trimester attended the antenatal clinic where recruitment was taking place .
this small number was excluded from the study , but this demonstrates the difficulty in gaining data during this stage of gestation .
density of peripheral parasites peaks between 13 and 16 weeks of gestation , suggesting that susceptibility to pam is increased in the first trimester [ 8 , 40 ] .
the peak in parasitaemia was first identified in a large group of women living in areas of high transmission .
although this figure is highly cited , the reliability of this finding is limited by the two methods used for determining gestational age ; calculation from last monthly period is affected by recall bias and fundal height measurement is unreliable before 24 weeks of gestation .
furthermore , malaria is known to cause iugr and therefore a reduction in uterine size , leading to inaccuracy when utilising the latter as a determinant .
the reasons for the discrepancies in foetal measurements between studies have been reviewed recently elsewhere , and these inaccuracies demonstrate a need for standardised methods for the provision of comparable data .
the use of ultrasound to determine gestational age is more accurate , and it is hoped that increasing use of this method will provide more robust results .
subsequently , a decrease in peripheral parasite density was reported after 16 weeks of gestation .
however , it was observed that this reduction in peripheral levels coincided with completion of placental development , leading to the conclusion that parasites may sequester in the placenta at this time . of note , both pg and mg women recovered at the same time , supporting this hypothesis .
following delivery , women appear to undergo rapid clearance of parasitaemia , and evidence suggests that subsequent to this they are at risk of peripheral infection . in pregnancy , the dominant receptor for adhesion is thought to be the chondroitin sulphate a ( csa ) component of the chondroitin sulphate proteoglycan ( cspg ) [ 4650 ] .
placental - parasite variants that adhere to csa show an absence of binding to cd36 and icam-1 ligands , in contrast to parasite variants taken from infected non - pregnant women [ 5153 ] .
selection of prbc that adhere to csa in vitro leads to the loss of antigens that bind to cd36 and icam-1 ; hence , it is thought that parasite variants that bind to csa are mutually exclusive to those that bind to icam-1 and cd36 [ 47 , 5355 ] . in some instances
this is an infrequent observation and may result from the presence of two antigenically distinct variant molecules on a single prbc .
however , mounting evidence supporting the mutually exclusive behaviour of antigen presentation suggests that this is unlikely [ 52 , 5860 ] .
placental - binding isolates are unable to form rosettes and do not agglutinate when exposed to immune serum from non - pregnant individuals [ 53 , 6164 ] .
csa is a sulphated glycosaminoglycan ( gag ) present on the syncytiotrophoblast in the intervillous space of the placenta , located as a side chain on the tissue anticoagulant thrombomodulin .
a plethora of functions for proteoglycans have been identified , including regulation of cell proliferation , differentiation , and adhesion , as reviewed in .
binding to placental csa may alter gene transcription or signal transduction or activate intracellular signalling mechanisms that lead to increased expression of inflammatory mediators [ 6668 ] .
csa is expressed by nearly all cells but it is unclear why parasites bind only to csa expressed by the placenta , although this may be explained by the specific patterns of sulphation of placental csa and the structure it forms on the trophoblast membrane .
previously , other placental molecules , such as hyaluronic acid ( ha ) , have been implicated in placental binding of prbc , and some parasite lines have been shown to have affinity for three receptors ; csa , ha , and cd36 .
however , the strength of binding does not match that of csa - parasite adherence alone .
it is now well established that the parasite protein able to adhere to csa in the placenta is var2csa coded for by the var2csa gene [ 58 , 72 ] .
this protein is a member of the p. falciparum erythrocyte membrane protein 1 ( pfemp1 ) family [ 16 , 73 ] .
encoded by the var multigene family , pfemp1 molecules vary greatly between variants and strains , but each protein retains its c - terminal intracellular domain , an extracellular domain , and a single transmembrane helix .
the ectodomain , responsible for discrete receptor - binding properties , consists of multiple duffy binding - like ( dbl ) domains and cysteine - rich interdomain regions ( cidrs ) [ 7476 ] .
vsas that are thought to specifically cause disease in pam , such as var2csa , are collectively referred to as vsapam .
infection with p. vivax during pregnancy is associated with maternal anaemia and foetal lbw [ 7881 ] , but is not thought to increase the risk of ptd .
pregnant women are at increased risk of infection with p. vivax , although this species does not appear to sequester in the placenta .
p. vivax is suppressed by co - infection with p. falciparum , although co - infection may lower the risk of severe anaemia [ 32 , 82 ] .
little is known about placental infection with p. malariae , p. ovale , and p. knowlesi : both p. ovale and p. malariae can infect pregnant women , but pregnancy does not appear to increase susceptibility to infection with these species [ 7 , 80 , 83 ] .
prior to the appearance of the placenta during pregnancy , women are not exposed to vsapam - expressing variants and therefore lack specific antibodies [ 47 , 62 ] . serum taken from mg women with previous exposure to these variants has been shown to inhibit adhesion of prbc isolated from pg women [ 47 , 62 , 9395 ] .
inhibition of binding was assumed to be protective because these same women proceeded to have several additional successful pregnancies .
in contrast , immune sera from pg women and adult men , with no previous exposure to vsapam - expressing variants , could not prevent binding to csa .
levels of pregnancy - specific antibodies have been correlated with the degree to which binding of prbc to csa is inhibited [ 63 , 95 , 96 ] .
levels of protective antibodies increase with gravidity [ 62 , 63 , 95 , 96 ] .
inhibition of binding by antibodies contributes to parasite clonal variation , antigenic switching and hence immune evasion , although it has been reported recently that antigenic switching may occur due to intrinsic regulatory systems .
antibodies are detected in both pg and mg women ; low levels have been detected at 14 weeks of gestation in pg women [ 91 , 98 ] , in contrast to previous reports of detection being possible only after 20 weeks [ 95 , 99 ] .
although these women appear capable of producing antibodies , they may not confer protection in pg women because the antibody repertoire is not broad enough to inhibit binding of more than one or two variants .
complex infections with numerous phenotypes may disrupt the ability to combat effectively the response to a single variant .
in addition , the presence of non - specific , non - protective immunoglobulin ( ig ) may delay or interfere with the acquisition of memory b cells .
of the five classes of ig , igg is known to be the most important in malaria immunity , and , in humans , the subclasses igg1 and igg3 have been found to correlate most with protection from disease [ 25 , 101 ] .
igg - mediated protection is thought to be achieved through anti - adhesion and opsonic activity [ 102104 ] .
anti - adhesion antibodies have been shown to correlate with reduced levels of placental parasitaemia and to act by promoting splenic removal of parasites [ 62 , 105 ] .
the anti - adhesive properties of antibodies have been studied more extensively than their cytophilic properties .
recent reports of correlations of opsonizing var2csa - specific igg and protection from pm may indicate that both means of parasite clearance need to be assessed in vitro .
furthermore , opsonic antibodies may be a more specific predictor of outcome than overall igg levels . in one study ,
strong associations between levels of antibodies and protection from anaemia were reported at delivery in the absence of correlations with protection from lbw .
anti - adhesive antibodies lower the parasite density , which is associated with an increase in birth weight and length of gestation . whether the increased birth weight is a result of decreased chronic malaria or due to increased length of gestation is not clear , but lbw is a major risk factor for infant mortality .
if a pregnant woman is unable to adequately clear parasites , chronic infection of the placenta may ensue .
, studying women in senegal , found that women could be divided into two groups .
pregnant women were either infected with parasites that persisted in the placenta until birth ( from as early as 69 days before delivery ) or were constantly being reinfected with new , antigenically distinct parasites , emerging throughout gestation . in this latter group , samples clear of parasites were taken between those that contained parasites of new genotypes , indicating that this group of women was able to achieve effective parasite clearance between each infection .
parity status , birth weight , and time of delivery did not differ between the two groups , but women in the first group described had significantly lower levels of var2csa - specific igg initially , although levels were similar by the time of delivery .
absence of antibodies in pregnancy may lead to long - lasting parasite genotypes sequestered in the placenta , which may interfere with further antibody production .
lack of vsapam - specific igg production is associated with an increased risk of developing chronic pm and anaemia .
levels of vsa - specific igg for non - placental variants do not appear to confer protection against poor pregnancy outcomes , but levels of these antibodies appear to remain constant during pregnancy [ 25 , 98 ] .
similar levels of igg that inhibit binding to icam-1 and cd36 have been found in non - pregnant and pregnant women in the same transmission settings .
mice with prior immunity to p. berghei succumb to recrudescent parasites during pregnancy and suddenly become symptomatic in the second week of gestation .
recrudescence poses a risk for women who become pregnant after emigrating from an area of malaria transmission .
compared the antibody responses of pregnant women living in two areas of cameroon with different levels of transmission ( 2.4 infective bites / day versus 0.11.1 infective bites / month ) . in the low transmission setting ,
all women , regardless of age or parity , had significantly lower levels of igg than women living in a high transmission setting .
the sample size of the latter group was smaller than the group from the low transmission setting but the antibody responses reported are in keeping with previous studies .
in the high transmission setting , pg women produced vsapam - specific igg much more rapidly than those in the area of low transmission .
these findings support earlier reports that indicate transmission intensity is important for antibody acquisition [ 94 , 105 ] , yet although these trends are well described , comparison of results from different studies is limited due to vast variations in transmission levels . where transmission intensity is greatest , even women in their second pregnancy may have been exposed to enough variants in their first pregnancy to be protected from pm .
mg women who live in areas of perennial transmission may be less able to control mixed placental infections in subsequent pregnancies than those in areas of seasonal transmission , where polyallelic infections have been correlated with lbw [ 102 , 110 , 111 ] .
this indicates that the differences in antibody responses are not simply divided by geographical variations in transmission rates , which vary greatly across areas of sub - saharan africa .
few data have been published on antibody levels in women with no previous exposure to parasites .
where pregnant women do not appear to have been exposed during pregnancy , they have been shown to be at risk of recrudescent infections that may still cause pm due to previous exposure prior to conception [ 114 , 115 ] .
also , in non - immune mice , infection with p. berghei is usually fatal and placental infection often leads to spontaneous abortion .
retrospective and prospective data have found that increasing the dose of iptp in the third trimester reduces the production of vsapam - specific igg [ 98 , 117 ] .
observations from a longitudinal study suggest that levels of antibodies in women taking iptp remain low for the duration of pregnancy , although antibody levels were seen to fluctuate throughout gestation
. this may be due to variation in the levels of parasite exposure , increased virulence of certain phenotypes , or measured differences following decay of igg antibodies .
these observations indicate that women who have received treatment in their first pregnancy will need continued therapy in subsequent pregnancies and demonstrate that results from previous cross - sectional studies may be inaccurate in representing antibody responses during gestation .
this particular study does have its limitations ; all women had favourable outcomes and there was a lack of placental histological examination at delivery .
interestingly , immunity to malaria has been seen to increase efficacy of antimalarial chemotherapy , and this effect has been reported in pam also .
this implies that production of a vaccine would have an additional benefit ; if antibody levels do not reach those required for parasite clearance , they are at least likely to increase the efficacy of pharmacological interventions . serum from mg women can recognise a number of strains of the var2csa - expressing parasite variant .
distinct strains are recognised by monoclonal antibodies ( mabs ) although maternal antibodies may cross - react with different var2csa - transcribing placental isolates from distinct geographical regions without previous exposure [ 71 , 119 ] .
approximately 42% of pregnant women in a study cohort from malawi and papua new guinea reacted to two or more globally isolated parasite lines .
high levels of cross - reactivity seen in these populations may result from serum being cross - reactive , but not necessarily cross - inhibitory , although cross - inhibition by serum has been reported by fried et al . .
cross - reactivity of serum is thought to be either due to clonally conserved epitopes on individual var2csa molecules or to polymorphic epitopes that are found in all isolates .
levels of vsapam - specific igg decline post - partum , but they have been detected at six months after delivery .
previous studies have demonstrated that in mg women after delivery , up to one in 4,000 b cells show specificity for exposed epitopes of var2csa [ 120 , 121 ] .
persistence of memory b cells has not been examined , rendering a gap in our understanding of how mg women are able to maintain immune memory once the placenta has been expelled and antigenic exposure is lost .
the cytokine balance in pregnancy is shifted towards a predominantly anti - inflammatory response by the t helper ( th)2 subset of cd4 t lymphocytes .
this balance is mediated by the maternal placental decidua and provides a specific environment to allow persistence of the semi - allograft foetus ( expressing paternal antigens ) within the mother . at the blastocyst stage of pregnancy , th1 proinflammatory cytokines , including interleukin ( il)-2 , tumour necrosis factor ( tnf- ) , and interferon gamma ( ifn- ) , are essential for implantation .
ifn- is involved in remodelling of the spiral arteries to achieve adequate placental blood flow and tnf- is necessary for induction of labour [ 123 , 124 ] . following implantation , a th2 response is favoured which permits foetal development by production of the th2 cytokines il-4 , il-5 , il-10 , and il-13 [ 125 , 126 ] and transforming growth factor ( tgf- ) [ 127 , 128 ] .
levels of progesterone and oestrogen rise in the early stages of pregnancy , and both promote a th2 response .
secreted by the corpus luteum , progesterone maintains the endometrium , providing a welcome environment for the blastocyst and for subsequent embryo development [ 126 , 130 ] .
progesterone is a potent inducer of il-4 and il-5 , which oppose ifn- while inhibiting proliferation of cd8 t cells
relaxin is thought to counterbalance th2 activity of progesterone and promotes development of t cells that produce ifn- so is likely to play a more protective role in pregnancy . in non
- pregnant individuals , both th1 and th2 cytokine profiles are associated with protection , the former more active in the acute phase , for parasite clearance , and the latter during chronic infection [ 131 , 132 ] .
, now recognised as a prevailing th2 response of second trimester pregnancy [ 125128 ] , is thought to favour parasite persistence and has been suggested to be responsible for the rise in parasite densities reported at 1316 weeks .
placental accumulation of prbc appears to stimulate th1 cytokine release by macrophages [ 133 , 134 ] to aid parasite clearance , possibly through increased phagocytic activity and by production of reactive oxygen species and nitric oxide ( no ) metabolites [ 133136 ] .
however , parasite densities may need to reach a threshold before inducing th1 responses in the placenta . in mice , strong th1 responses cause foetal loss , but
in human pregnancies induction of these cytokines has been associated with maternal anaemia , spontaneous abortions , and ptd [ 137 , 138 ] .
concentrations of tnf- appear to correspond to infiltration of monocytes and the degree of sequestration [ 133 , 135 ] .
macrophages activated by haemozoin ingestion are thought to be the main source of both tnf- and il-8 . elevated
tnf- levels can enhance cytoadherence , promote monocyte recruitment , and affect hormonal regulation and structural integrity within the placenta [ 143 , 144 ] .
higher concentrations of plasma tnf- have been found in febrile , symptomatic pregnant women and teenage mothers , perhaps indicating an association with age - related immune acquisition .
gravidity - related differences in tnf- have been reported inconsistently [ 145 , 146 ] .
the soluble tnf receptors , tnfr1 and 2 , modulate the activity of tnf- , and dysregulation of their control mechanisms may be linked to the development of severe malaria [ 147 , 148 ] .
high levels of ifn- have been found in placental and peripheral blood samples [ 133 , 134 , 149 ] , with significantly higher levels found in infected pregnant women than non - infected pregnant women .
ifn- is produced by maternal cd8 and cd4 t cells and natural killer ( nk ) cells , but it is produced also by the foetal trophoblast . typically , elevated levels of ifn- are not associated with poor pregnancy outcomes but have been correlated with gravidity - dependent protection .
protection , without pathological consequences , is likely to be related to the maternal ability to prevent ifn- levels from exceeding an unknown pathological cut - off point .
ifn- concentrations have been found to be higher in mg women in acute pm , and a subsequent drop in cytokine levels is observed , whereas in pg women this cytokine peaks at a lower level but remains there .
migration inhibitory factor ( mif ) is secreted from the foetal syncytiotrophoblast , which may be as a direct result of binding to csa [ 68 , 150 ] .
mif stimulates phagocytosis of prbc , and increased levels of mif have been seen in pm [ 150 , 151 ] .
mif encourages accumulation of macrophages , which is consistent with the increased numbers of macrophages seen on histopathological examination at delivery [ 150 , 151 ] . in one study of pg and
mg women , substantially higher levels of mif were found in placental sera than in peripheral sera , with greater concentrations of mif in placental samples from pg compared to mg individuals .
hence , it is possible that an increase in mif may provide protection in the placenta .
these differences may play a part in gravidity - specific immunity , yet equally the differences seen may be due to higher parasite densities experienced in pg women or to raised steroid levels in pg that are known to increase mif concentrations .
however , the small sample size in this study limits the reliability of the data , and future research is needed in this area .
it is currently not known how early th1 responses may be stimulated or whether these responses can be induced independently of placental binding . however , a th1 cytokine response to clear parasites also appears to occur in mg women who continue to have successful pregnancies .
this would indicate that the alteration in cytokine balance may not be as detrimental to the foetus as might be expected . similarly
, this may demonstrate the nature of the host / parasite relationship because a rapid death of both mother and foetus would be lethal for the parasite .
although numerous studies have reported elevated levels of th1 cytokines in pm , it is not a consistent finding [ 153 , 154 ] . raised levels of th2 cytokines have also been found in pm which may indicate a positive feedback response to restore th2 dominance .
local upregulation of il-10 , which acts directly on macrophages and causes a decrease in il-12 production , has been reported in multiple studies [ 133 , 134 , 146 , 155 ] . in one study cohort ,
women with pm were reported to have a predominant th2 response which did not correlate with parity , age or sex , but parasite densities were consistently low .
tgf- is thought to protect against severe pm , demonstrated by extended survival of p. berghei - infected mice when administered tgf- , although raised levels have not been consistently correlated with parasite densities of women with predominantly successful outcomes .
peripheral levels of cytokine concentrations do not correlate with cytokine levels in the placenta or with numbers of cd4 t cells measured [ 145 , 157 ] .
however , cytokine responses can be examined using p. berghei [ 108 , 114 , 158 ] .
murine models are simpler , cheaper , and raise fewer ethical issues than simian models although data from these should be used with caution due to differences in the architecture of human and murine placentas .
in addition , mice show a similar th1th2 shift during pregnancy to that seen in humans . data from cross - sectional studies which examine cytokine dynamics during pregnancy are difficult to use because of the type - one error incurred by measuring numerous levels of cytokines that do not increase or decrease independently [ 133 , 156 ] . discrepancies between studies could further be accounted for by the short - lived persistence of cytokines in the blood , indicating the need for more intense sampling or development of methods of cytokine quantification with increased sensitivity and specificity .
women may be more susceptible to malaria during pregnancy due to a reduction in t cell numbers .
reports of decreased t cell responses could be due to sequestration of t cells in the ivs [ 157 , 161 ] .
parasite - specific t cell proliferative responses may be increased in mg women who exhibit protection from pm ; fievet et al .
reported that mg women produced increased levels of th1 cytokines to csa - adhering strains of p. falciparum but not to non - csa binding strains .
cytotoxic cd8 t cells are implicated in the protective immune response to pre - erythrocytic malaria parasites .
their role in pm has not been determined , primarily since in murine models their function beyond the liver stage of the plasmodium life cycle remains controversial .
it has been a long held opinion that the mechanism of activation of cd8 t cells precludes a protective role against blood stage malaria .
this is because cd8 t cells are stimulated by antigens in association with major histocompatibility complex ( mhc ) class i molecules which are not expressed by rbc .
however , reticulocytes ( immature rbc ) express mhc class i molecules and numbers of reticulocytes increase during pregnancy , and these can be infected by mature parasites .
cd8 t cells may potentially play a protective role in pm if they are found to respond to these antigens .
recent observations of raised levels of cd8 t cells in pregnant women with absent pm following parasite clearance may indicate that they may have an anti - parasite effect via a non - ifn- pathway .
dendritic cells , macrophages , nk cells , nk t cells , and t cells interact non - specifically with foreign pathogens .
t cells are known to be important in non - specific targeting of p. falciparum although their role , in addition to that of dendritic cells and nk t cells , has not been studied in pm thus far .
nk cells rapidly produce tnf- and ifn- which can inhibit replication of p. falciparum , and their presence is implicated in the antibody - dependent nk - mediated lysis of prbc [ 170172 ] .
unique subsets of nk cells are involved in the maintenance of early pregnancy , although alterations in nk cell behaviour may predispose to infection . in an endemic area
, a higher proportion of activated nk cells were found in the placenta , and this was associated with an absence of accompanying parasitaemia .
interestingly , numbers of nk cells were not increased , but higher concentrations of ifn- were measured .
if women could stimulate immediate ifn- release , they were able to control parasitaemia more effectively . unfortunately , this study only looked at women with favourable birth outcomes , and high numbers of nk cells have previously been associated with poor outcomes .
whether or not this is related to the concentration of ifn- rather than to the number of cells remains to be seen .
in contrast , decreased activity of nk cells has been linked to severe pm episodes , which may be due to the absence of nk recognition of parasite antigens , and therefore ifn- is not produced .
this finding is from in vitro experiments , where no other co - stimulants are present , which is unlikely to be the case in vivo .
the presence of mononuclear cells in the placenta has been correlated negatively with birth weight .
stimulation of these cells promotes secretion of chemokines which contribute to the initiation of the inflammatory cascade .
both cxc/ and cc/ chemokines may increase locally in pm , namely , ifn- inducible protein ( ip-10 ) , monocyte chemoattractant protein 1 ( mcp-1 ) , macrophage - inflammatory protein 1 ( mip-1 ) , and macrophage - inflammatory protein 1 ( mip-1 ) [ 17 , 133 ] .
these substances have been associated with angiogenesis , haematopoiesis , and protection from intracellular pathogens .
local activation is supported by observation of greater densities of activated monocytes in the placenta than are found in the peripheral circulation .
phagocytosis is further mediated through complement activation . in vitro observations using plasma from non - immune donors
indicate that if complement deposition is prevented , 8095% of phagocytosis of prbc is prevented .
thus , complement may play a supplementary role to uptake of antibody - opsonised prbc in macrophage clearance observed in semi - immune women .
however , as seen with cytokine levels , excessive levels of complement activation may contribute to the pathogenesis associated with inflammation .
in healthy pregnancies , complement component 3 ( c3 ) is reduced by expression of cd55 , cd59 , and a membrane cofactor protein which are expressed by the placenta to limit local damage [ 129 , 179 ] .
pg women with pm have been shown to have over 50% more complement at delivery than non - infected pregnant women , although this particular study did not compare levels with mg women .
nevertheless , excess complement activation may overwhelm complement regulatory proteins and contribute to placental injury . raised levels of complement component 5a ( c5a ) , activated by c3a ,
excessive levels of c5a have been identified as a mediator of placental and foetal injury in mice , often resulting in spontaneous abortion and iugr .
c5a enhances macrophage and neutrophil activity , and excessive levels indicate that regulation of complement activation has been lost .
levels of activated complement need to be examined in a larger group of women with pm and correlated with gravidity , pregnancy outcomes and degree of inflammatory infiltrate .
complement and cytokine release by macrophages may occur before placental binding takes place because toll - like receptors of the innate immune response are known to respond to the p. falciparum toxin glycosylphosphatidylinositol ( pfgpi ) , promoting local inflammation .
placental - dwelling macrophages may secrete tissue factor which initiates the clotting system ; clot formation can plug the intervillous space and disrupt blood flow . raised levels of cortisol during pregnancy
have been correlated with parasite load , with significantly higher levels in pg women than in mg women .
cortisol is known to increase mif-1 , decrease cmi , suppress nk cell activity , and delay antibody production and may decrease il-10 responses [ 175 , 186 , 187 ] .
these factors could explain why pg women are more susceptible to pam than mg women .
unfortunately , this study is confounded by the young age of pg study participants compared to the mg women ( mean ages 18 and 30 , respectively ) . in an area of unstable transmission ,
women of all gravidities were found to have raised levels of cortisol compared to non - infected pregnant women .
prolactin is thought to be host protective in pam , but it may be influenced by changing cortisol levels [ 175 , 186 ] .
a study that reported a correlation between low levels of prolactin in women with high parasite densities also found that in these women levels of il-10 were also low .
human immunodeficiency virus ( hiv ) alters the typical gravidity - specific pattern of malaria risk by shifting the burden from primarily pg and secundigravid women to all pregnant women . in a retrospective analysis of 11 reports published over a15-year period ,
the proportional increase of p. falciparum infection during pregnancy attributable to hiv was estimated to be between 5.5 and 18.8% for populations with hiv prevalences ranging from 10 to 40% .
in addition , viral load has been found to increase with malaria infection in pregnant women [ 189 , 190 ] .
lower levels of vsapam - specific igg and decreased levels of opsonic igg activity have been reported in women who are hiv positive .
hiv infection lowers numbers of cd4 t cells , with lower levels correlating with more severe disease .
hiv infection further impairs cytokine responses ; il-12 may be reduced so an early th1 shift may not occur , leading to loss of the protective rise of ifn- .
table 2 summarizes the key maternal and foetal outcomes of placental malaria and the immunological basis for the pathological process leading to each outcome .
placental damage stimulates cytotrophoblast proliferation resulting in a thickened cytotrophoblast membrane which may decrease the exposure of placental and foetal tissues to inflammation .
maternal - foetal transfer of nutrients , oxygen , and waste products may be compromised by mechanical blockage and inflammatory cells .
risk of iugr is increased if infections include complex multiallelic variants [ 98 , 102 ] , are increased in frequency , or occur during the second trimester rather than the third .
a major limitation of our understanding of the pathological mechanisms involved in pm surrounds the processes that lead to iugr .
the first trimester is a critical period for foetal organogenesis ; the majority of growth takes place in the second trimester , and organ and cell maturation are completed during the third trimester . prior to placental completion , early accumulation of prbc in lacunae may induce complement activation or cytokine release which could impact negatively on embryogenesis .
the majority of lbw babies born to mothers with pm are uniformly small , implying that growth restriction has been symmetrical and most likely occurred in the first trimester .
raised levels of activated soluble inflammatory mediators are likely to cause pathology when unregulated during pm .
tnf- has been associated consistently with foetal lbw , either through iugr [ 135 , 139 ] ( associated with accumulation of high concentrations of monocytes during chronic placental infection ) or through ptd .
ifn- , although not associated convincingly with lbw [ 135 , 139 ] , can induce nk cells which may be involved in malaria - associated spontaneous foetal loss . however , it is more likely that ifn- has a protective role in pm .
ptd may be caused by a low tnf- : il-10 ratio ( due to raised levels of both tnf- and il-10 in the placenta ) , maternal anaemia secondary to an augmentation of il-10 , or a sudden acute increase in tnf- concentration .
active inflammation with monocyte infiltration may also lead to dysregulation of the insulin - like growth factor ( igf ) axis which is upregulated in the normal placenta to support growth .
vascular endothelial growth factor ( vegf ) and angiogenic factors , including angiopoietin 1 and 2 ( ang-1 , ang-2 ) , are important in the control of vascular development and remodelling during placental development .
raised levels of svegfr1 have been associated with excessive levels of c5a ; either c5a or the presence of parasite products that activate complement may be responsible for this .
dysregulation of angiopoietin levels has been reported in women with peripheral parasitaemia , and was correlated more closely in women who had lbw babies .
these levels were measured at delivery , but disturbance of the balance of these growth factors could occur earlier in gestation and impact negatively on foetal growth .
these findings support the hypothesis that the pathogenesis of pm is similar to that of pre - eclampsia ( pe ) .
a case - cohort study reported an absence of relative risk between pm and pe whereas , although this type of study design does not provide a causal link , a correlation was seen between pm and gestational hypertension [ 199 , 200 ] .
gestational hypertension may result from impaired placental blood flow , possibly from shallow trophoblast invasion and poor placental vascularisation , or from mechanical blockage of blood flow
. reduced placental perfusion , endothelial dysfunction , and placental ischaemia are thought to contribute to iugr .
women who harbour complex infections are at increased risk of anaemia , while the infants born to these women are more likely to have infected cord blood and increased risk of malaria in the first 30 months of life .
although parasite infection of cord blood is common [ 154 , 203 ] and newborns may harbour an asymptomatic parasitaemia [ 204 , 205 ] , disease is rare [ 77 , 205 ] .
protection from disease may be due to foetal haemoglobin being composed of different globin subtypes than adult haemoglobin , decreased infant exposure due to swaddling and transfer of maternal antibody [ 205207 ] .
pm may prime foetal immune t cells in utero to favour a th2 cytokine response due to exposure to maternal cytokines [ 205207 ] .
inflammation may disrupt igg transporters in the syncytiotrophoblast , thereby reducing placental transfer of igg in response to other pathogens including measles virus and streptococcus pneumoniae .
in order to produce an ideal vaccine for pam , all the protective responses that occur in natural infections need to be stimulated .
figure 2 summarizes the potential immunological interactions in pm and the protective responses that occur in mg women .
is the var2csa molecule , the structure of which differs to that of other pfemp1 molecules .
it comprises six dbl domains and a cidr , all of which display polymorphism between strains [ 69 , 116 ] . from 32 isolates from a sample of pregnant women in senegal , not one shared an identical sequence in the dbl5 domain .
the var2csa gene that codes for var2csa displays significant levels of polymorphism , demonstrated by the number of possible unique antigens that have been produced .
however , it is more conserved than other var genes , and var2csa retains 7583% of its amino acids between isolated strains .
however , the degree of antigenic variation between globally isolated parasite lines has not been determined .
vaccine developments with var2csa have been hampered by the difficulty in producing a recombinant protein of this size . to overcome this issue initially , individual domains of var2csa
have been studied to determine if a particular region of the molecule is responsible for receptor binding and induction of antibodies .
three of the six dbl regions ( dbl2-x , dbl3-x and dbl6- ) are known to bind to csa , but the remaining three ( dbl1-x , dbl4- , dbl5- ) display limited affinity for csa [ 218 , 219 ] .
it has proved difficult for study groups to adequately assess binding of different dbl regions , as interactions between recombinant proteins ( expressed by escherichia coli , baculovirus or pichia pastoris constructs [ 220222 ] ) and csa in vitro may not be representative of native binding .
furthermore , studies that have elicited adhesion inhibition have observed it in assays of csa on plastic mounts [ 103 , 220 , 224 ] , which , whilst they provide an easy laboratory method of assessing adhesive properties , do not contain the same levels of sulphation as csa on the syncytiotrophoblast . the most promising method to study
adhesion behaviour is to use bewo cells from human choriocarcinoma that provide a placental construct on which csa is naturally found [ 90 , 220 , 224 ] .
antibodies have been induced in mice and goats with recombinant dbl3 , dbl4 , and dbl5 domains [ 104 , 220222 , 225 , 226 ] .
antibodies to dbl3 and dbl5 recognised other var2csa - expressing strains from diverse geographical regions , whereas cross - reactivity was not observed following immunisation with dbl1 , 4 , or 6 .
despite displaying cross - reactivity , these antibodies did not inhibit binding , suggesting that only surface reactivity may occur with in vitro - induced antibodies .
interestingly , the most effective anti - adhesion antibodies have been induced in rats with dbl4 domains .
this domain is thought to display the lowest binding affinity for csa but is highly conserved between variants .
the dbl5 domain displays 6681% conservation between isolates , and strain - transcending adhesion inhibition has been seen under flow conditions using bewo cells lines and antibodies induced in mice and goats .
single domains from non - placental pfemp1 may also bind to csa in vitro but with much weaker affinity than binding of whole var2csa .
the full - length version induces anti - adhesion antibodies that are highly strain - specific .
whole recombinant var2csa has now been produced , and , although the ability to induce antibodies using this construct has been inconsistent , these findings demonstrate that all domains may be as important as each other in mediating binding and antibody stimulation [ 103 , 104 , 227 ]
. a combination of epitopes on each domain may form a binding complex or unique binding site by forming a quaternary structure .
if this is the case , individual polymorphisms in dbl regions may come together to alter the binding site of var2csa , which would account for the cross - reactive but not adhesion - inhibitory strain - transcending responses described .
convincing evidence is emerging that supports the formation of a binding site from the first four domains and interactions with the cidr and interdomain regions [ 228 , 229 ] .
inconsistent induction of antibodies with whole constructs could be caused by differing expression methods employed or could indicate limitations of using such a large immunogen [ 104 , 227 ] . although the biochemical interactions are beyond the scope of this review , our understanding of the true nature of parasite antigen - placenta interactions may not be far enough advanced for effective vaccine trials .
induction of cytophilic activity by igg molecules has been shown to be an effective immune mechanism , but this has been largely ignored in vaccine development studies to date . perhaps a novel way forward would involve shifting the focus towards induction of these antibodies : specifically , whether they may be induced using single domains or whole antigens ; and , if inducible , whether they display the same degree of specificity as anti - adhesive antibodies . the lack of identification of a conserved epitope thus far should not be considered disheartening as even antibodies that stimulate a protective response against one or two variant lines may be beneficial in pg women to help lower parasite load and increase efficacy of treatment .
induction of antibodies by single domains and whole var2csa has not yet been tested in humans , and it is likely that single variants will produce differing antibody responses to those found in naturally mixed allelic infections .
evidence suggests that the ability of a construct to induce antibodies depends greatly on the animal being immunised ; a recent study observed that immunisation responses varied greatly and unpredictably between mice , rabbits , and rats and the same is likely to be true with humans .
even if var2csa could be used , the highly specific antibody repertoire gained from this would only confer protection against one parasite strain .
it is not currently known if , or how , immunity develops to strains simultaneously , and this may further complicate trials of antibody stimulation in vivo . if an epitope is identified that allows women to develop inhibitory antibodies rapidly to a range of strains by focusing the immune response , it could provide better protection than that which is naturally acquired .
currently , findings indicate that a number of allelic variants will be needed in a vaccine due to the high levels of polymorphism within the parasite population .
a clear association has been shown between the presence of anti - adhesion antibodies and weight gain of foetuses , but precise pathological mechanisms by which antibodies reduce or inhibit associated inflammation are unknown .
the inhibition of binding may decrease inflammation by preventing activation of signalling pathways on the syncytiotrophoblast that lead to cytokine production .
the continued study of individual binding domains of var2csa may increase our knowledge of these mechanisms even if these studies do not lead to viable vaccine possibilities .
judging by the appearance of placental variants in the second trimester , a vaccine would be most effective given before pregnancy but could also provide protection if given during the first trimester .
this is improbable , however , because the majority of pregnancies in developing countries are not confirmed until the second trimester due to socioeconomic and cultural reasons affecting access to primary health care .
theoretically , stimulation of mabs using individual domains may be possible in prepubescent girls and repeated over successive years , but this is unlikely to be feasible .
the lack of understanding of how immunological memory is maintained hinders the validity of this option .
antibodies have been seen to persist for six months without continued antigen exposure , but it is uncertain if they would continue beyond this .
this indicates that decay of antibodies may occur by the time a woman becomes pregnant if the vaccine is given too early , although this may depend on the specific ig subclasses that are included in the vaccine .
women who lack naturally acquired immunity are not protected from peripheral binding variants and a var2csa would not inhibit binding of these parasites , resulting in peripheral infection . furthermore , selection pressure exerted by such a vaccine is likely to increase global antigenic diversity . continued efforts
to identify conserved epitopes are the aim of non - pam vaccines , and proof of principle studies have led to phase iii trials ( reviewed in ) .
the most advanced candidate , the rts , s vaccine against the circumsporozoite antigen , provided 25.659% protection in phase ii trials and became the first malaria vaccine to reach phase iii trials .
while this extensive study across seven sub - saharan countries will not be completed before 2014 , preliminary results show grounds for qualified optimism [ 232 , 233 ] .
it is unclear what protection this may provide during pregnancy because it is unlikely to achieve sterile immunity and despite women having antibodies against non - vsapam and other parasite proteins prior to pregnancy , the immunity that develops is not adequate to prevent pregnancy - associated infection .
a vaccine against p. falciparum will not protect against p. vivax which is a major problem in regions where transmission of p. falciparum is low , such as the indian subcontinent .
the protection gained from maternal anaemia due to mixed infections may be lost through a p. falciparum - specific vaccine .
further to this , the placental - binding property of p. falciparum to csa has provided a selective advantage , but p. vivax is known to accumulate in the placenta .
more recently , severe syndromes associated with p. vivax have been reported in children , which could indicate increasing virulence in this parasite .
similar receptors to the vsas have been found on the membrane of the p. vivax prbc , but sequestration is currently not thought to occur . as
yet , it is not clear if vaccination with single domains or whole var2csa is recognised by t cells . in the early stages of determining which epitopes stimulate protection , it is essential that t cell responses are considered in vaccine trials .
natural expression of antigens on prbc may stimulate specific antibodies in a different way , and natural interactions of t and b cells may also determine efficacy .
if var2csa is the key antigen in immune acquisition in pam , then it may prove possible to answer the questions below : to
which part of the molecule do antibodies react ? in models , are antibodies produced to isolated domains ?
what class of antibodies are produced using a vaccine ? how long do memory b cells persist ?
can t cell responses be induced ? if t cells are stimulated and produce a protective response that generates ifn- , then
will a tnf- response that harms the placenta also be induced ? will protective innate mechanisms be stimulated by a vaccine ? what end points would we use to measure the effectiveness of a vaccine ?
there are a number of areas that require further research to increase our understanding of both the pathogenesis and immunology of pam .
these include the following : pathological processes occurring in the first trimester ; pathological mechanisms leading to anaemia and lbw with p. vivax infections ; trials of new methods of diagnosing placental malaria infection ; analysis of peripheral cytokines as possible surrogate markers ; longitudinal studies in low transmission settings and longitudinal studies of cytokine dynamics ; whether the responses that lead to immunity and the responses that lead to pathology can be distinguished ; how hormones contribute directly to susceptibility in pam ; longitudinal studies to examine how infant cohorts are affected ; further analysis of the burden of pam outside africa .
the majority of studies described in this review are cross - sectional or retrospective analyses of antibody and parasite dynamics in pregnant women .
levels of both parasites and antibodies fluctuate during pregnancy , and true representations of these dynamics can only be obtained through longitudinal studies [ 34 , 98 , 102 ] .
in addition to the need for more robust studies , there is a risk that by focusing attention on a small part of the pathological processes occurring in pm , we will lose sight of what we already know .
for example , although binding of csa does not occur until the second trimester , the processes may not be as crucial to pathogenesis as currently thought : if binding to csa increases gene expression and secretion of inflammatory mediators , such as mif-1 that promotes macrophage aggregation , then inflammatory processes will not begin until after week 16 .
we can not be certain of the development of inflammation because there is no way of assessing when this begins in pregnant women .
the detection of peripheral levels of inflammatory markers , such as raised levels of tnfr1/2 , svegr1 , c5a , and il-10 , would be an ideal method of diagnosing active pm in asymptomatic women .
however , no marker has been found to correlate adequately with the degree of inflammation .
the pathological processes of pm are dynamic throughout gestation , but the presence of parasites in the placenta may be detrimental to embryo development before binding occurs .
this could potentially be studied using var2csa - null variants in vitro using bewo cells .
is pam vaccination possible ? at present , the creation of a vaccine looks unlikely . not enough is known about specific binding interactions between csa and var2csa , and globally conserved epitopes have not been identified .
these hurdles , combined with the task of including all necessary parasite strains in a single vaccine and the risk that a vaccine could potentially lead to an increase in the prevalence of other malaria species not covered by the vaccine , do not favour vaccine development .
if growth mechanisms are most affected in the first trimester , a var2csa vaccine would be ineffective at reducing the burden of iugr .
this paper has , however , identified some of the gaps in our knowledge , and filling these may lead to ways of overcoming these obstacles .
even if a vaccine is able only to stimulate the production of a small antibody repertoire this could boost treatment effects and decrease the financial burden of pam . in the light of growing resistance of p. falciparum to current chemotherapeutic regimens ,
even a vaccine that could result in lower doses and increased efficacy of these regimens has potential value , and research to that end should be welcomed .
Output:
| pregnancy - associated malaria , a manifestation of severe malaria , is the cause of up to 200,000 infant deaths a year , through the effects of placental insufficiency leading to growth restriction and preterm delivery .
development of a vaccine is one strategy for control .
plasmodium falciparum - infected red blood cells accumulate in the placenta through specific binding of pregnancy - associated parasite variants that express the var2csa antigen to chondroitin sulphate a on the surface of syncytiotrophoblast cells .
parasite accumulation , accompanied by an inflammatory infiltrate , disrupts the cytokine balance of pregnancy with the potential to cause placental damage and compromise foetal growth .
multigravid women develop immunity towards var2csa - expressing parasites in a gravidity - dependent manner which prevents unfavourable pregnancy outcomes .
although current vaccine design , targeting var2csa antigens , has succeeded in inducing antibodies artificially , this candidate may not provide protection during the first trimester and may only protect those women living in areas endemic for malaria .
it is concluded that while insufficient information about placental - parasite interactions is presently available to produce an effective vaccine , incremental progress is being made towards achieving this goal . |
PubmedSumm4823 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: vaccination programs for immune activation are vital for preventing the spread of infection and decreasing the severity of infection in individual patients.1 vaccines can be administered orally or by inhalation ; however , subcutaneous , intradermal , or intramuscular injections are still the most common routes of administration.2 family physicians regard fear of injections as an impediment to immunization compliance in adults .
although there are many studies on pain during vaccination in children,36 there are few studies focusing on the adult population,7,8 possibly because pain and fear of injection are presumed to be less intense in adults.3 these studies show that pain during vaccination can be decreased by the use of analgesic drugs.4,5 in addition , different types of physical interventions6 have been developed to decrease pain during injection .
however , time constraints , expense , and the possibility of side effects have limited the application of these interventions .
therefore , they are unfamiliar in general practice . in the united states and europe , influenza vaccination
is usually administered by intradermal injection.9 however , in japan , influenza vaccination guidelines recommend subcutaneous injection.10 in adults , application of local manual pressure at the injection site decreases pain during subsequent intramuscular injection.8 this manual pressure method is advantageous because it requires no additional medication , has few ( if any ) side effects , requires no additional equipment , and does not appreciably prolong treatment time .
therefore , this method can be an effective and practical means of decreasing pain during subcutaneous injection . in japan , although the manual pressure method is recommended for relieving pain during injection of the influenza vaccine , no study has assessed the efficacy of this method for the relief of pain during subcutaneous injection . to evaluate the pain - relieving effects of this procedure ,
we compared visual analog scale ( vas ) scores of adult patients who received subcutaneous injection immediately after 10 seconds of local pressure application at the injection site with those of controls who received no such treatment before injection .
this semirandomized , open - label study was conducted from november 11 , 2011 to december 31 , 2012 in rural clinics and general hospitals .
the study protocol was approved by the research ethics committee of yamaguchi grand medical center and conformed to the principles of the declaration of helsinki .
patients were assured that their participation was voluntary , and all participants provided written informed consent .
participants were adults ( > 20 years of age ) from the general population who were scheduled to receive the influenza vaccination by subcutaneous injection . patients were excluded if they did not provide written consent , were aged < 20 years , or could not complete the pain scales or other test forms .
the patients were semirandomly allocated to either the control ( odd ) or intervention ( even ) groups using case numbers . from a previous study
, we estimated that the e / s ( standard effect size / standard deviation ) was 0.4.8 we estimated that the e / s for our study was 0.25 in consideration of the clinical effect and difference between subcutaneous injection and intramuscular injection .
we set the target number for each group as 350 cases and a total of 700 cases in consideration of the exclusion criteria .
participants were not aware of their group allocation in advance , and the physician was not present during completion of the test measures for pain .
the experimental intervention used in this trial was the manual pressure method which was applied immediately before injection . using this method
the physician applied pressure using the thumb to depress the injection site ( posterior surface of the upper arm ) for 10 seconds immediately before immunization .
all other techniques were as per the 2003 influenza vaccination guidelines for japan10 and included the unified even talking technique .
the injection site was approximately one third down from the shoulder on the arm extensor of the patient s choice .
the injection needle used for all participants measured 26 g 0.45 , 13 mm .
in addition to pain , we evaluated age , gender , height , weight , body mass index , body temperature , and fat thickness at the brachial triceps muscle . to assess pain
, patients completed a 100 mm vas and a face scale ( fs , figure 1 ) .
we used the statistical package for the social sciences ii ( spss japan inc , tokyo , japan ) for the statistical analysis .
a p - value of < 0.05 ( two - tailed ) was considered to be statistically significant .
categorical variables were compared using chi - square tests and continuous variables were compared using unpaired t - tests between the intervention and control groups .
multivariate analysis was performed using the vas score or fs score as the dependent variable and weight , age , height , fat thickness at the brachial triceps muscle , and body temperature as independent variables .
this semirandomized , open - label study was conducted from november 11 , 2011 to december 31 , 2012 in rural clinics and general hospitals .
the study protocol was approved by the research ethics committee of yamaguchi grand medical center and conformed to the principles of the declaration of helsinki .
patients were assured that their participation was voluntary , and all participants provided written informed consent .
participants were adults ( > 20 years of age ) from the general population who were scheduled to receive the influenza vaccination by subcutaneous injection . patients were excluded if they did not provide written consent , were aged < 20 years , or could not complete the pain scales or other test forms .
the patients were semirandomly allocated to either the control ( odd ) or intervention ( even ) groups using case numbers . from a previous study , we estimated that the e / s ( standard effect size / standard deviation ) was 0.4.8 we estimated that the e / s for our study was 0.25 in consideration of the clinical effect and difference between subcutaneous injection and intramuscular injection .
we set the target number for each group as 350 cases and a total of 700 cases in consideration of the exclusion criteria .
participants were not aware of their group allocation in advance , and the physician was not present during completion of the test measures for pain .
the experimental intervention used in this trial was the manual pressure method which was applied immediately before injection . using this method
the physician applied pressure using the thumb to depress the injection site ( posterior surface of the upper arm ) for 10 seconds immediately before immunization .
all other techniques were as per the 2003 influenza vaccination guidelines for japan10 and included the unified even talking technique .
the injection site was approximately one third down from the shoulder on the arm extensor of the patient s choice .
the injection needle used for all participants measured 26 g 0.45 , 13 mm .
in addition to pain , we evaluated age , gender , height , weight , body mass index , body temperature , and fat thickness at the brachial triceps muscle . to assess pain
, patients completed a 100 mm vas and a face scale ( fs , figure 1 ) .
we used the statistical package for the social sciences ii ( spss japan inc , tokyo , japan ) for the statistical analysis . a p - value of < 0.05 ( two - tailed ) was considered to be statistically significant . a correlation coefficient ( r ) of > 0.2 was considered significant .
categorical variables were compared using chi - square tests and continuous variables were compared using unpaired t - tests between the intervention and control groups .
multivariate analysis was performed using the vas score or fs score as the dependent variable and weight , age , height , fat thickness at the brachial triceps muscle , and body temperature as independent variables .
a total of 693 adults participated , of whom 679 were included in our analyses ( 345 in the intervention group and 334 in the control group , figure 2 ) .
there were no significant differences in demographic or clinical variables between the two groups ( table 1 ) .
therefore , the number of cases used was sufficient to consider the effectiveness of this method .
although there were differences in the vas ( 22.5 23.0 versus 21.2 23.6 , p = 0.4 ) and fs ( 2.5 2.1 versus 2.4 2.1 , p = 0.4 ) scores between the intervention and control groups , the differences were not significant ( table 2 ) .
multivariate analysis showed that there was a significant negative association between each pain score and age ; younger participants reported more intense pain ( vas , r = 0.32 ; fs , r = 0.28 ) .
the manual pressure method was not effective for decreasing pain during subcutaneous injection of the influenza vaccine .
however , we clarified that the degree of pain associated with this influenza vaccine was judged to be mild ( approximately 2/10 ) as per the vas score . therefore , it remains to be determined if this method is more efficacious for more painful injections .
there were significant differences in the level of pain experienced by participants of different ages , with younger participants reporting more intense pain .
analgesia from manual pressure presumably involves interference of nociceptive transmissions by other somatosensory modalities , as explained by the gate control theory.11 of course , this study neither confirms nor refutes the gate control theory .
rather , we suggest that pain during subcutaneous injection is equally influenced by psychologic factors as it is by nociceptive stimulation , and older people and patients with diabetes have a higher pain threshold , probably because their receptors are worn out .
it was reported that pain during intramuscular injection was significantly more intense in women than in men , although there was no significant age dependence in this finding.7 in that study , the average age was lower and the age range narrower than in our study .
in contrast , we found no gender differences in the level of pain experienced in our study , at least in the age group < 65 years .
first , we only assessed pain experienced during injection and not the subsequent pain that many experience at the injection site .
second , there was no way of masking the treatment , and pain ratings were subjective , leading to the possibility of a placebo effect .
the manual pressure method used in this study was not effective for decreasing mild pain during subcutaneous injection of the influenza vaccine .
pain during subcutaneous injection of the influenza vaccine was low ( vas < 3 ) , to the point that analgesia was not required . if necessary
, we can consider the use of topical anesthetics as well as psychologic support for patients with extreme fear of needles .
Output:
| backgroundit is necessary to establish an effective subcutaneous injection procedure for adult and elderly individuals because many drugs such as hormones and interferon are generally delivered by subcutaneous injection .
we tested whether pain during subcutaneous injection can be decreased by prior application of localized manual pressure at the injection site.methodsin this semirandomized , open - label study evaluating the manual pressure method for transient analgesia , physicians applied pressure with their thumbs for 10 seconds to create a nonpainful skin depression at the injection site immediately before subcutaneous injection of the influenza vaccine to patients .
control patients received the vaccine by the same route , but without prior application of focal pressure .
in addition to pain , we evaluated patient age , gender , height , weight , body mass index , body temperature , and fat thickness at the brachial triceps muscle .
pain intensity was estimated using a 100 mm visual analog scale ( vas ) and the face scale ( fs ) .
categorical variables were compared using chi - square tests and continuous variables were compared using unpaired t - tests between the intervention group and control group .
multivariate analysis was performed using the vas or fs score as the dependent variable and weight , age , height , fat thickness at the brachial triceps muscle , and body temperature as independent variables.resultsthere were no significant differences in demographic variables , vas scores ( 22.5 23.0 versus 21.2 23.6 , p = 0.4 ) , or fs scores ( 2.5 2.1 versus 2.4 2.1 , p = 0.4 ) between the intervention and control groups .
there was a significant negative correlation between age and subjective pain intensity ( vas , r = 0.32 ; fs , r = 0.28).conclusionthe manual pressure method was not effective in decreasing pain during subcutaneous injection .
alternative methods of focal transient analgesia should be developed to improve vaccination rates and relieve anxiety associated with subcutaneous injection . |
PubmedSumm4824 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: patients with frequent angina ( 1 episode per week ) report greater physical limitations and decreased quality of life compared with patients with minimal angina.1 the goals of chronic stable angina management are not only to control symptoms , but also to reduce the risk of adverse clinical outcomes.26 as symptom control impacts the patient s quality of life , maximum consideration should be given to the array of available management options that aim to reduce angina symptoms . for many patients
, this would include a physical activity program aimed at improving exercise tolerance in accordance with current secondary prevention guidelines .
several studies have shown that optimal medical therapy , along with aggressive risk factor modification , is as effective as revascularization in reducing the risk of adverse coronary events.79 optimal medical therapy includes anti - anginal or anti - ischemic as well as disease- modifying therapy.8,10 the anti - ischemic agents include short- and long - acting nitrates , beta - blockers , and calcium channel blockers.3,4,11 these agents reduce angina symptoms and prolong exercise duration and/ or time to st - segment depression.3,11 frequently , a combination of drugs is necessary for optimal symptom control.3 nitrates work primarily by venodilation and afford rapid relief of angina.12 a number of placebo - controlled studies have shown that the sublingual application of nitroglycerin increases exercise duration in patients with stable angina.1317 published data also suggest that residual and recurrent angina is frequently experienced by patients who have already undergone either a percutaneous or surgical revascularization procedure , and these patients require continued medical therapy with multiple anti - anginal agents , including short- and long - acting nitrates , for control of their symptoms.8,18,19 increased physical exercise is also important in patients with stable angina to reduce the risk of cardiovascular events , and current recommendations call for the use of sublingual nitroglycerin as part of optimal medical therapy.5,20 this randomized , double - blind , placebo - controlled , crossover , dose - ranging multicenter study in patients with chronic stable angina evaluated the effect of a sublingual nitroglycerin spray formulation on time to onset of angina during exercise , total exercise duration , and time to exercise - induced myocardial ischemia , as evidenced by electrocardiographic st - segment depression .
brief results were previously published in german.21 the goal of the present article is to more fully describe the study methodology , patient characteristics , and detailed results in the context of current optimal medical therapy .
this study was carried out at four centers in the united states and conducted in accordance with the international conference on harmonisation guidelines for good clinical practice and food and drug administration guidelines .
all patients provided written informed consent at the screening visit , prior to starting any study - related procedures .
adults ( 18 years of age ) with coronary artery disease as documented by a 50% reduction in arterial lumen diameter in 1 or more major coronary arteries or their primary branches , a previously documented myocardial infarction , or reversible perfusion defect on stress thallium-201 scintigraphy and a diagnosis of chronic stable exertional angina that had been made at least 2 months prior to screening were eligible to be screened . in the 2 months
prior to study entry , patients were required to have been on a stable medical treatment regimen for their angina .
patients with unstable angina , myocardial infarction , coronary angioplasty , or cardiac surgery within 3 months of screening were excluded .
additional exclusion criteria included a history of congestive heart failure ( nyha iii or iv ) , significant disease of the cardiac conduction system , uncontrolled hypertension or hypotension , any physical conditions known to affect st - segment morphology , or severe organ damage or disease of any system .
patients were not permitted to receive concomitant therapy with long - acting nitrates or digitalis preparations during the study .
in addition , participation in an investigational drug study within 1 month prior to the screening visit or while participating in the study was prohibited .
patients with clinically significant deviations from normal in either the physical exam or lab parameters and patients with peripheral arterial disease that limited their exercise capacity were also excluded . according to the approved protocol , each center was to enroll a minimum of 12 patients to ensure evaluable outcomes for 40 patients at the end of study . following an initial screening visit , eligible patients returned for a baseline exercise tolerance test ( ettb ) according to a standard bruce protocol.22 of note
, exercise testing is associated with minimal complications ; death and myocardial infarction occur at a rate of 1 per 2,500 tests performed.15,23 patients who developed angina within 39 minutes of commencing exercise were eligible to continue in the study . following a 90-minute rest period , these patients were assessed for nitrate response .
patients who were able to exercise for 60 seconds longer in this ett ( ettres ) than in the ettb were eligible to continue in the study . at their next visit , patients completed a confirmatory ett ( ettconf ) to establish reproducibility ( within 20% ) of the time to development of moderate angina when compared to the ettb . in order to reduce baseline variability ,
study - related sublingual nitroglycerin was discontinued 6 hours prior to testing , while other anti - anginal medications were discontinued approximately 24 hours prior to each visit . after baseline and confirmatory etts
the goal of this crossover study design with each patient serving as his / her own control was to minimize the impact of any training effect on the mean values for each treatment dose .
the crossover period consisted of 5 additional visits within 14 days , at which patients were administered placebo or sublingual nitroglycerin spray ( 0.2 mg , 0.4 mg , 0.8 mg , or 1.6 mg ; nitrolingual pumpspray , g. pohl - boskamp gmbh & co. kg , germany ) . in order to minimize the impact of any training effect , patients completed a control ett ( ettc ) and an investigational ett ( ettinv ) at each visit .
ettc studies were carried out at approximately the same time of day as the introductory ett studies ( ettb and ettconf ) . following a 90-minute rest period ,
primary efficacy endpoints were time to onset of angina symptoms and time to development of moderate angina ( defined as the level of activity at which the patient would normally stop activity ) .
the secondary endpoint was time to 1-mm st - segment depression ( myocardial ischemia ) . to minimize the impact of any training effect , efficacy endpoints are described as the mean difference between ettinv and ettc at each visit .
the difference between the confirmation and baseline etts was then subtracted from this value to further reduce the impact of any training effect .
safety parameters included evaluation of all changes in physical examination , vital signs , ecg , and laboratory evaluations .
this study was carried out at four centers in the united states and conducted in accordance with the international conference on harmonisation guidelines for good clinical practice and food and drug administration guidelines .
all patients provided written informed consent at the screening visit , prior to starting any study - related procedures .
adults ( 18 years of age ) with coronary artery disease as documented by a 50% reduction in arterial lumen diameter in 1 or more major coronary arteries or their primary branches , a previously documented myocardial infarction , or reversible perfusion defect on stress thallium-201 scintigraphy and a diagnosis of chronic stable exertional angina that had been made at least 2 months prior to screening were eligible to be screened . in the 2 months
prior to study entry , patients were required to have been on a stable medical treatment regimen for their angina .
patients with unstable angina , myocardial infarction , coronary angioplasty , or cardiac surgery within 3 months of screening were excluded .
additional exclusion criteria included a history of congestive heart failure ( nyha iii or iv ) , significant disease of the cardiac conduction system , uncontrolled hypertension or hypotension , any physical conditions known to affect st - segment morphology , or severe organ damage or disease of any system .
patients were not permitted to receive concomitant therapy with long - acting nitrates or digitalis preparations during the study .
in addition , participation in an investigational drug study within 1 month prior to the screening visit or while participating in the study was prohibited .
patients with clinically significant deviations from normal in either the physical exam or lab parameters and patients with peripheral arterial disease that limited their exercise capacity were also excluded .
according to the approved protocol , each center was to enroll a minimum of 12 patients to ensure evaluable outcomes for 40 patients at the end of study . following an initial screening visit ,
eligible patients returned for a baseline exercise tolerance test ( ettb ) according to a standard bruce protocol.22 of note , exercise testing is associated with minimal complications ; death and myocardial infarction occur at a rate of 1 per 2,500 tests performed.15,23 patients who developed angina within 39 minutes of commencing exercise were eligible to continue in the study . following a 90-minute rest period , these patients were assessed for nitrate response .
patients who were able to exercise for 60 seconds longer in this ett ( ettres ) than in the ettb were eligible to continue in the study . at their next visit
, patients completed a confirmatory ett ( ettconf ) to establish reproducibility ( within 20% ) of the time to development of moderate angina when compared to the ettb . in order to reduce baseline variability ,
study - related sublingual nitroglycerin was discontinued 6 hours prior to testing , while other anti - anginal medications were discontinued approximately 24 hours prior to each visit . after baseline and confirmatory etts
the goal of this crossover study design with each patient serving as his / her own control was to minimize the impact of any training effect on the mean values for each treatment dose .
the crossover period consisted of 5 additional visits within 14 days , at which patients were administered placebo or sublingual nitroglycerin spray ( 0.2 mg , 0.4 mg , 0.8 mg , or 1.6 mg ; nitrolingual pumpspray , g. pohl - boskamp gmbh & co. kg , germany ) . in order to minimize the impact of any training effect , patients completed a control ett ( ettc ) and an investigational ett ( ettinv ) at each visit .
ettc studies were carried out at approximately the same time of day as the introductory ett studies ( ettb and ettconf ) . following a 90-minute rest period ,
primary efficacy endpoints were time to onset of angina symptoms and time to development of moderate angina ( defined as the level of activity at which the patient would normally stop activity ) .
the secondary endpoint was time to 1-mm st - segment depression ( myocardial ischemia ) . to minimize the impact of any training effect , efficacy endpoints are described as the mean difference between ettinv and ettc at each visit .
the difference between the confirmation and baseline etts was then subtracted from this value to further reduce the impact of any training effect .
safety parameters included evaluation of all changes in physical examination , vital signs , ecg , and laboratory evaluations .
of the 61 patients assessed for eligibility , 10 patients did not meet the protocol criteria and were therefore excluded .
a total of 51 patients performed the baseline exercise test and qualified for continuation . following a 90-minute rest period
, patients underwent a subsequent stress test after receiving 0.4 mg of open - label sublingual nitroglycerin spray .
all 51 patients showed an improvement in exercise duration of 60 seconds or greater ( range 1.024.7 minutes ) .
a total of 51 patients between the ages of 34 and 77 years continued in the double - blind phase and were randomized to 1 of 5 treatment sequences .
two patients did not complete the study ( 1 patient was lost to follow - up and 1 patient discontinued prematurely due to ventricular tachycardia / fibrillation requiring cardioversion after the control exercise test at visit 5 ; this event was not considered to be treatment related ) .
overall patient characteristics including angina and cardiovascular event history , along with concomitant medications , are described in table 1 . a dose - dependent increase in time to onset of moderate angina
the time to onset of angina was significantly higher in all treatment groups ( 0.2 mg , 0.4 mg , 0.8 mg , and 1.6 mg ) than in the placebo group ( table 2 , fig .
the increase in time to onset of angina and to onset of moderate angina was most pronounced in the 1.6-mg group , with dose linearity between 0.4- and 1.6-mg doses of nitroglycerin spray .
the occurrence of a minimum 1.0-mm st - segment depression was later in all treatment groups ( 0.2 mg , 0.4 mg , 0.8 mg , 1.6 mg ) compared with the placebo group ( table 2 , fig .
of 51 patients , 12 ( 24% ) reported adverse events at the qualification visit ( open - label sublingual nitroglycerin response test ) .
adverse events considered related to treatment were reported for 2 ( 4% ) , 4 ( 8% ) , 8 ( 16% ) , 9 ( 18% ) , and 13 ( 26% ) patients receiving placebo and 0.2 mg , 0.4 mg , 0.8 mg , and 1.6 mg nitroglycerin spray , respectively .
the most frequently reported adverse events of this nature were headache and dizziness , all of which were mild to moderate in severity .
the incidence of treatment - related adverse events was dose dependent , with the incidence of headache increasing from 0 with placebo to 3 ( 6% ) , 5 ( 10% ) , 6 ( 12% ) , and 8 ( 16% ) after 0.2 mg , 0.4 mg , 0.8 mg , and 1.6 mg nitroglycerin spray , respectively .
no serious adverse events related to treatment were reported . per protocol , patients with systolic blood pressure ( sbp ) less than 100 mmhg were excluded from the study .
symptomatic hypotension was not reported as an adverse event , however sbp decreased to a level of 100 mmhg or less in 1 ( 2% ) , 0 ( 0% ) , 1 ( 2% ) , 0 ( 0% ) , and 3 ( 5% ) patients after receiving placebo and 0.2 mg , 0.4 mg , 0.8 mg , and 1.6 mg nitroglycerin spray in the double - blind phase .
of the 61 patients assessed for eligibility , 10 patients did not meet the protocol criteria and were therefore excluded .
a total of 51 patients performed the baseline exercise test and qualified for continuation . following a 90-minute rest period
, patients underwent a subsequent stress test after receiving 0.4 mg of open - label sublingual nitroglycerin spray .
all 51 patients showed an improvement in exercise duration of 60 seconds or greater ( range 1.024.7 minutes ) .
a total of 51 patients between the ages of 34 and 77 years continued in the double - blind phase and were randomized to 1 of 5 treatment sequences .
two patients did not complete the study ( 1 patient was lost to follow - up and 1 patient discontinued prematurely due to ventricular tachycardia / fibrillation requiring cardioversion after the control exercise test at visit 5 ; this event was not considered to be treatment related ) .
overall patient characteristics including angina and cardiovascular event history , along with concomitant medications , are described in table 1 .
a dose - dependent increase in time to onset of moderate angina was seen following administration of nitroglycerin spray ( table 2 , fig .
the time to onset of angina was significantly higher in all treatment groups ( 0.2 mg , 0.4 mg , 0.8 mg , and 1.6 mg ) than in the placebo group ( table 2 , fig .
the increase in time to onset of angina and to onset of moderate angina was most pronounced in the 1.6-mg group , with dose linearity between 0.4- and 1.6-mg doses of nitroglycerin spray .
the occurrence of a minimum 1.0-mm st - segment depression was later in all treatment groups ( 0.2 mg , 0.4 mg , 0.8 mg , 1.6 mg ) compared with the placebo group ( table 2 , fig .
overall , nitroglycerin spray was generally well tolerated . of 51 patients , 12 ( 24% )
reported adverse events at the qualification visit ( open - label sublingual nitroglycerin response test ) .
adverse events considered related to treatment were reported for 2 ( 4% ) , 4 ( 8% ) , 8 ( 16% ) , 9 ( 18% ) , and 13 ( 26% ) patients receiving placebo and 0.2 mg , 0.4 mg , 0.8 mg , and 1.6 mg nitroglycerin spray , respectively .
the most frequently reported adverse events of this nature were headache and dizziness , all of which were mild to moderate in severity .
the incidence of treatment - related adverse events was dose dependent , with the incidence of headache increasing from 0 with placebo to 3 ( 6% ) , 5 ( 10% ) , 6 ( 12% ) , and 8 ( 16% ) after 0.2 mg , 0.4 mg , 0.8 mg , and 1.6 mg nitroglycerin spray , respectively .
no serious adverse events related to treatment were reported . per protocol , patients with systolic blood pressure ( sbp ) less than 100 mmhg were excluded from the study .
symptomatic hypotension was not reported as an adverse event , however sbp decreased to a level of 100 mmhg or less in 1 ( 2% ) , 0 ( 0% ) , 1 ( 2% ) , 0 ( 0% ) , and 3 ( 5% ) patients after receiving placebo and 0.2 mg , 0.4 mg , 0.8 mg , and 1.6 mg nitroglycerin spray in the double - blind phase .
lifestyle modifications , including supervised exercise therapy , play an important role in the success of optimal medical therapy.2427 however , patients with stable angina generally have impaired exercise tolerance and reduced daily physical activity.28 sublingual nitroglycerin increases physical exercise tolerance which , in turn , helps to increase the amount of exertion possible prior to the onset of angina.12,13 sublingual forms of nitroglycerin are readily absorbed through mucous membranes , and their effect is prompt , reliable , and more effective than other forms of nitroglycerin , including ointments , transdermal patches , and sustained - release preparations.11,29 the results of this study are in line with prior findings and demonstrate a significant improvement in exercise tolerance with sublingual nitroglycerin spray in patients with stable angina .
although sublingual nitroglycerin spray was generally well tolerated , an increase of treatment - related adverse events was observed with higher dose levels ( 26% of patients with 1.6 mg nitroglycerin spray ) .
one important issue that is not specifically addressed in this study is the clinical relevance of the nearly 1-minute improvement in exercise duration with sublingual nitroglycerin spray over placebo .
it must be recognized that this improvement was experienced by patients who were exercising at a higher work load ( higher speed and incline during the treadmill test ) after receiving the study medication .
as most real - world patients have a much slower walking pace , this finding indicates that prophylactic nitroglycerin spray might allow much greater increases in walking times during normal daily activities .
although this outcome was not formally evaluated in the present study or discussed in previous publications to our knowledge , patients have often reported a marked increase in angina - free walking time and exercise duration after taking prophylactic sublingual nitroglycerin .
since this study of sublingual nitroglycerin spray was conducted , there have been significant changes in optimal medical therapy for stable coronary artery disease .
this is particularly apparent in the greater use of beta - blockers compared with calcium channel blockers and long - acting nitrates to treat angina , and the routine use of daily aspirin and a statin to reduce serious cardiovascular outcomes.3,8 although beta - blockers are currently considered a standard treatment for stable angina , patients receiving these medications may continue to experience angina.30 however , patients with a history of beta - blocker use who are appropriately supplemented with sublingual nitroglycerin or long - acting nitrates show significant improvements in angina - free exercise duration and total walking time compared with placebo.3,5,29 the american college of cardiology and american heart association guidelines for the management of patients with chronic stable angina emphasize the initial use of medical therapy.5,20,31 these guidelines include the recommendation for all patients to undergo a risk assessment with a physical activity history and/or an exercise test to guide prognosis and prescription .
ett is associated with a very low rate of serious adverse events such as death ( 0.5 per 10,000 tests ) , myocardial infarction ( 3.58 per 10,000 tests ) , or serious arrhythmias ( 4.78 per 10,000 tests).15 guideline - compliant medical therapy improves clinical outcome in many patients with stable angina , as evidenced by an observational study in which increasingly guideline - compliant therapy was associated with a reduction in death and myocardial infarction in patients with stable angina during 1 year of follow - up.32 indeed , implementation of a quality improvement program in utah to enhance the prescription of appropriate discharge medications among patients with cardiovascular disease was associated with improvements in cardiovascular readmission rates and reductions in mortality.33 a number of studies have compared the effect of optimal medical therapy versus revascularization on symptoms and outcomes in patients with coronary artery disease and stable angina . in general , these studies have shown that optimal medical therapy is effective in controlling symptoms and , along with risk factor modification , can reduce the risk of adverse cardiac events.8,34 moreover , these studies have shown that there is no significant difference in serious adverse clinical events , such as myocardial infarction and death , between patients who have received medical therapy and those who have undergone revascularization.2,5,8 the clinical outcomes utilizing revascularization and aggressive drug evaluation ( courage ) trial , which compared the efficacy of percutaneous coronary intervention ( pci ) plus optimal medical therapy versus optimal medical therapy alone , demonstrated similar rates of death and nonfatal myocardial infarction in both patient groups over a follow - up period of 55 months.8 moreover , both groups demonstrated a substantial reduction in angina symptoms , with 74% and 72% of patients in the pci and optimal medical therapy groups , respectively , angina - free after 5 years of follow - up.8 further analysis of data from the courage study found that both groups of patients had marked improvements in health status , including reductions in angina symptoms , and improved quality of life .
although the pci group demonstrated significantly greater health benefits in the short term , these benefits disappeared after longer - term follow - up , and by 36 months there was no significant difference in health status between the 2 groups.9 the bypass angioplasty revascularization investigation 2 diabetes trial in patients with diabetes , coronary artery disease , and classic angina compared the effects of revascularization with medical therapy alone on clinical outcomes . during the 5-year follow - up
, no difference was found between the medical therapy and revascularization groups on the risk of all - cause death , myocardial infarction , or stroke.34 furthermore , a meta - analysis of 11 randomized trials comparing pci with conservative treatment in patients with stable coronary artery disease found no significant difference between the 2 treatment strategies with regard to overall mortality , cardiac death , or myocardial infarction.7 current recommendations state that patients with stable angina may defer surgical intervention without additional risk to allow for determination of response to optimal medical therapy.5,11 despite the published outcome data and current guideline recommendations , many patients are still referred for revascularization , mainly due to a belief that these procedures reduce the risk of myocardial infarction or death more effectively than optimal medical therapy alone.2,3,8,35 additional studies assessing the long - term benefits of exercise in the context of medical therapy compared with revascularization outcomes could help to further inform the clinical decision making process .
in this study , sublingual nitroglycerin spray was shown to increase time to onset of moderate angina during exercise .
this improvement in physical exercise tolerance may be of great clinical relevance , as the prophylactic use of sublingual nitroglycerin spray allows patients to face exertion with confidence and permits exercise for a longer amount of time .
these results support the use of sublingual nitroglycerin spray as nitrate therapy in patients with stable angina who are being managed with optimal medical therapy .
this approach may also be beneficial for patients who have persistent angina post - revascularization .
further studies are needed to evaluate the long - term beneficial effects of using routine prophylactic nitroglycerin spray in patients with stable angina to increase exercise duration and improve quality of life and well - being .
Output:
| backgroundsublingual nitroglycerin increases exercise duration in patients with stable angina .
brief results from this study were published previously in german . here , we more fully describe the study methodology , patient characteristics , and detailed results.methodsthis double - blind , crossover study enrolled 51 patients with stable angina .
patients were randomized to 1 of 5 treatment sequences and were administered placebo or nitroglycerin spray ( 0.2 mg , 0.4 mg , 0.8 mg , or 1.6 mg ) .
patients carried out 1 control exercise tolerance test ( ett ) and 1 investigational ett at each visit.resultsdose-dependent increases in time to onset of angina , time to onset of moderate angina , and the occurrence of a minimum 1.0-mm st - segment depression were seen following administration of nitroglycerin spray.conclusionsthese results support the use of sublingual nitroglycerin spray in patients with stable angina who are being managed with medical therapy and in patients who have persistent angina post - revascularization . |
PubmedSumm4825 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: a number of epidemiological studies carried out around the world have shown that the prevalence of epilepsy rises rapidly above this age , even increasing beyond the other prevalence peak which appears in infancy . on the one hand , we have those patients whose epilepsy started at whatever age and who are now over 60 year - old , and on the other hand those in whom it started after this age , the latter representing 25% of the new cases of epilepsy ( sander and shoevon 1996 ) .
the incidence of epilepsies in the over 60s is double the figure for those aged between 40 and 59 years old and follows a lineal growth reaching a figure of 140/100,000 for the over 80s , three times the figure for those in the 6069 year - old age group ( loiseau et al 1990 ; tallis et al 1991 ; hauser 1992 ; hauser et al 1993 ) .
thus , epilepsy together with cerebrovascular pathology and dementias is one of the most common neurological pathologies in old age . moreover , as will be seen below , both cerebrovascular pathology and dementias may be a cause of epilepsy . given the tendency towards an ageing population in the west , an increase in the number of epileptic patients , particularly in this segment of the population , can be expected . in spite of
the fact that more and more often , the epileptic patients encountered in the surgery are over 60 years old , this age group is rarely represented in the clinical trials which have led to the approval of the different antiepileptic drugs ( aeds ) .
the high co - morbidity , the frequency of polypharmacy , the increased risk of secondary effects and of mortality due to intercurrent causes in these patients are , among others , the reasons for their almost systematic exclusion from clinical trials . therefore , given the lack of evidence based on clinical trials , we shall try to determine the most appropriate antiepileptic drugs for these patients according to the characteristics of their epilepsy , the modifications in the metabolic capacity of the drugs which arise with age , the possibility of secondary effects of special relevance to the elderly and the characteristics of the different drugs .
in elderly patients , the critical phenomenology presents peculiarities which may make diagnosis more difficult .
for example , automatisms and auras are unusual in the elderly and often the crises present themselves as episodes of confusion or syncopal events . therefore ,
in almost half of the elderly patients who are finally diagnosed with epilepsy , epilepsy is not the initial suspected diagnosis ( ramsay et al 2004 ) .
furthermore , the appearance of an epileptic status as a form of presentation of the epilepsy is also more common among the elderly ( pryor et al 2002 ) .
it should be remembered that the elderly are more at risk of presenting reactive crises .
the metabolic disorders which may provoke a crisis , including hypo- or hyperglycemia , uremia , hyponatremia or hypocalcaemia , are more common among the elderly .
in addition , this section of the population tends to use drugs more frequently , including drugs potentially capable of inducing an epileptic crisis , as are some antidepressants , neuroleptics and certain antibiotics .
however , this increase in the incident rate only corresponds to certain types of epilepsy .
almost no idiopathic epilepsies start in this age group . in any case , we may encounter patients with idiopathic epilepsies which started at much earlier ages and who have reached old age . therefore , the possibility of a generalized epilepsy commencing in old age is remote , and given an patient aged over 60 who has developed epilepsy we should consider a focal epilepsy even when there is no clear focal start to the crises ( hiyoshi and yagi 2000 ) .
practically two thirds of epilepsies which develop at this age are symptomatic , and the other third are cryptogenic .
the most common cause of epilepsy among the over 60s is the cerebral - vascular pathology , related to almost 50% of epilepsies among the elderly ( asconape and penry 1991 ) .
moreover , epilepsy may be the first sign of an underlying vascular pathology which has not yet surfaced .
thus , the risk of epilepsy in hypertensive patients is five times higher than in those who are not hypertensive , probably in relation to a pathology of small blood vessels causing irritating symptoms before provoking an ictus ( ng et al 1993 ) .
cleary et al monitored a cohort of 4,709 patients with cryptogenic epilepsy which started at over 60 years old , and found that the relative risk of suffering an ictus in these patients compared with controls from the same population was 2.89 , suggesting that in many of these patients there was an alteration to the cerebral blood flow which manifested itself first as an epilepsy and then as an ictus ( cleary et al 2004 ) .
other frequently related causes of epilepsy in the elderly are brain tumors , cranial trauma and dementia .
the fact that we encounter symptomatic epilepsies conditions the therapeutic attitude , as the risk of recurrence is very high ( bergey 2004 ) , over 90% , and therefore starting treatment after the first crisis can be considered . in the majority of cases , good control of these epilepsies can be expected , but treatment will be indefinite , and the suspension of treatment even after several years without a crisis can not be considered , as recurrence is almost certain .
however this should be assessed for each particular case , as it will largely depend upon the risks that the patient and the doctor are willing to assume ( serrano castro , ramos lizana et al 2005 ) .
the physiology of elderly patients presents alterations which modify the pharmacokinetics of aeds , making patients more susceptible to secondary effects .
firstly , there is an atrophy of the gastric mucosa and a reduction in the intestinal motility , which may modify the absorption of aeds making it irregular .
in addition , there is a reduction in total body water , leading to a modification of the volume of distribution of the drugs and their half life , which may on occasions have significant consequences .
thus , the half life of diazepam goes from 20 hours in young people to 80 hours in those individuals aged over 80 , with the resulting risk of a build - up of the drug .
the free fraction of drugs which bond well to proteins , such as valproic acid , phenitoin or tiagabine may increase by as much as 60% , bringing with this the risk of secondary effects due to intoxication ( serrano castro , casado - chocan et al 2005 ) . finally , the capacity to eliminate drugs is also lower in the elderly than in young people .
the hepatic metabolism is much slower , which may lead to a build - up of drugs with intense hepatic metabolism , such as carbamazepine , phenitoin or lamotrigine .
moreover , these patients will have a higher sensitivity to phenomenons of hepatic induction or inhibition , given that their hepatic reserve is reduced . in addition , glomerular filtration is also reduced , which must be remembered when prescribing renally eliminated drugs such as levetiracetam , gabapentin or pregabalin .
an added problem is that the elderly often take multiple medications , increasing the risk of interactions and the possibility of secondary effects . in this respect ,
the lower the bonding to proteins and the lower the hepatic metabolism of a drug , the easier it will be to use and the lower the risk of interaction with other possible concomitant drugs .
in general , elderly patients are more sensitive to the secondary effects of drugs , even at reduced doses . in addition , certain secondary effects frequently related to aeds are of special relevance to the elderly . due to the inhibiting action on the central nervous system , many aeds may cause cognitive disturbances .
elderly patients often present a reduction in their cerebral reserve capacity , making them particularly sensitive to this secondary effect .
the possibility of inducing cognitive disturbances is very high with drugs such as phenobarbital , primadone , or the benzodiazepines , and is more moderate with phenitoin and topiramate .
drugs less frequently causing cognitive disturbances , and which are therefore safer for use by this segment of the population include oxcarbazepine , levetiracetam , gabapentin and lamotrigine .
osteoporosis is a common disorder among the over 60s , particularly among women , and may be the cause of significant disability due to chronic pain and a predisposition to fractures .
various aeds may induce osteoporosis , emphasizing a risk which is already high merely as a result of ageing .
some , such as phenobarbital , phenitoin or carbamazepine , do so by interfering with the metabolism as vitamin d. valproate can also induce osteoporosis by activating the osteoblasts which destroy bone tissue .
the risk of complications due to osteoporosis is multiplied in an elderly patient if we add in an aed capable of inducing osteoporosis .
therefore , the risk of hip fractures in women over 65 is doubled when taking one of these drugs ( ensrud et al 2004 ) . as such , a priori , we should avoid the use of osteoporosis inducing drugs in this segment of the population .
the possibility of various aeds causing an increase in weight is well known . in general , we tend to consider this secondary effect when treating young patients , especially women , based on the assumption that these patients may be most concerned about their figure
. however , it is extremely important to consider the possibility of causing an increase in weight in elderly patients , not for aesthetic reasons but for reasons of health .
an increase in weight increases the risk of type ii diabetes , cardiovascular mortality and osteoarticular problems in a population where the risk is already higher .
moreover , an increase in weight leads to clumsiness in a population which tends to be clumsy , and increases the risk of falls in a population with an increased risk of osteoporosis , and therefore , greater risk of fractures .
the adfs most frequently associated to weight increase include valproate ( more than half the patients ) , carbamazepine ( approximately a quarter of patients ) , gabapentin ( 15%20% ) and pregabalin ( 14% ) ( de toledo et al 1997 ; easter et al 1997 ; biton 2003 ; arroyo et al 2004 ) .
topiramate may induce weight loss , which can be useful for overweight patients , but in other cases this effect may also be harmful and lead to malnutrition ( ben - menachem et al 2003 ) .
therefore , the most recommended drugs for this segment of the population are those which do not tend to modify weight , including lamotrigine , levetiracetam and oxcarbazepine ( devinsky et al 2000 ; gidal , sheth , magnus et al 2003 ) .
from the above , we can deduce that we are faced with a population which will frequently present symptomatic focal epilepsies , for which a good response to medical treatment can be expected , even at lower dosages ( kwan and brodie 2001 ) .
the majority of aeds available have demonstrated a similar efficacy for treating this type of crisis ( mattson et al 1985 , 1992 ; brodie et al 1999 , 2002 ) .
therefore , the choice of drug will fundamentally depend upon its pharmacokinetic profile and the likelihood of causing secondary effects ( snchez - alvarez et al 2005 ) which , as we have seen , have particular repercussions among the elderly .
phenobarbital is a powerful antiepileptic , but its significant cognitive effects , the possibility of inducing osteoporosis and possible pharmacological interactions rule it out for the treatment of epilepsies developing for the first time among this group of patients .
phenytoin is probably the most widely used drug among the elderly due to the possibility of a rapid titration and intravenous administration .
however , the complexity of its pharmacokinetics , the possibility of interaction with other drugs , of inducing osteoporosis and its cognitive effects make it unadvisable ( birnbaum et al 2003 ) .
valproic acid is an antiepileptic with a broad spectrum , being very efficient for both focal and generalized epilepsies , although we are principally concerned with the former among this population .
it can be administered intravenously , enabling rapid titration , the treatment of status epileptics and can be prescribed without problem where the patient is required to follow a strict diet due to an intercurrent disease .
the pharmacokinetics present certain problems , including its high bonding to proteins and its capacity for hepatic inhibition , which may provoke pharmacological interactions .
but the main problem lies in the frequency with which it causes weight gain , which , as we have seen , is of particular significance to health among these patients .
other secondary effects of significance among elderly patients include osteoporosis and tremor , and even parkinson s , in a population particularly exposed to suffering from osteoporosis and tremors or parkinson s due to their age .
its main disadvantage is its hepatic capacity , making the risk of interaction with other drugs high , of particular significance in a population where polypharmacy is common .
another two side effects to consider due to their higher frequency among the elderly are hyponatremia and alterations to the heart conduction system , which may cause confused or syncopal episodes respectively .
the problems presented by carbamazepine have largely been resolved with oxcarbazepine , whose capacity for hepatic induction and alterations to the heart conduction system are lower than its predecessor .
however , it induces hyponatremia more frequently than carbamazepine does ( kutluay et al 2003 ) .
topiramate is a powerful antiepileptic but the frequency with which it causes cognitive disorders , especially naming defects makes it unadvisable as a first choice for this population .
other secondary effects to consider given their possible gravity , although uncommon , include renal lithiasis and metabolic acidosis .
finally , the frequency of secondary effects requires a very slow titration of the drug , implying a long lapse in time until the patient is protected ( reife et al 2000 ) .
lamotrigine is a powerful antiepileptic without cognitive effects , with linear kinetics , making it highly suitable for this population . from a pharmacokinetics perspective
, the main disadvantage is its hepatic metabolism , which may be induced by other drugs , with a significant reduction in plasmatic levels ( anderson et al 2002 ) . on the contrary
, valproic acid significantly raises its levels and may double its half life ( gidal , sheth , parnell et al 2003 ) .
moreover , the possibility of serious allergic reactions makes very slow titration necessary , taking several weeks for an efficient dose to be reached .
this time period is usually lower among elderly patients , as , in general , lower doses are required to control their epilepsy .
tiagabine is a gaba - ergic drug with little antiepileptic power , requiring administration in three doses , and which often induces significant somnolence , and therefore it is not recommendable for this population .
gabapentin has a most favorable pharmacokinetical profile , but its low antiepileptic activity makes it unadvisable .
its successor , pregabalin , has the same pharmacokinetic profile , with the advantage that its antiepileptic power is similar to that of other greater aeds ( gil - nagel and gomez alonso 2005 ) .
the main disadvantages are its capacity to induce somnolence and weight gain ( french et al 2003 ; brodie 2004 ) .
finally , levetiracetam is a powerful antiepileptic with a highly favorable pharmacokinetic profile , as it does not bond with proteins , nor does it metabolize in the liver and neither induces nor is induced .
it titrates rapidly , and therefore from the start of treatment the patient has an efficient dosage . the only disadvantage is its possibility of provoking slight irritability or psychiatric alterations in under 7% of elderly patients , usually in patients with prior psychomotor retardation ( ferrendelli et al 2003 ; morrell et al 2003 ; white et al 2003 ) .
table 1 summarizes the main advantages and disadvantages of each of the aeds . in view of these characteristics
, we could say that , for a similar a priori efficacy , the drugs with the most favorable pharmacokinetic profile are levetiracetam and pregabalin , followed by oxcarbazepine and lamotrigine , whose hepatic metabolism and bonding to proteins slightly increases the risk of drug interactions .
moreover , these drugs have few cognitive effects , do not cause osteoporosis and , except for pregabalin , do not affect bodyweight , making them particularly attractive for treating epilepsies in the elderly .
these patients usually have partial symptomatic crises , which tend to reoccur , but which respond well to antiepileptic treatment . given that a priori the efficacy of all the major aeds is similar in the treatment of partial symptomatic crises , the choice of aed for use in this population will depend upon the pharmacokinetic properties and side effects . in this respect ,
the aeds with a more favorable profile for starting antiepileptic treatment in elderly patients include levetiracetam , pregabalin , lamotrigine and oxcarbazepine .
Output:
| epilepsy among the elderly is a frequently occurring pathology , differing in etiology , clinical presentation and prognosis from those of young people . in addition , beyond a certain age , physiological modifications are produced in the metabolism which alter the pharmacokinetics of antiepileptic drugs ( aeds ) , increasing the risk of pharmacological interactions , already greater in these patients due to the frequency of polypharmacy .
furthermore , elderly patients are particularly sensitive to certain secondary effects of aeds , as for example , cognitive disturbances , osteoporosis or weight increase . given that the efficacy of the major aeds is a priori quite similar , and that the epilepsies occurring in this age - group generally have a good prognosis , the selection of an aed will depend more upon its pharmacokinetics and ability to induce certain secondary effects than on its efficacy . in this respect ,
levetiracetam and pregabalin , followed by oxcarbazepine and lamotrigine have the most favorable pharmocokinetical profile .
moreover , on the whole these drugs have very few cognitive effects , do not induce osteoporosis and , with the exception of pregabalin , do not affect weight , making them the first selection for use in the treatment of epilepsy in the elderly . |
PubmedSumm4826 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the recently published notice of proposed rulemaking ( nprm ) for the common rule acknowledges the potential loss of public trust associated with high - profile disputes over biospecimens collected in research , including the havasupai case and the lacks family settlement .
these events have consequences for the researchers involved and diminish benefits achieved through data sharing .
the nprm seeks to modernize the common rule and proposes two general changes affecting research with biospecimens .
specifically , the nprm proposes a broad informed consent that would incorporate future research on the biospecimen collected from an individual .
the nprm , in addition to the recently issued national institutes of health genetic data sharing policy ( gds ) , would alter human subjects protections for genetic data sharing . while the nprm and gds both propose that these revisions will have a role in improving public trust through transparency , neither fully addresses ongoing challenges specific to trust and stigma for vulnerable individuals and groups in genetic data sharing .
in their response piece , it depends whose data are being shared : considerations for genomic data sharing policies , robinson et al .
evaluate human subject protections in genetic data - sharing policies and elaborate on the challenges inherent in balancing the benefit of data - sharing and protecting privacy .
the authors highlight the importance of public trust and provide the global alliance for genomics and health as a collaborative model for fostering trust .
research on individual preferences demonstrate that participants are generally supportive of data being shared among researchers .
point out , individuals and vulnerable populations may have differing views and preferences on how and under what circumstances data are shared .
robinson et al . argue for research participant control over data and highlight dynamic consent as a potential model that would allow participants to specify and update their consent preferences .
this article builds upon themes discussed by robinson et al . and considers the role of consent and privacy protections in building trust with research participants , particularly those who are members of a vulnerable population .
in addition to considering the roles of individual consent , we also consider how vulnerable populations may be consulted to improve protections from stigma and discrimination .
vulnerable populations have previously been defined as social groups who have an increased relative risk or susceptibility to adverse health outcomes. federal regulations provide specific protections to pregnant women , neonates , fetuses , prisoners , and children . as a default
, these groups have been characterized as vulnerable populations for purposes of research protections . yet
individuals and groups who are vulnerable for purposes of data - sharing may or may not also be groups , or members of groups , who are at increased risks of poor health outcomes .
regardless , it is not the potential health outcome which makes them vulnerable in this context .
instead , it is the potential loss of privacy and confidentiality which may expose individuals or populations to risks of stigma or discrimination based upon conclusions of research .
social groups categorized according to ( i ) race and ethnicity , ( ii ) disease population , and ( iii ) american indians / alaskan natives lineage may be particularly vulnerable to discrimination and stigma associated with genetic data sharing , based in part on a history of discrimination .
first , at the individual level , disclosure of confidential information linking an individual 's identity with genetic data connected to a stigmatized population may result in consequences for the individual .
if research determines that an individual , who has consented to data being shared through a repository , is genetically disposed to develop alzheimer 's disease , the individual may be at risk of workplace discrimination or other forms of stigma . at the individual level ,
second , at the group level , research that aims to identify an increased risk factor based on genetic status may have unanticipated consequence for a particular group .
for example , the information gathered by arizona state university which led to the case against it by the havasupai tribe , indicated an increased risk for schizophrenia . while this information may have some value for predicting health outcomes , it also placed significant stigma on the tribe . despite the history of incidents like the hela cells release and the havasupai case , neither the gds nor the nprm explicitly provides protections specific to vulnerable groups .
additionally , individual informed consent or privacy protections are not sufficient to reduce the risk of stigma associated with groups .
it is not the release of private information alone , but also the research results that place labels on a group which may expose members to stigma and discrimination . the nprm shifts how biospecimens are treated , from a discarded tissue sample described in moore v. regents of the university of california to an extension of the human subject . as a result ,
the mode of consent and subject control of data must also shift . as robinson et al .
articulated , numerous repositories support genomic data and personal health information , including private repositories ( ie , google genomics and apple researchkit ) and federally supported repositories ( ie , cancer genomics hub ( cghub ) and dbgap ) .
. however , unless a private institution receives nih funding , the institution is not within the scope of the gds . as a result , private institutions policies regarding research subjects protections may vary .
diverse protection mechanisms and informed consent models are starting points for providing protections at the individual level and engendering trust .
broad and dynamic consent models are proposed in different forms through policies and institutional recommendations .
broad consent , currently required by the gds and proposed by the nprm , seeks to inform participants that the specimen will be shared and used by future researchers .
broad consent is currently used by several repositories , including the alzheimer 's disease neuroimaging initiative and the oxford biobank .
this model of consent may inform participants and document their willingness to participate , but it fails to provide the level of individual control that is highlighted by robinson et al . upon consent , researchers and data access committees ( dacs ) gain the power to determine what type of research may be appropriate , without requiring consideration of individual or group values . additionally , it is unclear whether broad consent can provide sufficient information about future research that would allow a participant to fully understand the consequences of consent .
proponents of the dynamic consent model propose to utilize technology to create a digital informed consent process .
dynamic consent would allow participants to give or revoke consent to research involving their samples / information , provide a virtual record of transactions , alter contact information , learn and consent to new research projects , and complete online surveys . under the proposed model
, a participant can adjust consent preferences to give broad consent or be contacted for each study .
this allows the participant to be as engaged or removed from the process , according to their preferences , while maintaining control over their samples .
this approach is consistent with research by mcguire et al . which reported participant preferences for a tiered decision - making structure .
the dynamic consent model may be consistent with literature reflecting variation of individuals and group preferences , as highlighted by robinson et al .
if an individual no longer wants to include their sample in research or decline a specific study , the sample must be re - identified and removed . as a result
individuals are at an increased risk of loss of confidentiality . while the dynamic consent model is not currently implemented , the apple researchkit has some features of the approach .
participants of the researchkit are able to select studies to participate in , information they would like to provide , and to leave a research study at any time .
apple researchkit allows researchers to upload consent documents consistent with the researcher 's institution irb policies , add visuals to help participants understand key points , ask the participant if they would like to share data , and create a quiz to ensure the participants knowledge of the study .
the nih dacs are charged with reviewing requests for access to data stored within the dbgap and ensuring that requests are consistent with the data use limitations of the data set . for data repositories not funded by federal funds , a range of approaches
sufficient protections would require initial researchers to place appropriate limitations on data that restrict secondary use with consequences for a given vulnerable population .
secondly , dacs do not allow for the incorporation of individual or group preferences identified by robinson et al .
a dac review does not provide any guarantee that data will not be used by secondary researchers for research purposes beyond an individual 's or group 's preference .
finally , enforcement for violation of the terms and conditions of the research agreement is not fully defined by the gds , which simply states that the nih will take appropriate action. insufficient enforcement and a lack of sensitivity to individual and group preferences reduce the potential for providing protections which may be critical to protecting vulnerable populations and engendering trust .
broad and dynamic consent models at the individual level are likely insufficient to reduce consequences for vulnerable populations at the group level .
broad consent limits the avenue for individuals or vulnerable groups to weigh in on research which may have consequences for the group ( ie , linking a sickle cell trait to african americans ) .
vulnerable groups may be inadvertently harmed by the results of research utilizing broad consent where an individual 's demographics are collected alongside the sample .
however , there are prior examples of resolutions , policies , and research design methods which address challenges at the group level . the lacks family settlement provided for a lacks family member representative to be at the table for consideration of research that would use the hela genetic line .
similar arrangements have been developed for community representation in research design , particularly within tribal communities .
for example , the inter tribal counsel of arizona has agreements between tribes and local universities to address issues ( ie , protection of cultural interests ) which may arise in research enrollment of tribe members .
this raises the question : should group representatives should be included in the review of secondary researcher requests to access data ? should vulnerable groups have a representative who can agree or disagree on behalf of the group on whether to consent to research which may have consequences for vulnerable populations ? incorporating individual and community perspectives in research development and execution is increasingly prevalent .
the patient centered outcome research institute requires that researchers include a member of the patient population in the design of research funded by the institute .
the food and drug administration includes patient representatives on its advisory committees and has begun considering methods further incorporating patient perspectives during risk - benefit assessment in the drug - approval process .
similarly , rencher and wolf propose that the common rule require community consultation in the institutional review board process for research involving vulnerable populations . and
finally , community advisory boards in disease populations have been successful in informing research protocol development .
for example , they report on research demonstrating that hiv - positive individuals prioritize privacy over advancing research .
while dynamic consent has been proposed as a method of respecting individual preferences , another method would be to include group representatives when reviewing requests for access to data by secondary researchers .
building upon the models discussed above , including group representatives as members of dacs or similar committees could provide an avenue for extending protections at the group level to mitigate potential stigma and discrimination . currently , dbgap dacs are made up of senior federal employees with appropriate scientific , bioethics , and human subjects research expertise. including representatives from vulnerable populations in the process would encourage dacs or other similar committees to be informed of and consider cultural or other group - centric issues prior to approving requests to access data .
first , this would require identifying some criteria by which a research proposal includes or affects a vulnerable population .
an initial step would be defining vulnerable populations for this purpose and whether the research has consequences for the population . while previously articulated definitions of
vulnerability may be informative , vulnerability for this context should reflect the nuance of risks associated with data - sharing .
second , this additional requirement would increase regulatory burden on investigators , possibly slowing down the research process or preventing some kinds of potentially helpful population - level research .
it might also generate bias if not all observations from the study population are treated similarly , or limit the validity of research findings if some research tools can not be used in a study .
finally , we have drawn a distinction between protections at a group level and protections at an individual level .
given the heterogeneity in preferences at an individual level , there may well be tensions between group preferences and the preferences of an individual member within that group . a model for how these conflicts can best be resolved will need to be developed .
issues around vulnerable populations , individuals values , and preferences about data - sharing will continue to develop and shift .
the tuskegee syphilis study , lacks family settlement , and havasupai case have shaped research and scientific policies and practices .
future events and advancements in science will continue to alter how human subject protections are evaluated and implemented .
a recent survey of geneticists conducted by pham - kanter , zinner , and campbell found that 42 per cent of geneticists reported patient confidentiality as a very important or moderately important reason for withholding data , in contrast to 21 per cent just 10 years prior .
this survey also found that data repositories were perceived by scientists to be an important facilitator of data - sharing in genetics and the life sciences , and the use of repositories has dramatically expanded over the past decade . negotiating the tensions inherent in these trends , and their implications for research participants and particularly vulnerable populations ,
the inclusion of biospecimens within the definition of research subjects will create new requirements , including but not limited to consent for researchers . as a result , genetic data - sharing policies should incorporate mechanisms to guide how access and secondary use is regulated to mitigate stigmatizing populations vulnerable to discrimination
. consent policies and engaging group representatives in the dac review process can be constructive additional steps to engage research participants , engender trust , and provide protections from stigma and discrimination .
Output:
| recent policies and proposed regulations , including the notice of proposed rulemaking for the common rule and the 2014 nih genetic data sharing policy , seek to improve research subject protections . protections for subjects whose genetic data is shared are critical to reduce risks such as loss of confidentiality , stigma , and discrimination . in the article
it depends whose data are being shared : considerations for genomic data sharing policies , robinson et al .
provide a response to our article , the growth and gaps of genetic data sharing policies. robinson et al . highlight the importance of individual and group preferences . in this article
, we extend the conversation on models for improving protections which will mitigate consequences for individuals and groups that are vulnerable to stigma and discrimination . |
PubmedSumm4827 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: protein sequencing by tandem mass spectrometry ( ms / ms ) has evolved into a standard and widely applied method [ 1 , 2 ] . the most common approach in ms - based proteomics involves digestion with specific enzymes after performing a reduction / alkylation step , referred to as bottom - up or peptide - centric readout [ 35 ] .
the digestion step is often not applied for the analysis of native or endogenous peptides , and is even avoided for top - down protein ms [ 4 , 610 ] .
the analysis of intact peptides or proteins allows the characterization of one of the most common post - translational modifications ( ptms ) in proteomics , namely disulfide bonds .
s s bridges , stabilize the three - dimensional structure of a protein and , therefore , are crucial elements for their biological function . on the other hand , disulfide bonds can also hinder ms / ms - fragmentation in different ways . in an ms
/ ms - collision induced dissociation ( cid ) experiment primarily peptide backbone fragmentations are observed , with a preference for cleavages of the weakest amide bond , resulting in either b- or y - ions . in the presence of a disulfide bond , such backbone characterization is often hampered and thus poses a challenge for middle- and top - down analysis of intact proteins .
also , proper assignment becomes difficult when the fragments themselves remain connected via an s s bridge . with the introduction of electron capture dissociation ( ecd ) and later electron transfer dissociation ( etd ) , new possibilities emerged for fragmenting disulfide bonds [ 13 , 14 ] .
s bonds , thus allowing for sequencing of regions that are involved in intra- or intermolecular linkages . nevertheless , even after cleavage of the s s bond , the resulting fragment ion may still be intact because of the remaining connectivity in the peptide backbone . consequently , off - line reduction of disulfide bonds with a reagent such as dithiothreitol ( dtt ) still is a pivotal step in obtaining full sequence coverage of a protein , similar to the one carried out in a bottom - up experiment .
however , the use of dtt requires removal before ms analysis , and alternative thiol - free reducing agents also involve laborious sample preparation . with the current rise of ultrahigh resolution instruments ,
often , top - down experiments are performed using electrospray ionization ( esi ) of intact proteins ; however , there is also growing interest for in source decay ( isd ) during matrix - assisted laser desorption ionization ( maldi ) [ 17 , 18 ] .
low - ppm mass measurement precision allows a detailed analysis of for instance ptms , or even all proteoforms [ 10 , 19 ] . in this context ,
recently , it has been shown by the group of chen that electrochemical reduction of s s bridges can be performed on - line using desorption electrospray ionization ( desi ) [ 2023 ] . in this study , we coupled electrochemistry ( ec ) to direct infusion esi - ms / ms performed on an ultrahigh resolution fourier transform ion cyclotron ( fticr ) system equipped with a 15 tesla magnet . on - line
the development of special electrodes and electronic systems has opened ways for electrochemical reactions on biomolecules , such as peptides and proteins [ 24 , 25 ] . with regard to studies on the oxidative metabolism of drugs ,
furthermore , ec can be used to reduce disulfide bonds in proteins for analytical purposes , as was recently demonstrated for -lactoglobulin a and lysozyme .
obviously , the absence of reactants is a major advantage of ec , as well as is the short time scale of interaction with the electrodes . in order to evaluate the performance of such an on - line ec - ms / ms approach , cid- and etd - spectra of two peptide model systems
it has been shown that through alternating or consecutive use of cid and etd in bottom - up proteomics lc - ms / ms experiments , based on the decision tree approach , distinct peptide sets are obtained and that the number of protein identifications ( ids ) in complex proteomes can be increased [ 25 , 2932 ] . an increased peptide sequence has also been reported from simultaneous use of two different fragmentation techniques .
similarly , the use of both fragmentation techniques provides complementary data for middle- and top - down analysis of peptides or proteins .
first , the benefits of ec on a relatively simple peptide containing only one disulfide bridge are evaluated .
oxytocin is a small hormone and neurotransmitter with an s s bridge between the cysteine residues at positions 1 and 6 , thus fixing secondary and tertiary structure .
then , on - line ec is evaluated for a more complex middle - down peptide containing four disulfide bridges , namely hepcidin , which is a 25 amino acid - containing hormone that regulates iron metabolism and has a tightly folded hairpin structure .
oxytocin and hepcidin were purchased from sigma - aldrich ( steinheim , germany ) and anaspec ( san diego , ca , usa ) , respectively .
hplc - grade methanol , acetonitrile , isopropanol , and formic acid ( 95 % , purity ) were supplied by sigma - aldrich .
direct infusion esi - fticr experiments were performed on a bruker 15 tesla solarix fticr mass spectrometer as previously reported [ 11 , 35 ] .
briefly , a quadrupole ( q ) was used for precursor ion selection and a hexapole collision cell for cid and etd .
direct infusion esi experiments were carried out at an infusion rate of 50 l / min .
the ion funnels operated at 100 and 6.0 v , respectively , with the skimmers at 15 and 5 v. the trapping potentials were set at 1.0 and 1.0 v , the analyzer entrance was maintained at 10 v , and side kick technology was used to further optimize peak shape and signal intensity .
the required excitation power was 19 % with a pulse time of 10 s .
ms / ms - experiments were performed by cid and fragment ion mass analysis in the icr cell . for these experiments ,
the collision energy , the accumulation time in the hexapole collision cell , and the isolation window in the q were optimized for each precursor ion .
collision energies varied from 4.0 to 16.5 v , whereas the accumulation times varied from 0.5 to 10 s. both the etd reagent accumulation time and the reaction time were 0.4 s. electrochemical reduction of disulfide bond(s ) was performed and evaluated on the nine amino acid - containing peptide oxytocin ( one disulfide bridge ) and the 25 amino acid - containing peptide hepcidin ( four disulfide bridges ) .
an electrochemical cell with titanium - based electrodes ( -prepcell , cell volume 11 l ; antec , zoeterwoude , the netherlands ) , controlled by a potentiostat ( roxy potentiostat , antec ) , was used on - line in a direct infusion electrospray ionization ( di - esi ) setup on the fticr - ms system .
typically , 13 m solutions of the peptide or protein were infused through the prepcell at a flow rate of 50 l / min .
optimized settings ( i.e. , times ) were used according to manufacturer guidelines ( unpublished data ) , namely a pulse setting with a 1990 ms interval for e1 , followed by a 1010 ms interval for e2 .
oxytocin and hepcidin were purchased from sigma - aldrich ( steinheim , germany ) and anaspec ( san diego , ca , usa ) , respectively .
hplc - grade methanol , acetonitrile , isopropanol , and formic acid ( 95 % , purity ) were supplied by sigma - aldrich .
direct infusion esi - fticr experiments were performed on a bruker 15 tesla solarix fticr mass spectrometer as previously reported [ 11 , 35 ] .
briefly , a quadrupole ( q ) was used for precursor ion selection and a hexapole collision cell for cid and etd .
direct infusion esi experiments were carried out at an infusion rate of 50 l / min .
the ion funnels operated at 100 and 6.0 v , respectively , with the skimmers at 15 and 5 v. the trapping potentials were set at 1.0 and 1.0 v , the analyzer entrance was maintained at 10 v , and side kick technology was used to further optimize peak shape and signal intensity .
the required excitation power was 19 % with a pulse time of 10 s .
ms / ms - experiments were performed by cid and fragment ion mass analysis in the icr cell . for these experiments ,
the collision energy , the accumulation time in the hexapole collision cell , and the isolation window in the q were optimized for each precursor ion .
collision energies varied from 4.0 to 16.5 v , whereas the accumulation times varied from 0.5 to 10 s. both the etd reagent accumulation time and the reaction time were 0.4 s.
electrochemical reduction of disulfide bond(s ) was performed and evaluated on the nine amino acid - containing peptide oxytocin ( one disulfide bridge ) and the 25 amino acid - containing peptide hepcidin ( four disulfide bridges ) . an electrochemical cell with titanium - based electrodes (
-prepcell , cell volume 11 l ; antec , zoeterwoude , the netherlands ) , controlled by a potentiostat ( roxy potentiostat , antec ) , was used on - line in a direct infusion electrospray ionization ( di - esi ) setup on the fticr - ms system .
typically , 13 m solutions of the peptide or protein were infused through the prepcell at a flow rate of 50 l / min .
optimized settings ( i.e. , times ) were used according to manufacturer guidelines ( unpublished data ) , namely a pulse setting with a 1990 ms interval for e1 , followed by a 1010 ms interval for e2 .
oxytocin was directly infused from a syringe pump via the -prepcell into an ultrahigh resolution fticr mass spectrometer . by switching
the ec device on - and - off the disulfide bond in oxytocin either remained intact or was reduced into two sh - groups .
first , the esi solvent conditions were optimized with regard to the ms1 signal intensity and the ec conversion .
it was found that a solvent ratio of water and acetonitrile of 90/10 containing 1 % formic acid ( fa ) was optimal .
the use of methanol resulted in a decreased conversion and an increasing amount of organic solvent generally resulted in lower signal intensities .
in addition , the use of isopropanol gave unstable signal and conversion ( data not shown ) .
next , the e1 and e2 potentials were evaluated for the on - line reduction of oxytocin , using pulse settings as described in the materials and methods section .
it becomes clear that with decreasing e1 ( i.e. , from 1 to 3 v ) , the amount of native ( s s bridge containing ) oxytocin decreases , and that with increasing e2 ( i.e. , from + 1 to + 2v ) the signal of reduced oxytocin is enhanced .
it was found that further increase of e2 resulted in a ( small ) decrease of reduced oxytocin . as can be seen from figure 2a , the maximum conversion of oxytocin into its reduced form was approximately 80 % at e2 = 2.2 v.figure 1schematic experimental setup for the reduction of disulfide bonds and on - line infusion into an ultrahigh resolution fticr mass spectrometer .
collision - induced dissociation ( cid ) and electron - transfer dissociation ( etd ) were used to characterize both native and reduced form of oxytocin and hepcidinfigure 2evaluation of the -prepcell potentials for the on - line reduction of the disulfide bridge of oxytocin ( a ) .
the maximum conversion rate of approximately 80 % was obtained at e1 = 2.2 v and e2 = 2.2 v. evaluation of the conversion rate ( red - ox ) monitoring the signal intensity of the doubly charged oxytocin ( b ) measured with a resolving power of 250,000 .
the two overlapping isotopic profiles of the doubly protonated molecular ions of native ( [ m + 2h ] ; left - hand panel ) and reduced oxytocin ( [ mred + 2h ] ; right - hand panel ) were resolved . the case of a partial reduction of oxytocin is shown in the middle panel . here , three peaks are resolved at m / z 505.2 shown in the enlarged part , corresponding to the third isotopic peak of [ m + 2h ] with s and c2 , respectively , and the monoisotopic peak of [ mred + 2h ]
schematic experimental setup for the reduction of disulfide bonds and on - line infusion into an ultrahigh resolution fticr mass spectrometer .
collision - induced dissociation ( cid ) and electron - transfer dissociation ( etd ) were used to characterize both native and reduced form of oxytocin and hepcidin evaluation of the -prepcell potentials for the on - line reduction of the disulfide bridge of oxytocin ( a ) .
the maximum conversion rate of approximately 80 % was obtained at e1 = 2.2 v and e2 = 2.2 v. evaluation of the conversion rate ( red - ox ) monitoring the signal intensity of the doubly charged oxytocin ( b ) measured with a resolving power of 250,000 .
the two overlapping isotopic profiles of the doubly protonated molecular ions of native ( [ m + 2h ] ; left - hand panel ) and reduced oxytocin ( [ mred + 2h ] ; right - hand panel ) were resolved .
the case of a partial reduction of oxytocin is shown in the middle panel . here , three peaks are resolved at m / z 505.2 shown in the enlarged part , corresponding to the third isotopic peak of [ m + 2h ] with s and c2 , respectively , and the monoisotopic peak of [ mred + 2h ]
note that the ultrahigh resolving power of the fticr system allowed the detailed analysis of two overlapping isotopic profiles of the doubly protonated molecular ions of native ( [ m + 2h ] ) and reduced oxytocin ( [ m + 2h + 2h ] , further referred to as ( [ mred + 2h ] ) .
the differences within the third isotopic peak at approximately m / z 505.2 are shown in figure 2b . in the case of native oxytocin ,
this signal consists of two peaks attributable to the presence or absence of a s isotope , with a difference of 5.6 milli - mass units ( left - hand panel of figure 2b ) . in the case of reduced oxytocin ,
the corresponding signal at m / z 505.2 has turned into a monoisotopic signal and , thus , contains only one peak , which is observed at 4.3 milli - mass units higher than the third isotopic peak of doubly protonated native oxytocin ( right - hand panel of figure 2b ) .
both species are present when the on - line reduction of the disulfide bond is not complete , exemplified by the overlap of two isotopic profiles ( middle panel of figure 2b ) .
subsequently , the system as depicted in figure 1 was used to generate ms / ms - data from both native and reduced oxytocin .
the cid spectrum of doubly protonated native oxytocin is depicted in figure 3 , as well as the one that was obtained after on - line reduction of the s
the large majority of fragment ions could be explained from standard b / y - fragmentation , including neutral losses .
in addition , a few ions were assigned as a - ions or as internal fragments resulting from two - bond cleavages .
the fragment ions observed from native oxytocin , and the resulting sequence coverage , were in good agreement with previously obtained data from sustained off - resonance induced ( sori ) cid - experiments , with dominant cleavages of the three amino acid tail and minor fragmentation of the six amino acid - containing ring ( tocin ring ) .
the only noticeable difference between the current and the sori - cid data was the absence of a b3-ion in the cid spectrum of native oxytocin , next to variation in the ion abundances . from the comparison of the cid spectra of native and reduced oxytocin ,
it becomes evident that many additional fragment ions from tocin - ring cleavages have appeared after the on - line ec reduction of the s
s bridge ( e.g. , b2/y7 , b3/y6 , b4/y5 , b5/y4 ) . as a result
similarly , the application of etd yielded large differences between fragmentation spectra of native and reduced oxytocin .
this is depicted in figure 4 the benefits in terms of sequence coverage are not as obvious as in the case of cid spectra , albeit that the number of sequence - informative fragment ions doubled from 8 to 16 and that the total number of ( assigned ) fragment ions was higher for the reduced species . upon comparison of the etd spectrum of doubly protonated native oxytocin with previous results obtained from ecd experiments , it was noted that the type of fragments were the same , i.e. typical b / y - fragments and typical c - fragments .
interestingly , the number of tocin - ring cleavages was lower in etd than in ecd spectra : b3- , b5- , and c5-ions were absent in etd , as well as y4- , y5- and y7-ions .
on the other hand , in the etd spectra , new y8- , b8- , c7- , and c8-ions were observed .
it was further noted that both b / y- and c / z - fragments were observed in the etd spectrum of ec - reduced , doubly protonated oxytocin . this is somewhat different from the previous ecd results , in which reduced and carboxymethylated doubly protonated oxytocin yielded solely b / y - fragments.figure 3cid spectrum of doubly protonated native ( a ) and on - line reduced ( b ) oxytocin . the online reduction results in a richer ms / ms spectrum and , consequently , a more comprehensive characterization of the peptide sequencefigure 4etd spectrum of doubly protonated native ( a ) and on - line reduced ( b ) oxytocin
. the differences between the two spectra are less apparent than in the case of cid spectra .
the on - line reduction of the disulfide bridge results in a more comprehensive characterization of the tocin - ring cid spectrum of doubly protonated native ( a ) and on - line reduced ( b ) oxytocin .
the online reduction results in a richer ms / ms spectrum and , consequently , a more comprehensive characterization of the peptide sequence etd spectrum of doubly protonated native ( a ) and on - line reduced ( b ) oxytocin .
the differences between the two spectra are less apparent than in the case of cid spectra .
the on - line reduction of the disulfide bridge results in a more comprehensive characterization of the tocin - ring the system depicted in figure 1 was used for a top - down analysis of the 25 amino acid - containing hormone hepcidin .
the cid spectrum of native hepcidin was recorded , showing mostly typical b / y - fragments and a few a - fragment ions . from the sequence coverage shown in figure 5 ,
it becomes clear that the observed fragment ions resulted solely from peptide backbone cleavages that are not involved in the region containing the four disulfide bonds .
in other words , the disulfide bonds clearly hamper sequencing the part from cys7 to cys23 . after on - line
electrochemical reduction of all four s s bridges , the cid spectrum contained many more fragment ions , as can be seen in figure 5 .
the ms / ms - data are still dominated by b- and y - fragments and , in addition , more internal fragments were observed ( resulting from two - bond cleavages ) .
the beneficial effect of using on - line ec becomes clear from the sequence coverage : only seven bonds were fragmented in the native species , whereas 21 out of 24 peptide bonds were cleaved in the fully reduced hepcidin .
previous ms identifications of hepcidin were based mostly on ( accurate ) mass measurements [ 34 , 37 ] . to our knowledge , this is the first study where such high sequence coverage of hepcidin was obtained , although lc - ms / ms methods have been used to identify and quantify hepcidin in body fluids [ 38 , 39].figure 5cid spectrum of native ( a - i , -ii , -iii , -iv , and -v ) and on - line reduced ( b - i , -ii , -iii , -iv , and -v ) hepcidin .
the fragmentation of the native hepcidin led to backbone cleavages that are not involved in the region containing the four disulfide bonds .
the on - line reduction of the four s s bridges prior the ms / ms experiment led to a more extensive fragmentation resulting in 21 out of 24 cleaved peptide bonds .
the following internal fragments were also observed as doubly charged ions : ( 1 ) cifccgcchrskcgmcck ; ( 2 ) cifccgcchrskcgmcck ; ( 3 ) picifccgcchrskcgmcck ; ( 4 ) fpicifccgcchrskcgmcck ; ( 5 ) ccgcchrskcgmcck ; ( 6 ) fccgcchrskcgmcck ; ( 7 ) cifccgcchrskcgmcck ; ( 8) picifccgcchrskcgmcck cid spectrum of native ( a - i , -ii , -iii , -iv , and -v ) and on - line reduced ( b - i , -ii , -iii , -iv , and -v ) hepcidin .
the fragmentation of the native hepcidin led to backbone cleavages that are not involved in the region containing the four disulfide bonds .
the on - line reduction of the four s s bridges prior the ms / ms experiment led to a more extensive fragmentation resulting in 21 out of 24 cleaved peptide bonds .
the following internal fragments were also observed as doubly charged ions : ( 1 ) cifccgcchrskcgmcck ; ( 2 ) cifccgcchrskcgmcck ; ( 3 ) picifccgcchrskcgmcck ; ( 4 ) fpicifccgcchrskcgmcck ; ( 5 ) ccgcchrskcgmcck ; ( 6 ) fccgcchrskcgmcck ; ( 7 ) cifccgcchrskcgmcck ; ( 8) picifccgcchrskcgmcck in summary , the presented study here shows that disulfide bridges can be successfully reduced in an on - line esi set - up using electrochemistry .
these findings are similar to those obtained by other authors using desi [ 2022 ] .
it will be of great interest to further study the coupling of ec with lc - based separation of proteins and on - line digestion , as this might finally lead to a fully integrated workflow overcoming the reduction / alkylation step in standard bottom - up proteomics .
in addition , the coupling of ec with lc - based peptide separation may open new avenues in the field of de novo and middle - down sequencing of ( large ) peptides .
oxytocin was directly infused from a syringe pump via the -prepcell into an ultrahigh resolution fticr mass spectrometer . by switching
the ec device on - and - off the disulfide bond in oxytocin either remained intact or was reduced into two sh - groups .
first , the esi solvent conditions were optimized with regard to the ms1 signal intensity and the ec conversion .
it was found that a solvent ratio of water and acetonitrile of 90/10 containing 1 % formic acid ( fa ) was optimal .
the use of methanol resulted in a decreased conversion and an increasing amount of organic solvent generally resulted in lower signal intensities .
in addition , the use of isopropanol gave unstable signal and conversion ( data not shown ) .
next , the e1 and e2 potentials were evaluated for the on - line reduction of oxytocin , using pulse settings as described in the materials and methods section .
it becomes clear that with decreasing e1 ( i.e. , from 1 to 3 v ) , the amount of native ( s s bridge containing ) oxytocin decreases , and that with increasing e2 ( i.e. , from + 1 to + 2v ) the signal of reduced oxytocin is enhanced .
it was found that further increase of e2 resulted in a ( small ) decrease of reduced oxytocin . as can be seen from figure 2a , the maximum conversion of oxytocin into its reduced form was approximately 80 % at e2 = 2.2 v.figure 1schematic experimental setup for the reduction of disulfide bonds and on - line infusion into an ultrahigh resolution fticr mass spectrometer .
collision - induced dissociation ( cid ) and electron - transfer dissociation ( etd ) were used to characterize both native and reduced form of oxytocin and hepcidinfigure 2evaluation of the -prepcell potentials for the on - line reduction of the disulfide bridge of oxytocin ( a ) .
the maximum conversion rate of approximately 80 % was obtained at e1 = 2.2 v and e2 = 2.2 v. evaluation of the conversion rate ( red - ox ) monitoring the signal intensity of the doubly charged oxytocin ( b ) measured with a resolving power of 250,000 .
the two overlapping isotopic profiles of the doubly protonated molecular ions of native ( [ m + 2h ] ; left - hand panel ) and reduced oxytocin ( [ mred + 2h ] ; right - hand panel ) were resolved . the case of a partial reduction of oxytocin is shown in the middle panel . here , three peaks are resolved at m / z 505.2 shown in the enlarged part , corresponding to the third isotopic peak of [ m + 2h ] with s and c2 , respectively , and the monoisotopic peak of [ mred + 2h ]
schematic experimental setup for the reduction of disulfide bonds and on - line infusion into an ultrahigh resolution fticr mass spectrometer .
collision - induced dissociation ( cid ) and electron - transfer dissociation ( etd ) were used to characterize both native and reduced form of oxytocin and hepcidin evaluation of the -prepcell potentials for the on - line reduction of the disulfide bridge of oxytocin ( a ) .
the maximum conversion rate of approximately 80 % was obtained at e1 = 2.2 v and e2 = 2.2 v. evaluation of the conversion rate ( red - ox ) monitoring the signal intensity of the doubly charged oxytocin ( b ) measured with a resolving power of 250,000 .
the two overlapping isotopic profiles of the doubly protonated molecular ions of native ( [ m + 2h ] ; left - hand panel ) and reduced oxytocin ( [ mred + 2h ] ; right - hand panel ) were resolved .
the case of a partial reduction of oxytocin is shown in the middle panel . here , three peaks are resolved at m / z 505.2 shown in the enlarged part , corresponding to the third isotopic peak of [ m + 2h ] with s and c2 , respectively , and the monoisotopic peak of [ mred + 2h ]
note that the ultrahigh resolving power of the fticr system allowed the detailed analysis of two overlapping isotopic profiles of the doubly protonated molecular ions of native ( [ m + 2h ] ) and reduced oxytocin ( [ m + 2h + 2h ] , further referred to as ( [ mred + 2h ] ) .
the differences within the third isotopic peak at approximately m / z 505.2 are shown in figure 2b . in the case of native oxytocin ,
this signal consists of two peaks attributable to the presence or absence of a s isotope , with a difference of 5.6 milli - mass units ( left - hand panel of figure 2b ) . in the case of reduced oxytocin ,
the corresponding signal at m / z 505.2 has turned into a monoisotopic signal and , thus , contains only one peak , which is observed at 4.3 milli - mass units higher than the third isotopic peak of doubly protonated native oxytocin ( right - hand panel of figure 2b ) .
both species are present when the on - line reduction of the disulfide bond is not complete , exemplified by the overlap of two isotopic profiles ( middle panel of figure 2b ) .
subsequently , the system as depicted in figure 1 was used to generate ms / ms - data from both native and reduced oxytocin .
the cid spectrum of doubly protonated native oxytocin is depicted in figure 3 , as well as the one that was obtained after on - line reduction of the s
the large majority of fragment ions could be explained from standard b / y - fragmentation , including neutral losses .
in addition , a few ions were assigned as a - ions or as internal fragments resulting from two - bond cleavages .
the fragment ions observed from native oxytocin , and the resulting sequence coverage , were in good agreement with previously obtained data from sustained off - resonance induced ( sori ) cid - experiments , with dominant cleavages of the three amino acid tail and minor fragmentation of the six amino acid - containing ring ( tocin ring ) .
the only noticeable difference between the current and the sori - cid data was the absence of a b3-ion in the cid spectrum of native oxytocin , next to variation in the ion abundances . from the comparison of the cid spectra of native and reduced oxytocin ,
it becomes evident that many additional fragment ions from tocin - ring cleavages have appeared after the on - line ec reduction of the s
s bridge ( e.g. , b2/y7 , b3/y6 , b4/y5 , b5/y4 ) . as a result
similarly , the application of etd yielded large differences between fragmentation spectra of native and reduced oxytocin .
this is depicted in figure 4 the benefits in terms of sequence coverage are not as obvious as in the case of cid spectra , albeit that the number of sequence - informative fragment ions doubled from 8 to 16 and that the total number of ( assigned ) fragment ions was higher for the reduced species . upon comparison of the etd spectrum of doubly protonated native oxytocin with previous results obtained from ecd experiments , it was noted that the type of fragments were the same , i.e. typical b / y - fragments and typical c - fragments .
interestingly , the number of tocin - ring cleavages was lower in etd than in ecd spectra : b3- , b5- , and c5-ions were absent in etd , as well as y4- , y5- and y7-ions .
on the other hand , in the etd spectra , new y8- , b8- , c7- , and c8-ions were observed .
it was further noted that both b / y- and c / z - fragments were observed in the etd spectrum of ec - reduced , doubly protonated oxytocin . this is somewhat different from the previous ecd results , in which reduced and carboxymethylated doubly protonated oxytocin yielded solely b / y - fragments.figure 3cid spectrum of doubly protonated native ( a ) and on - line reduced ( b ) oxytocin . the online reduction results in a richer ms / ms spectrum and , consequently , a more comprehensive characterization of the peptide sequencefigure 4etd spectrum of doubly protonated native ( a ) and on - line reduced ( b ) oxytocin
. the differences between the two spectra are less apparent than in the case of cid spectra .
the on - line reduction of the disulfide bridge results in a more comprehensive characterization of the tocin - ring cid spectrum of doubly protonated native ( a ) and on - line reduced ( b ) oxytocin .
the online reduction results in a richer ms / ms spectrum and , consequently , a more comprehensive characterization of the peptide sequence etd spectrum of doubly protonated native ( a ) and on - line reduced ( b ) oxytocin .
the differences between the two spectra are less apparent than in the case of cid spectra .
the on - line reduction of the disulfide bridge results in a more comprehensive characterization of the tocin - ring
the system depicted in figure 1 was used for a top - down analysis of the 25 amino acid - containing hormone hepcidin .
the cid spectrum of native hepcidin was recorded , showing mostly typical b / y - fragments and a few a - fragment ions . from the sequence coverage shown in figure 5 ,
it becomes clear that the observed fragment ions resulted solely from peptide backbone cleavages that are not involved in the region containing the four disulfide bonds .
in other words , the disulfide bonds clearly hamper sequencing the part from cys7 to cys23 . after on - line
electrochemical reduction of all four s s bridges , the cid spectrum contained many more fragment ions , as can be seen in figure 5 .
the ms / ms - data are still dominated by b- and y - fragments and , in addition , more internal fragments were observed ( resulting from two - bond cleavages ) .
the beneficial effect of using on - line ec becomes clear from the sequence coverage : only seven bonds were fragmented in the native species , whereas 21 out of 24 peptide bonds were cleaved in the fully reduced hepcidin .
previous ms identifications of hepcidin were based mostly on ( accurate ) mass measurements [ 34 , 37 ] . to our knowledge , this is the first study where such high sequence coverage of hepcidin was obtained , although lc - ms / ms methods have been used to identify and quantify hepcidin in body fluids [ 38 , 39].figure 5cid spectrum of native ( a - i , -ii , -iii , -iv , and -v ) and on - line reduced ( b - i , -ii , -iii , -iv , and -v ) hepcidin .
the fragmentation of the native hepcidin led to backbone cleavages that are not involved in the region containing the four disulfide bonds .
the on - line reduction of the four s s bridges prior the ms / ms experiment led to a more extensive fragmentation resulting in 21 out of 24 cleaved peptide bonds .
the following internal fragments were also observed as doubly charged ions : ( 1 ) cifccgcchrskcgmcck ; ( 2 ) cifccgcchrskcgmcck ; ( 3 ) picifccgcchrskcgmcck ; ( 4 ) fpicifccgcchrskcgmcck ; ( 5 ) ccgcchrskcgmcck ; ( 6 ) fccgcchrskcgmcck ; ( 7 ) cifccgcchrskcgmcck ; ( 8) picifccgcchrskcgmcck cid spectrum of native ( a - i , -ii , -iii , -iv , and -v ) and on - line reduced ( b - i , -ii , -iii , -iv , and -v ) hepcidin . the fragmentation of the native hepcidin led to backbone cleavages that are not involved in the region containing the four disulfide bonds .
the on - line reduction of the four s s bridges prior the ms / ms experiment led to a more extensive fragmentation resulting in 21 out of 24 cleaved peptide bonds . the following internal fragments were also observed as doubly charged ions : ( 1 ) cifccgcchrskcgmcck ; ( 2 ) cifccgcchrskcgmcck ; ( 3 ) picifccgcchrskcgmcck ; ( 4 ) fpicifccgcchrskcgmcck ; ( 5 ) ccgcchrskcgmcck ; ( 6 ) fccgcchrskcgmcck ; ( 7 ) cifccgcchrskcgmcck ; ( 8) picifccgcchrskcgmcck in summary , the presented study here shows that disulfide bridges can be successfully reduced in an on - line esi set - up using electrochemistry .
these findings are similar to those obtained by other authors using desi [ 2022 ] .
it will be of great interest to further study the coupling of ec with lc - based separation of proteins and on - line digestion , as this might finally lead to a fully integrated workflow overcoming the reduction / alkylation step in standard bottom - up proteomics .
in addition , the coupling of ec with lc - based peptide separation may open new avenues in the field of de novo and middle - down sequencing of ( large ) peptides .
Output:
| particularly in the field of middle- and top - down peptide and protein analysis , disulfide bridges can severely hinder fragmentation and thus impede sequence analysis ( coverage ) . here
we present an on - line / electrochemistry / esi - fticr - ms approach , which was applied to the analysis of the primary structure of oxytocin , containing one disulfide bridge , and of hepcidin , containing four disulfide bridges .
the presented workflow provided up to 80 % ( on - line ) conversion of disulfide bonds in both peptides . with minimal sample preparation ,
such reduction resulted in a higher number of peptide backbone cleavages upon cid or etd fragmentation , and thus yielded improved sequence coverage .
the cycle times , including electrode recovery , were rapid and , therefore , might very well be coupled with liquid chromatography for protein or peptide separation , which has great potential for high - throughput analysis . |
PubmedSumm4828 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: one of the most common fracture pattern is a simple lateral split ( ao / ota type 41-b1.1 , schatzker type i).this type of fracture usually occurs in two different groups : young patients after high - energy trauma or elderly osteopenic patients after low - energy injuries . in the latter , a depression component is often associated .
the main trauma mechanism in this fracture type is pure abduction force or valgus combined with axial load .
soft tissue injury , bone quality , patient 's age , redisplacement , and posttraumatic arthritis are important factors influencing the outcome of proximal tibia fractures . during the last decades , the treatment shifted from predominantly conservative with unsatisfactory results to a more operative one .
most authors advocate reduction and internal fixation in case of an articular step of 2 to 3 mm and above , an instability of more than 5 to 10 in full extension and to prevent tibia plateau widening during fracture consolidation . in these injuries ,
koval et al and parker et al published biomechanical studies supporting the use of solely two 6.5 mm cancellous screws in lateral split fractures .
current fixation techniques of lateral tibia plateau fractures include 6.5 mm cancellous lag screws , 3.5 or 4.5 mm cortical lag screws , both with optional antiglide plate or l and t - shaped angle stable locking compression plates ( lcp ) .
some of these methods can be performed either in an open or percutaneous fashion . to achieve interfragmentary compression with the use of a locking plate
, an additional lag screw has to be applied before plate fixation or the plate has to be fixed and compressed to the reduced fracture by a reduction clamp prior to locking screw insertion .
the aim of this study was to investigate the interfragmentary compression of 3 different fixation techniques for lateral tibia plateau split fracture fixation , using 3.5 mm cortical lag screws , 6.5 mm cancellous lag screws , and 3.5 mm lcp proximal lateral tibia plate preliminary compressed by a reduction clamp .
the interfragmentary compression was measured in 2 surrogate bone models , simulating osteoporotic and non - osteoporotic bone quality .
thirty right adult synthetic human tibiae with cortical and cancellous bone structure ( synbone , malans , switzerland ) were used in this study .
each specimen provided hard or soft cancellous bone to mimic non - osteoporotic and osteoporotic bone quality , respectively .
it has been shown in previous studies , that synthetic human tibiae are a valid substitute for human bones .
the surrogate tibiae were randomly assigned into 6 groups in total , consisting of 3 groups with non - osteoporotic bone quality and 3 groups with osteoporotic bone quality .
three different fixation techniques were investigated using implants made of tial6n7 ( tan ) alloy ( synthes gmbh , solothurn switzerland ) : two 6.5 mm cancellous screws ( length 60 mm , thread length 16 mm ) ; four 3.5 mm cortex screws ( length 65 mm ) and right lateral 3.5 mm lcp proximal tibia plate ( 4 holes , length 81 mm , synthes , solothurn switzerland ) , fixed proximally with four 3.5 mm self - tapping locking screws ( length 56 mm ) ( figure 1 ) .
instrumented specimens : two 6.5 mm cancellous lag screws with washers ( left ) , four 3.5 mm cortical lag screws ( middle ) and 3.5 mm lcp proximal lateral tibia plate ( right ) .
an - osteotomy on the lateral tibia plateau was set , representing a simple split fracture of the lateral tibia plateau ( ao / ota type 41-b1.1 , schatzker type i ) .
the osteotomy was oriented in the sagittal plane orthogonal to the tibia plateau plane , 17 mm medial from the lateral edge of the tibia plateau , created by a 1 mm saw blade .
the drill holes were set according to the distance of the plate head locking holes of the 3.5 mm lcp proximal tibia plate to provide a standardized and comparable orientation of the holes between the groups .
the lcp proximal tibia plate was placed on the lateral aspect of the tibia head with the locking - head screw holes located in the subcortical area of the tibia plateau .
the proximal edge of the plate was oriented in parallel to the joint line so that the locking holes were located 7.5 mm below the tibia plateau surface .
the four holes for 3.5 mm cortical lag screw instrumentation were drilled in the same position as the locking holes in the plate head with a 2.5 mm drill bit , oriented in parallel to the dorsal edge of the tibia plateau .
the lateral fragment was overdrilled with a 3.5 mm drill bit to set a gliding hole for lag screw application . due to a limited space between the screw heads ,
the two 6.5 mm cancellous screws were set at the position of the most anterior and posterior hole of the locking plate head and oriented in parallel to the dorsal edge of the tibia plateau .
each screw was equipped with a washer ( synthes gmbh , solothurn , switzerland ) .
prior to screw tightening , a pressure sensor film ( model 5033 , tekscan inc .
, south boston , ma ) , protected by two rubber pads of 1 mm thickness on each side , was introduced in the osteotomy gap from the articular side to determine the amount of interfragmentary compression at the osteotomy gap at the level of the tibia plateau ( figure 2 ) . test setup .
specimen instrumented with a pressure sensor film in the osteotomy gap and four 3.5 mm cortical lag screws .
two rubber pads of 1 mm thickness were applied at each side of the sensor for a better transmission of the pressure to the sensor film and smoothening of the pressure peaks due to minimal local mismatch at the osteotomy . for instrumentation of the lcp , two kirschner wires were used to preliminarily fix the plate in the position mentioned above and 2.8 mm drill holes were set via a 2.8 mm drill guide in the 4 plate head locking holes according to the manufacturer 's guidelines .
after removal of the kirschner wires , the sensor film and the rubber pads were installed as mentioned above .
the plate was fixed to the reduced fracture by a clamp with the sensor film in place and the interfragmentary compression effected by the clamp was registered .
after instrumentation of the 4 locking screws at the plate head , the clamp was removed and the compression force at the fracture site was measured again .
pressure was recorded along the articular osteotomy gap and mean pressure of each sample was calculated .
statistical analysis was performed using spss software package ( spss 20.0.0 ; spss , chicago , il ) .
normal distribution of the data within each study group was indicated by the shapiro wilk test .
significant differences between the study groups regarding mean pressure at the fracture site were tested statistically with one - way analysis of variance ( anova ) and bonferroni post hoc test .
significance level was set at p = 0.05 . since no human material and no patient - related data were used , ethical approval was not necessary .
thirty right adult synthetic human tibiae with cortical and cancellous bone structure ( synbone , malans , switzerland ) were used in this study .
each specimen provided hard or soft cancellous bone to mimic non - osteoporotic and osteoporotic bone quality , respectively .
it has been shown in previous studies , that synthetic human tibiae are a valid substitute for human bones .
the surrogate tibiae were randomly assigned into 6 groups in total , consisting of 3 groups with non - osteoporotic bone quality and 3 groups with osteoporotic bone quality .
three different fixation techniques were investigated using implants made of tial6n7 ( tan ) alloy ( synthes gmbh , solothurn switzerland ) : two 6.5 mm cancellous screws ( length 60 mm , thread length 16 mm ) ; four 3.5 mm cortex screws ( length 65 mm ) and right lateral 3.5 mm lcp proximal tibia plate ( 4 holes , length 81 mm , synthes , solothurn switzerland ) , fixed proximally with four 3.5 mm self - tapping locking screws ( length 56 mm ) ( figure 1 ) .
instrumented specimens : two 6.5 mm cancellous lag screws with washers ( left ) , four 3.5 mm cortical lag screws ( middle ) and 3.5 mm lcp proximal lateral tibia plate ( right ) .
an - osteotomy on the lateral tibia plateau was set , representing a simple split fracture of the lateral tibia plateau ( ao / ota type 41-b1.1 , schatzker type i ) .
the osteotomy was oriented in the sagittal plane orthogonal to the tibia plateau plane , 17 mm medial from the lateral edge of the tibia plateau , created by a 1 mm saw blade .
the drill holes were set according to the distance of the plate head locking holes of the 3.5 mm lcp proximal tibia plate to provide a standardized and comparable orientation of the holes between the groups .
the lcp proximal tibia plate was placed on the lateral aspect of the tibia head with the locking - head screw holes located in the subcortical area of the tibia plateau .
the proximal edge of the plate was oriented in parallel to the joint line so that the locking holes were located 7.5 mm below the tibia plateau surface .
the four holes for 3.5 mm cortical lag screw instrumentation were drilled in the same position as the locking holes in the plate head with a 2.5 mm drill bit , oriented in parallel to the dorsal edge of the tibia plateau .
the lateral fragment was overdrilled with a 3.5 mm drill bit to set a gliding hole for lag screw application . due to a limited space between the screw heads ,
the two 6.5 mm cancellous screws were set at the position of the most anterior and posterior hole of the locking plate head and oriented in parallel to the dorsal edge of the tibia plateau .
each screw was equipped with a washer ( synthes gmbh , solothurn , switzerland ) . prior to screw tightening , a pressure sensor film ( model 5033 , tekscan inc .
, south boston , ma ) , protected by two rubber pads of 1 mm thickness on each side , was introduced in the osteotomy gap from the articular side to determine the amount of interfragmentary compression at the osteotomy gap at the level of the tibia plateau ( figure 2 )
specimen instrumented with a pressure sensor film in the osteotomy gap and four 3.5 mm cortical lag screws .
two rubber pads of 1 mm thickness were applied at each side of the sensor for a better transmission of the pressure to the sensor film and smoothening of the pressure peaks due to minimal local mismatch at the osteotomy . for instrumentation of the lcp , two kirschner wires were used to preliminarily fix the plate in the position mentioned above and 2.8 mm drill holes were set via a 2.8 mm drill guide in the 4 plate head locking holes according to the manufacturer 's guidelines .
after removal of the kirschner wires , the sensor film and the rubber pads were installed as mentioned above .
the plate was fixed to the reduced fracture by a clamp with the sensor film in place and the interfragmentary compression effected by the clamp was registered .
after instrumentation of the 4 locking screws at the plate head , the clamp was removed and the compression force at the fracture site was measured again .
pressure was recorded along the articular osteotomy gap and mean pressure of each sample was calculated .
statistical analysis was performed using spss software package ( spss 20.0.0 ; spss , chicago , il ) .
normal distribution of the data within each study group was indicated by the shapiro wilk test .
significant differences between the study groups regarding mean pressure at the fracture site were tested statistically with one - way analysis of variance ( anova ) and bonferroni post hoc test .
significance level was set at p = 0.05 . since no human material and no patient - related data were used , ethical approval was not necessary .
both lag screw techniques , 2 cancellous screws ( 2.12 mpa sd 0.59 ) and 4 cortical screws ( 1.69 mpa sd 0.65 ) exhibited a comparable interfragmentary compression in non - osteoporotic bone ( p = 1.00 ) .
interfragmentary compression in osteoporotic bone was not significantly different using 4 cortical lag screws 1.42 mpa ( sd 0.46 ) or 2 cancellous screws 0.77 mpa ( sd 0.21 ) ( p = 0.32 ) . comparing the 4 cortical lag screw fixation in non - osteoporotic and osteoporotic bone , the amount of interfragmentary compression was similar in both groups ( p = 1.00 ) .
two cancellous screws exhibited a significantly higher compression in non - osteoporotic bone compared to osteoporotic bone ( p < 0.01 ) .
a significantly lower interfragmentary compression was achieved when the plate was fixed by a reduction clamp in comparison to both lag screw techniques in non - osteoporotic bone ( p < 0.01 ) and in comparison to 4 cortical lag screws in osteoporotic bone ( p = 0.03 ) .
the locking plate , instrumented under compression was able to maintain the interfragmentary compression , applied during preliminary fixation by the reduction clamp in both , non - osteoporotic and osteoporotic bone . the mean pressure was 0.60 mpa ( sd 0.11 ) under preliminary clamp fixation and 0.53 mpa ( sd 0.10 ) after plate fixation ( p = 0.4 ) in non - osteoporotic bone .
in osteoporotic bone the mean pressure under preliminary clamp fixation was 0.55mpa ( sd 0.14 ) and 0.50mpa ( sd 0.14 ) after plate fixation ( p = 0.6 ) .
mean interfragmentary compression of two 6.5 mm cancellous lag screws ( 2sc ) , four 3.5 mm cortical lag screws ( 4sc ) , and 3.5 mm lcp lateral proximal tibia locking plate ( pl ) investigated in non - osteoporotic ( no ) and osteoporotic ( o ) surrogate bone .
the interfragmentary compression in the plate group was determined after preliminary fixation of the plate to the reduced fracture by a reduction clamp ( clamp ) and subsequent definite plate fixation and clamp removal ( fixed ) .
the columns and error bars indicate mean pressure ( mpa ) with standard deviation in each study group , consisting of 5 specimens ( n = 5 ) .
mean pressure values between the study groups fixed with two 6.5 mm cancellous screws in osteoporotic and non - osteoporotic bone were significantly different .
mean pressure values in all plate groups under clamping and after definite plate instrumentation and clamp removal were not significantly different .
the mean pressure values between the groups with 4 cortical screw fixation in osteoporotic and non - osteoporotic bone were not significantly different .
lasting interfragmentary compression can be achieved by lag screw techniques and locking plates , preliminarily compressed by a reduction clamp .
interfragmentary compression with two 6.5 mm cancellous screws was in a comparable range to four 3.5 mm cortical screws .
the choice between these 2 options would depend on the fracture pattern : for osteosynthesis of a simple split fracture of the lateral tibia plateau , two 6.5 mm cancellous screws would be sufficient . in split fractures with additional central depression fragment , four 3.5 mm cortical screws would be more appropriate as demonstrated by karunakar et al , who observed a significantly lower local depression stiffness in this fracture type , fixed with two 6.5 mm cancellous screws compared to four 3.5 mm cortical screws .
an antiglide plate placed at the inferior edge of the fracture secures the fracture fragment from inferior dislocation .
the same effect can be achieved using a buttress plate . using an osteoporotic bone foam model with a split depression fracture , patil et
al observed a significantly higher force required to produce a depression in the four 3.5 mm cortical screw construct than in the two 6.5 mm cancellous screw construct . in the non - osteoporotic bone foam model ,
difference in force required to produce a depression was not significant in - between the two constructs , indicating that the two cancellous screw technique would be better suited for non - osteoporotic bones . comparing the two 6.5 mm cancellous screw fixation placed orthogonally to the fracture in a posterolateral coronal shear fracture model of the tibia plateau to a laterally placed 3.5 mm lcp proximal tibia plate , a smaller displacement under axial load was observed in the plate group , although the plate was not ideally placed for this fracture type .
mueller et al reported no significant difference between two dual plating constructs and a lateral fixed angle plate construct in terms of stiffness , maximum load to failure , and medial condylar displacement .
consistent with our results , pullout force of subchondrally placed screws of 6.5 and 3.5 mm diameter , did not differ significantly in a human tibia model .
although locking plates function via the principle of angular stability , holding the tibia plateau comparable to a ceiling beam , preliminarily applied compression after proper reduction is advisable for sufficient fracture fixation .
the lateral 3.5 mm proximal tibia locking plate construct maintained the compression preliminarily applied by the weber clamp in non - osteoporotic and osteoporotic bone . even though a lesser amount of compression was achieved by the weber clamp
compared to both screw constructs , persisting compression combined with good interdigitation of the fracture fragments would prevent loss of reduction .
the ability of each construct to maintain the fracture reduction under physiologic motion of the knee joint was not evaluated .
two 6.5 mm cancellous screws should only be used in non - osteoporotic bone , since interfragmentary compression was significantly lower for these screws in osteoporotic bone .
four 3.5 mm cortical screws could be applied in both bone qualities , because interfragmentary compression was comparable in osteoporotic and non - osteoporotic bone .
locked implants like the locking compression plate maintain the interfragmentary compression preliminarily applied by a reduction clamp .
Output:
| abstractreliable osteosynthesis of intraarticular fractures depends on lasting interfragmentary compression .
its amount differs in the applied fixation method .
the interfragmentary compression of cancellous and cortical lag screws and angle stable locking plates was quantified in an osteoporotic and non - osteoporotic synthetic human bone model.a split fracture of the lateral tibia plateau ( ao / ota type 41-b1.1 ) was mimicked by an osteotomy in right adult synthetic human tibiae with hard or soft cancellous bone .
specimens were fixed with either two 6.5 mm cancellous , four 3.5 mm cortical lag screws , or 3.5 mm lcp proximal lateral tibia plate preliminary compresed by a reduction clamp ( n = 5 per group ) .
a pressure sensor film was used to register the interfragmentary compression .
one - way analysis of variance ( anova ) with bonferroni post hoc correction was performed for statistical analysis ( p < 0.05).interfragmentary compression under reduction clamp was 0.59 0.12 mpa in the non - osteoporotic and 0.55 0.14 mpa in the osteoporotic group .
the locking plate itself maintained the compression in non - osteoporotic ( 0.53 0.11 mpa ) and osteoporotic bone ( 0.50 0.14 mpa ) .
four 3.5 mm cortical lag screws provided a compression of 1.69 0.65 mpa in non - osteoporotic bone , being not significantly different to the osteoporotic bone group ( 1.43 0.47 mpa , p = 1.0 ) .
two 6.5 mm cancellous lag screws showed a significantly higher compression in non - osteoporotic ( 2.1 0.59 mpa ) compared to osteoporotic ( 0.77 0.21 mpa , p < 0.01 ) bone.angle stable locking plates maintained the compression preliminarily applied by a reduction clamp .
two 6.5 mm cancellous lag screws are especially suited for non - osteoporotic bone , whereas four 3.5 mm cortical screws exhibited comparable compression in both bone qualities . |
PubmedSumm4829 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: to achieve an accurate pathological evaluation in toxicity studies , it is particularly important to know the background histopathology , that is , to be familiar with pictures of incidental findings . as
abundant studies using rats are common in laboratories , toxicological pathologists know the background data of spontaneous lesion in rats and can visualize these histological figures easily . however , most pathologists do not have much experience with studies of beagles . therefore
, toxicological pathologists can not help but depend on the literature or textbooks when performing pathological evaluations in dog studies .
in veterinary pathology , many textbooks have been published , and information concerning disease pathology in dogs is readily available
. however , the descriptions of background lesions in beagles are insufficient in veterinary pathology textbooks due to the lack of understanding of the importance of publishing incidental findings , which are pathologically insignificant spontaneous lesions with no sign of disease .
the papers that have reported background data did not aim to show histological pictures exhaustively .
therefore , in this report , we provide pictures of spontaneous lesions in beagles that were detected in background data collection studies and ordinary toxicity studies in our laboratory .
the figures are grouped and arranged according to the cardiovascular , lymphoid , respiratory , alimentary , urinary , reproductive , endocrine , nervous and integumentary systems .
a total of 1188 beagles ( 605 males and 583 females ) were subjected to background data collection studies and ordinary toxicity studies conducted in our laboratory from 1995 to 2011 .
( former known as toyo beagle , 169 males and 152 females ) , covance research products inc .
, 268 males and 267 females ) , marshall bioresources ( 6 males and 6 females ) , beijing marshall biotechnology co. , ltd .
( 4 males and 4 females ) , nrd beagle ( 5 males and 5 females ) , csk research park inc .
( 5 males and 5 females ) and the institute for animal reproduction ( 2 males and 2 females ) .
the animals were housed individually in metal cages ( 700 800 700 mm , 780 880 780 mm or 900 1106 808 mm ) in conventional air - conditioned rooms at 19 c to 25 c with 35% to 75% relative humidity and a 12-hour light/12-hour dark cycle .
they were provided every day with 300 g or 250 g ( for marshall beagles ) of commercially available food ( ds , ds-5 or ds - a , oriental yeast co. , ltd . ) and were also allowed free access to drinking water .
the animals were cared for according to the principles outlined in the guides for the care and use of laboratory animals prepared by the japanese association for laboratory animal science and our institution .
organs fixed in 10% neutral phosphate - buffered formalin were embedded in paraffin , and sections were made and stained with hematoxylin and eosin ( he ) for microscopic examination .
we chose 155 typical findings or rare lesions from the background data of the beagles , and they are shown as follows .
heart : blood cyst in the atrioventricular valve . a blood cyst surrounded by endothelia occurs occasionally in the atrioventricular valve , although anatomically , the cardiac valves are nonvascular tissue .
1 . heart : blood cyst in the atrioventricular valve heart : hemorrhage in the atrioventricular valve .
hemorrhage without inflammation or hemosiderosis occurs occasionally in the atrioventricular valve , suggesting that the change is agonal hemorrhage during the euthanasia and exsanguination .
2 . heart : hemorrhage in the atrioventricular valve heart : thickening of the intramural arterial wall .
3 . heart : thickening of the intramural arterial wall heart : proliferation of the epicardial mesothelium .
focal papillary proliferation of single layered mesothelial cells occurs occasionally in the right or left atrial epicardium .
4 . heart : proliferation of the epicardial mesothelium heart : hemorrhage in the endocardium .
slight focal hemorrhage in the endocardium and subendocardium occurs occasionally and is mainly considered an agonal change .
it is necessary to distinguish this agonal change from drug - induced hemorrhage by certain drugs such as minoxidil , theobromine and other vasodilating drugs .
heart : hemorrhage in the endocardium heart : focal inflammatory cell infiltration in the myocardium .
heart : focal inflammatory cell infiltration in the myocardium heart : fatty infiltration in the myocardium .
812 ) the term of arteritis refers to various inflammatory changes of the arterial wall .
endarteritis , periarteritis and panarteritis are used to describe the affected part , and polyarteritis is used for multiple lesions .
various adjectives are added to describe the morphological characteristics such as acute arteritis , necrotizing arteritis , polyarteritis nodosa or granulomatous arteritis .
immunologic disorders or other latent infections are suggested to be the causes in beagles ; however , the detailed pathogenesis has not yet been clarified .
frequent sites of arteritis are the heart , spleen , pancreas , epididymis and spinal cord .
the most frequent site of arteritis in beagles is the extramural atrial branch of the right coronary artery .
it is difficult to distinguish spontaneously occurring vasculitis from drug - induced vasculitis resulting from such things as minoxidil , theobromine and other vasodilating drugs .
arteritis is less frequently seen in the spleen as an isolated lesion or part of polyarteritis .
the change is characterized by fibrous thickening with inflammatory cell infiltration into the tunica intima and fibrinoid necrosis of the tunica media . fig
the artery in the pancreas is one of the arteries with a high incidence of arteritis .
the epididymal artery is one of the arteries with a high incidence of arteritis , often in the form of periarteritis .
fig . 12 . artery : arteritis in the epididymis aorta : mineralization in the aortic wall .
mineralization in the tunica media of the aorta is rare and focal in young beagles .
erythrophagia is common in the lymphatic sinus undergoing blood absorption as an agonal change , especially in the mesenteric lymph node .
the cause is unclear , but it is thought to be a nonspecific reactive change to some irritation such as inflammation , foreign body and parasite .
lymph node : granuloma lymph node : increased number of pigment - laden macrophages .
brown pigment - laden macrophages accumulate predominantly in the medullary region , especially in the mandibular lymph node .
lymph node : increased number of pigment - laden macrophages lymph node : foreign body granuloma .
macrophages accumulate and form multinucleated giant cells around foreign bodies such as hair fragments or parasites .
lymph node : foreign body granuloma lymph node : increased number of foam cells in the sinuses .
the number of foam cells ( foamy macrophages ) occasionally increases in the lymphatic sinuses , especially in the mesenteric lymph node .
lymph node : increased number of foam cells in the sinuses thymus : involution ( physiological atrophy ) . a decrease in lymphoid cells from both the cortex and medulla with replacement by adipose tissues causes reduction in size and organ weight .
thymus : involution ( physiological atrophy ) thymus : proliferation of the thymic epithelium .
the change is characterized by proliferation of prominent tubular structures lined by the cuboidal epithelium .
solitary or multilocular cysts are associated with remnants of embryonic ducts connecting the parathyroid and thymus .
the cysts are covered by a cuboidal epithelium , partially ciliated , and contain the same eosinophilic proteinic substances as parathyroid cysts ( fig .
thymus : cyst thymus : lymph follicle formation in the medulla . a germinal center is commonly formed in the medulla .
the change is known to be associated with myasthenia gravis in humans , whereas it is irrelevant and incidental in beagles .
vaccination is considered to be attributable to the change , so attention must be paid to the immunologic failure or overresponse if the follicle formation is severe .
the aberration of splenic tissue separated from the original body and surrounding capsule occurs occasionally in the greater omentum and mesenterium as a congenital anomaly .
an increase in hematopoietic cells , predominantly erythrocytic series , occurs occasionally in the red pulp under normal conditions .
a focus consisting of relatively dense fibrous tissue or collagenous fibers impregnated with iron pigment and calcium salts is common usually in the splenic hilum and probably results from organization and scarring of the sites where a small perivascular hemorrhage occurred .
spleen : necrosis of the splenic follicle spleen : pigment deposition in the red pulp .
this is a common lesion that shows an increase in brown pigment - laden macrophages usually containing hemosiderin .
spleen : pigment deposition in the red pulp spleen : nodular hyperplasia ( lymphoid follicle ) .
nodular hyperplasia is essentially focal proliferation of various types of splenic components compressing slightly normal splenic tissues , although a large aggregation of lymphocytes is the main feature .
the nodule takes an appearance like a giant follicle without the normal structures of a lymph follicle such as a central artery , periarterial lymphoid sheath ( pals ) or germinal center .
spleen : nodular hyperplasia ( lymphoid follicle ) bone marrow : lymph follicle formation .
tonsilla : mineralization in the lymphoid tissue tonsilla : neutrophilic migration in the mucosa .
larynx : focal inflammatory cell infiltration larynx : erosion / ulcer of the mucosa .
larynx : erosion / ulcer of the mucosa trachea : focal inflammatory cell infiltration .
trachea : focal inflammatory cell infiltration trachea : hyperplasia of the mucosal epithelium in the tracheal bifurcation .
hyperplasia of the mucosal epithelium is frequently seen in the region near the bifurcation .
trachea : hyperplasia of the mucosal epithelium in the tracheal bifurcation trachea : squamous metaplasia in the tracheal bifurcation .
squamous metaplasia of the mucosal epithelium leading from a hyperplastic lesion occurs occasionally in the region near the bifurcation .
35 ) and squamous metaplasia because this region is most likely to receive the physiological irritant effects .
trachea : squamous metaplasia in the tracheal bifurcation lung : accumulation of foam cells in the alveolus .
focal accumulation of foam cells without other inflammatory cells is frequently seen in the alveoli . fig .
lobar atelectasis ( stenosis of the bronchiole and alveoli ) and bronchial cartilage aplasia occur occasionally .
lung : focal hemorrhage in the alveolus lung : inflammatory cell infiltration in the alveolus . inflammatory cell infiltration with / without hemorrhage occurs occasionally .
lung : inflammatory cell infiltration in the alveolus lung : fibrosis of the alveolar wall .
osseous metaplasia presumably caused by differentiation from fibroblasts to osteoblasts occurs occasionally and is similar to that seen in rats and mice .
thrombosis is frequently seen in the pulmonary vessels of beagles used in toxicity studies by intravenous injection .
this change results from aspiration of stomach contents or food particles ( arrow ) .
stenosis of the vascular lumen by a fibrous organization of thrombus containing hair fragments is rare .
foreign body granuloma caused by a hair fragment stuck on the tongue occurs occasionally in the lamina propria or muscle layer .
tongue : foreign body granuloma tongue : focal infiltration of macrophages in the muscle layer .
tongue : focal infiltration of macrophages in the muscle layer esophagus : focal atrophy of the esophageal gland .
esophagus : focal atrophy of the esophageal gland esophagus : hypertrophy of the esophageal gland .
esophagus : hypertrophy of the esophageal gland esophagus : focal inflammatory cell infiltration in the lamina propria .
esophagus : focal inflammatory cell infiltration in the lamina propria stomach : infection by helicobacter heilmannii in the gastric mucosa .
stomach : infection by helicobacter heilmannii in the gastric mucosa stomach : mineralization in the lamina propria .
stomach : mineralization in the lamina propria duodenum : hyperplasia of the lymphoid tissue .
hyperplasia of the lymphoid tissue occurs occasionally in not only the duodenum but other intestinal tracts .
dilatation of the crypt filled with / without cell debris or inflammatory cell infiltration is frequently seen .
the change most frequently occurs in the duodenum but also occurs in the other intestines .
ectopic pancreatic tissue is frequently seen in the submucosa near the major duodenal papilla .
focal lymphocytic infiltration , occasionally accompanied by lymph follicle formation , is common around the ducts or acini .
focal fibrosis with atrophy and loss of the acini is frequently seen , especially in the parotid gland . fig .
a small mineralized calculus occurs occasionally in a duct of a relatively large caliber .
the mucous epithelium increases occasionally in the parotid gland , though the parotid gland of the beagles is composed mainly of a serous epithelium . fig .
salivary gland : increase in the mucous gland liver : accumulation of glycogen in hepatocytes .
the change is common in beagles and characterized by a clear appearance of hepatic cytoplasm after formalin fixation .
the quantity of glycogen in cytoplasm varies among individuals under normal conditions . fig . 64 .
microgranuloma is accumulation of inflammatory cells , mainly macrophages , lymphocytes and a small number of neutrophils , and may be associated with minute necrosis of hepatocytes .
lipofuscin pigments are common in centrilobular hepatocytes of young beagles but are particularly prominent in older dogs . fig .
a necrotic focus of hepatocytes with inflammatory cell infiltration occurs occasionally without any apparent cause .
liver : pigment deposition in kupffer cells liver : increased number of ito cells with lipid accumulation .
liver : increased number of ito cells with lipid accumulation gall bladder : cystic mucinous hyperplasia of the mucosal epithelium . a cystic change or cystic hyperplasia of the mucosal epithelium with copious mucin production occurs occasionally .
gall bladder : cystic mucinous hyperplasia of the mucosal epithelium gall bladder : hyperplasia of the mucosal epithelium .
gall bladder : hyperplasia of the mucosal epithelium gall bladder : hyperplasia of the lymphoid tissue .
prominent lymphoid tissues with / without lymph follicle formation are common in the lamina propria .
irregularly shaped islets and small clusters of endocrine cells closely associate with ductules or intercalated ductules .
immature glomerulus is more frequently seen in the outer layer of the cortex , reflecting delayed maturation of the glomeruli in the outer cortex than those in the deeper layer .
a lesion such as that resulting from collapse of the capillary loops due to the proliferation of mesangial cells and increase in matrix is called sclerosis . fig . 79 .
a typical lesion of renal dysplasia consists of a scarring focus containing mesenchymal cells , immature renal tubules ( large arrows ) , small - sized glomeruli ( small arrows ) and dilatation of the collecting tubule ( arrowheads ) in the medulla to the cortex .
focal regenerative changes of damaged tubules are detected frequently as basophilic tubules with a high nuclear density in the cortex or outer stripe of the renal medulla .
kidney : regeneration of the tubular epithelium kidney : focal inflammatory cell infiltration in the interstitium .
a solitary cast occurs occasionally in the distal segment or collecting tubule in the outer medulla , but it is not associated with chronic progressive nephropathy as in rats .
focal interstitial fibrosis occurs occasionally and is accompanied by interstitial inflammation , pyelitis and infarction .
kidney : focal interstitial fibrosis kidney : brown pigment deposition in the tubular epithelium .
kidney : brown pigment deposition in the tubular epithelium kidney : fatty change of the proximal tubular epithelium .
tubules containing fine lipid droplets are frequently seen in the epithelia of the straight portion of the proximal tubules in most female dogs .
kidney : fatty change of the proximal tubular epithelium kidney : inclusion bodies in the collecting tubular epithelium .
kidney : inclusion bodies in the collecting tubular epithelium kidney : mineralization in the medulla .
small mineralized calculus is frequently seen in the renal papillary collecting tubules . fig .
kidney : mineralization in the medulla kidney : focal hyperplasia of the pelvic epithelium .
focal hyperplasia of the transitional epithelium ( urothelium ) covering the papilla with inflammation occurs occasionally , but the lesion without inflammation , as in this case , is rare .
focal lymphocytic infiltration including lymph follicle formation is frequently seen in the lamina propria of the renal pelvis .
kidney : pyelitis kidney : pyelonephritis . a severe case of pelvic inflammation penetrating all mucosal regions and
this tubulointerstitial inflammation can be assumed to be accompanied by pyelitis because the lesion distributed along nephron is suggested to be an ascending spread of inflammatory lesions from the pelvis .
kidney : interstitial nephritis urinary bladder : round ligament of the urinary bladder . a fibromuscular band with mineralization is rarely attached to the urinary bladder .
only a small number of spermatids are present , whereas development up to the spermatocytes completes in the seminiferous tubules . fig .
when seminiferous tubules sustain a permanent damage , the end - stage feature shows sertoli - cell - only tubules .
testis : sertoli - cell - only tubule testis : appearance of multinucleated giant cells .
this change is caused by disturbance of spermatozoa flow due to seminiferous tubular damage .
cell debris of spermatocytes or spermatids occurs occasionally in the epididymal lumen in normal beagles .
an intraepithelial lumen is frequently seen and is lined by ciliated cells . fig .
foreign body granuloma occurs occasionally in the interstitium and contains a mass of spermatozoa surrounded by macrophages and lymphocytes .
epididymis : spermatic granuloma ( sperm granuloma ) epididymis : focal inflammatory cell infiltration in the interstitium .
the glandular epithelia are small and flat , and lumens are narrow because of no prostatic secretion .
maturation of the prostatic gland varies in young beagles aged 6 - 7 months .
prostate : focal inflammatory cell infiltration cyclic changes in female reproductive system ( figs . 110114 ) .
ovary ( containing postovulatory corpus luteum ) , uterus , vagina , mammary gland fig .
ovary ( containing functional corpus luteum ) , uterus , vagina , mammary gland fig .
ovary ( containing previously formed corpus luteum ) , uterus , vagina , mammary gland fig
the embryonic remnants of rete ovarii are frequently seen in the hilum of the ovary and occasionally undergo glandular hyperplasia .
the luminal surface is lined by a single layer of flat or cuboidal ciliated epithelial cells .
cystic epithelial proliferation of the endometrium separated into two layers is formed in the uterus in beagles .
pituitary cysts are frequently seen in each lobe ( anterior , intermediate , posterior ) but are most often found in the anterior lobe .
pituitary : focal inflammatory cell infiltration in the posterior lobe thyroid ( parathyroid ) : ectopic thymic tissue .
the parathyroid , thyroid and thymic primordia derive from the same primordium , the pharyngeal pouches , during embryonic development .
thyroid ( parathyroid ) : ectopic thymic tissue thyroid : c - cell complex .
solid islands of c - cell - like clear cells are frequently seen in the thyroid tissue .
they are considered to be remnants of ultimobranchial bodies formed before differentiation into follicular cells and c - cells .
the cysts are lined by a cuboidal epithelium that is often ciliated like a parathyroid cyst ( fig .
the duct is a remnant of the ultimobranchial body in the thyroid or parathyroid gland .
the follicles are focally small in size and contain a small amount of colloid inside with abundant connective tissue between each atrophic follicle . fig .
papillary proliferation of the epithelial cells and an increase in small follicles are absent ; these may be the differential points from focal follicular hyperplasia .
this change is frequently seen and is characterized by lymphocytic infiltration often forming a prominent germinal center in the interstitium .
the follicles are destroyed and infiltrated also by lymphocytes , and residual follicles are lined with hypertrophic epithelial cells .
the cyst is lined by a cuboidal epithelium , often ciliated , and contains proteinous substance in the lumens .
this cyst is an embryonal remnant of the duct connecting the parathyroid - thymus tissue in the iii and iv pharyngeal pouches .
the aberration of adrenocortical tissue separated from the original body and surrounding capsule is called accessory adrenocortical tissue , and it is common inside and outside of the adrenal capsule .
adrenal : accessory adrenocortical tissue adrenal : vacuolation of the cells of the zona glomerulosa .
accumulation of large lipid droplets containing cells is frequently seen in the zona glomerulosa in beagles .
adrenal : vacuolation of the cells of the zona glomerulosa adrenal : osseous metaplasia .
adrenal : osseous metaplasia adrenal : vacuolation of the cells of the zona fasciculata .
various degrees of zonal vacuolation in the cells of the zona fasciculata occur occasionally , especially near the zona reticularis .
adrenal : vacuolation of the cells of the zona fasciculata adrenal : extramedullary hematopoiesis .
deposition of yellow - brown pigments occurs occasionally in the cytoplasm of cortical cells near the corticomedullary junction .
adrenal : pigment deposition in the corticomedullary junction brain : focal inflammatory cell infiltration in the choroid plexus .
brain : focal inflammatory cell infiltration in the choroid plexus brain : extramedullary hematopoiesis in the choroid plexus .
hematopoietic cells of granulocytic series with rare megakaryocytes ( arrow ) occasionally aggregate in the choroid plexus .
brain : extramedullary hematopoiesis in the choroid plexus brain : mineralization of the meninx .
fibrous thickening of the meninx may have resulted from chronic inflammation or circulatory disturbance and is very rare .
brain : fibrous thickening of the meninx brain : hamartoma in the callosal sulcus .
this rare lesion consists of choroid plexus components that are epithelia , fatty tissues , abundant collagen fibers and small vessels .
its function is thought to be protection of the peripheral nerve fibers from pressure damage .
a cyst covered by epidermis with a skin appendage structure occurs occasionally in the dermis .
ulcer is rare as a secondary change associated with folliculitis or other skin lesions .
the causes of this lesion may be congenital failures of optic fissure closure ( retinal coloboma ) , dysplasia of retinal structures or focal damage of the retina in the fetal developmental stage .
eye : disarrangement of the retinal structures eye : focal inflammatory cell infiltration in the conjunctiva .
eye : focal inflammatory cell infiltration in the conjunctiva lacrimal gland : focal fibrosis .
focal fibrosis of the interstitium with lymphocytic infiltration and acinar atrophy occur occasionally in the lacrimal gland .
in veterinary pathology , many textbooks have been published , and information concerning disease pathology in dogs is readily available . furthermore , there are some reports referring to spontaneous lesions of beagles in veterinary and toxicologic journals .
however , few publications showing pictures of spontaneous lesions exhaustively are available as a histopathology atlas .
therefore , we provided many pictures of spontaneous lesions in beagles that were detected in background data collection studies and ordinary toxicity studies in our laboratory .
1 ) was reported by takeda et al . , who showed that the endothelium surrounding the blood cysts revealed focal positive staining for the factor viii - related antigen .
there was no difference in the incidence of the lesion between male and female dogs or the right and left atria .
morphological similarities between spontaneous and drug - induced arterial lesions may make it difficult to evaluate a lesion in the toxicity studies of chemicals such as vasodilating agents . at an early stage ,
however , drug - induced arterial lesions are composed of medial necrosis and medial and adventitial hemorrhage with very few or no inflammatory cells ; these may be the differential points from spontaneous arteritis .
70 ) occurs spontaneously , but the change is also induced by long - term dosing of certain some steroids .
furthermore , we picked up the previous reports concerning spontaneous lesions in dogs , especially beagles , such as mineralization in the gastric lamina propria ( fig .
59 ) , pancreatic nesidioblastosis ( fig . 75 ) , renal cytoplasmic inclusion body in the collecting tubular epithelium ( fig .
117 ) , in the journal of toxicologic pathology . concerning the common lesions of beagles , we introduced reports of renal glomerular lipidosis ( fig .
these background lesions may not have an effect on the results of toxicity studies but should be taken into account along with their potential to influence safety assessment in drug administration .
Output:
| the purpose of our publication is to widely communicate the pictures of spontaneous findings occurring in beagles .
spontaneous arteritis occurs commonly in beagles .
frequent sites of arteritis are the heart , spleen , pancreas , epididymis and spinal cord .
morphological similarities between spontaneous and drug - induced arterial lesions may cause confusion when evaluating vascular toxicity of chemicals such as vasodilating agents .
focal and minimal inflammatory lesions are occasionally seen in the lung and may be associated with aspiration of food particles or of unknown causes .
a cystic change with copious mucin production occurs occasionally in the mucosal epithelium of the gall bladder .
nesidioblastosis is seen rarely in the pancreas of beagles .
c - cell complex and lymphocytic thyroiditis are common thyroid lesions .
spontaneous focal hypospermatogenesis and lobular sertoli - cell - only seminiferous tubules occurring frequently in beagles must be distinguished from drug - induced damage of the seminiferous tubules in toxicity studies .
the morphological differences of the female genital system in each cycle need to be understood ; therefore , we present the normal features of the cyclic changes of the female genital organs .
further , we provide more information on spontaneous findings in beagles for exact diagnoses in toxicity studies . |
PubmedSumm4830 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: experiments
were carried out using polystyrene nps with either
an anionic , carboxylate - modified or cationic , amine - modified surface
( table 1 ) .
dark , nonfluorescent nps
were used for experiments in which the np fluorescence would interfere
with the measurement .
we use the diameter supplied by the manufacturer ,
which can differ from the hydrodynamic diameter depending on characterization
method , to denote the np throughout the text .
adsorption of proteins
onto both anionic and cationic nps has been observed previously by
our group and others .
np complexes are formed from both anionic and cationic
nps ( figures s1 , s2 , and s3 of the supporting
information ) .
importantly , bsa np complexes formed with
anionic and cationic nps have identical corona compositions and surface
charges ( 18.5 mv and 19.0 mv , respectively , figure
s2 of the supporting information ) .
cells are commonly cultured in a buffered solution , such as minimum
essential medium ( mem ) , containing inorganic salts , amino acids , and
vitamins .
the medium is supplemented with serum proteins , typically
fetal bovine serum ( fbs ) .
since our goal was to observe molecular - level
effects , we used isolated bsa for the majority of experiments .
fluorescent
nps were incubated with monkey kidney epithelial ( bs - c-1 ) cells in
mem or in mem supplemented with 10 mg ml bsa .
this concentration of bsa is approximately equal to the total protein
concentration used in typical cell culture ( materials
and methods ) .
cellular binding studies were carried out at
4 c , which allows np binding to the cell surface but blocks
cellular internalization of the nps . for the anionic , carboxylate - modified
nps , we observed np binding in mem ( figure 1a ) .
interestingly ,
we observe the opposite trend for the cationic , amine - modified nps .
minimal cellular binding was observed in mem , while bsa enhances cationic
np binding ( figure 1b ) .
similar results were
observed for chinese hamster ovary ( cho ) cells , indicating that this
trend is independent of cell type ( figure s4 of the supporting information ) .
fluorescence microscopy images show cellular
binding of nps ( green )
in mem and mem supplemented with 10 mg ml bsa
( mem + bsa ) to monkey kidney epithelial cells ( bs - c-1 ) at 4 c .
cellular binding of the anionic , carboxylate - modified
nps was inhibited by bsa ( figure 1a ) , suggesting
that bsa
np complexes formed from anionic nps compete with
bsa for binding to the native albumin receptor . to test this hypothesis
,
we carried out cellular binding competition studies with increasing
concentrations of bsa . using flow cytometry as a high - throughput ,
quantitative measure of cellular binding , we observe decreased bsa
np
binding in the presence of increasing concentrations of bsa ( figure 2a ) . at a bsa concentration of 10 mg ml , similar to the concentration used in cell culture , bsa
np
binding was reduced to 32% relative to 100% in the absence of bsa .
nps formed from anionic
nps bind to native albumin receptors on the cell surface .
previous
studies have shown that some nps and protein np complexes bind
to scavenger receptors , specifically scavenger receptors with an affinity for modified albumins . to determine if the bsa nps formed from cationic nps bind
to scavenger receptors , we carried out competition studies in the
presence of both fucoidan ( figure 2b ) and polyinosinic
acid ( figure 2c ) , known competitors for scavenger
receptors . increasing concentrations
of fucoidan and polyinosinic acid both led to decreased cellular binding
of the bsa np complexes , although fucoidan was a stronger competitor
( 11% binding at 2500 g ml compared to 25% ) .
as a control
, we measured cellular binding of bsa nps formed
from cationic nps in the presence of polyadenylic acid ( figure 2d ) .
polyadenylic acid has a similar structure to
polyinosinic acid but is not a competitor for scavenger receptors .
we did not observe competition in the presence
of polyadenylic acid ( 88% binding compared to a control normalized
to 100% ) .
identification of cell surface receptors using cellular binding
competition assays measured with flow cytometry .
( a ) cellular binding
of 93 nm anionic , carboxylate - modified nps in mem with increasing
concentrations of bsa .
( b ) cellular binding of 87 nm cationic , amine - modified
nps in mem supplemented with 10 mg ml bsa with
increasing concentrations of fucoidan .
( c ) cellular binding of 87
nm cationic , amine - modified nps in mem supplemented with 10 mg ml bsa with increasing concentrations of polyinosinic
acid .
( d ) control experiments show cellular binding of 87 nm amine - modified
nps in the presence of polyadenylic acid ( polya ) and the autofluorescence
from cells in the absence of nps ( cells only , error bar is too small
to see ) .
the same protein binding to different cell surface receptors ,
especially scavenger receptors , suggests a structural difference in
bsa following adsorption on the anionic and cationic nps .
we used
circular dichroism ( cd ) spectroscopy to probe the structure of bsa
following incubation with dark , nonfluorescent , polystyrene nps . for
isolated bsa , a primarily -helix protein , the far - uv cd spectrum
contains a positive band at 195 nm and two negative bands at 208 and
222 nm ( figure 3a ) , in good agreement with
previous cd measurements .
incubation with 60
nm anionic , carboxylate - modified nps shows little change in the cd
spectrum ( figure 3a ) . in comparison ,
incubation
with 58 nm cationic , amine - modified nps results in more positive mean
residue ellipticity ( mre ) values , indicating a loss in protein secondary
structure ( figure 3a ) .
cd difference spectra
were calculated by subtracting the spectrum of bsa alone from the
spectrum of bsa in the presence of nps ( figure 3b ) .
the difference spectra reveal a larger change in bsa secondary
structure in the presence of cationic , compared to anionic , nps .
we
observe similar results for bsa in the presence of 200 nm nps ( figure
s5 of the supporting information ) .
percent
-helicity was calculated using the cd peak at 208 nm ( table 2 , materials and methods ) .
for bsa in the presence of the 58 and 200
nm cationic , amine - modified nps , a loss in -helicity was observed
( 48% and 37% , respectively ) . for bsa in the presence of 60 nm anionic ,
carboxylate - modified nps , a slight increase in -helicity to
71% was observed . for the 200 nm carboxylate - modified nps ,
the equilibrium association constant ,
enthalpy , and binding stoichiometry of bsa adsorbed on nps was determined
using itc ( figure 4 and figures s6 and s7 of
the supporting information ) .
cd spectra
of bsa in the presence of 60 nm carboxylate - modified
nps ( red ) , 58 nm amine - modified nps ( blue ) , and in the absence of
nps ( black ) .
spectra , in units of mean residue ellipticity ( mre ) ,
are the average of 10 consecutive scans .
( b ) cd
difference spectra were calculated by subtracting the spectrum of
bsa from bsa in the presence of 60 nm carboxylate - modified ( red ) or
58 nm amine - modified nps ( blue ) .
black dashed lines correspond to
spectral peaks at 195 , 208 , and 222 nm .
similar results were obtained
for 200 nm nps ( figure s5 of the supporting information ) .
an independent
site model was used to fit the integrated titration
curves and extract thermodynamic parameters ( table 3 , materials and methods ) .
the association
constant was nearly an order of magnitude higher for bsa adsorbed
on anionic nps with ka values of 2.4
0.9 10 m and 4.0 0.5
10 m for 60 nm anionic , carboxylate - modified
and 58 nm cationic , amine - modified nps , respectively .
the enthalpy
of bsa binding to the 60 nm carboxylate - modified ( 1.4
0.4 10 kj mol ) and 58 nm amine - modified
nps ( 1.4 0.7 10 kj mol ) was almost identical .
a significantly greater number of bsa molecules
adsorbed onto the surface of the 60 nm carboxylate - modified nps ( 871
21 proteins per np ) compared to the 58 nm amine - modified nps
( 27 8 proteins per np ) , although this is likely an underestimate
for the 58 nm nps due to dimerization of these nps under these conditions
( figure s8 of the supporting information ) .
the percent coverage , relative to a monolayer of 100% , was calculated
assuming bsa binds end - on , maximizing the number of bsa molecules
in a monolayer .
the coverage of bsa on the 60
nm carboxylate - modified nps was 230 6% , compared with 8
2% on the 58 nm amine - modified nps .
fluorescence spectroscopy was used as a
complementary technique to measure equilibrium association constants
by monitoring the quenching of tryptophan at 340 nm ( figure 5a ) .
the ratio of fluorescence intensities in the absence
and presence of nps were plotted versus np concentration in a stern
as the plots were nonlinear
at higher np concentrations , the first four points were used for a
linear fit to extract an effective ksv , equivalent to an effective ka ( materials and methods ) . for bsa in the presence
of 60 nm carboxylate - modified nps ,
the effective ka is 1.8 0.1 10 m , compared to the 58 nm amine - modified nps with an effective ka of 7.7 0.1 10 m. isothermal titration calorimetry ( itc ) plots of differential
power
throughout the titration ( top ) and integrated heat as a function of
the mole ratio of bsa adsorbed on nps ( bottom ) .
the heat of dilution
of bsa into buffer ( figure s6 of the supporting
information ) was subtracted for each injection from the heat
of bsa titrated into a np solution .
( a ) bsa titrated into a solution
of 60 nm carboxylate - modified nps .
( b ) bsa titrated into a solution
of 58 nm amine - modified nps .
raw data plotted in the ta instruments
software , nanoanalyze , is shown in figure s7 of the supporting information . ( a ) raw fluorescence spectra of bsa in
the presence of 60 nm carboxylate - modified
nps ( red ) , 58 nm amine - modified nps ( blue ) , and in the absence of
nps ( black ) .
the black dashed line at 340 nm corresponds to the emission
from tryptophan residues in bsa .
( b ) stern volmer plot of bsa
quenching in the presence of increasing concentrations of nps .
the
contribution from nps alone and buffer were subtracted , and initial
emission at 250 nm was set to zero .
dashed lines are the initial slope
used to calculate an effective equilibrium constant ( eq 3 ) .
nps
used in any biological application are exposed to a complex
mixture of extracellular proteins that form a protein corona on the
np surface .
we have characterized the changes in protein secondary
structure that result from adsorption of bsa on np surfaces and then
relate these structural changes to the cell surface receptor used
by the protein np complex .
although bsa np complexes
formed with anionic and cationic
nps have identical corona compositions and surface charges ( figures
s1 and s2 of the supporting information ) , the cellular binding trends are drastically different .
cellular
binding of bsa np complexes formed with anionic nps is inhibited
by the presence of excess bsa ( figure 1a ) .
in comparison ,
the cellular binding of complexes formed with cationic
nps is strongly enhanced by bsa ( figure 1b ) .
this difference in binding is independent of cell type , as similar
results were obtained for cho cells ( figure s4 of the supporting information ) .
the differences in cellular
binding suggest that the bsa np complexes formed with anionic
and cationic nps bind to different receptors . in a series of cellular
binding competition studies
np complexes
formed from anionic nps bind to native albumin receptors ( figure 2a ) .
albumin has a dedicated receptor on the cell
surface as it is an essential blood serum protein . in comparison , bsa np complexes formed with initially cationic
nps bind to scavenger receptors ( figure 2 ,
panels b and c ) .
scavenger receptors are a broad class of receptors
that bind modified proteins , polysaccharides , and polyribonucleotides , as well as nps and protein np complexes .
schnitzer et al . determined
that chemically or structurally modified albumins , including albumin
gold
np complexes , bind preferentially to the glycoprotein scavenger receptors
gp30 and gp18 rather than the general class of modified protein receptors .
mirkin et al . have observed that oligonucleotide - conjugated gold
nps bind to scavenger receptors .
previous results
using a complete mixture of fbs showed identical binding trends , demonstrating that this result is not specific
to isolated bsa .
interestingly , for the bsa np complexes
formed from cationic
nps , we observed that fucoidan is a much stronger competitor than
polyinosinic acid ( figure 2 , panels b and c ) .
at the highest competitor concentration ( 2500 g ml ) , bsa np binding was 11% in the presence of fucoidan compared
to 25% in the presence of polyinosinic acid .
it is important to note
that this concentration of polyinosinic acid is relatively high compared
to previously reported concentrations for cellular binding competition , further confirming that polyinosinic acid is a less efficient competitor .
polyinosinic acid is a competitor for both gp30 and gp18 , as well as the general class of modified protein receptors . in comparison , fucoidan is only a competitor
for the gp30 and gp18 receptors .
np
complexes formed from the cationic nps only bind to the receptors
for modified albumins , gp30 and gp18 , and not the general receptors
for modified proteins .
this highlights the subtle differences in molecular - level
interactions of nps with cells .
the opposite binding trends
observed for bsa np complexes
formed from anionic and cationic nps provided an ideal model system
to study the effect of protein structure on the cellular receptors
used by bsa
we hypothesized that bsa adsorbed
on anionic nps retained its native structure , allowing the bsa
bsa adsorbed
on cationic nps was disrupted , likely partially denatured , such that
it is no longer recognizable by the native protein receptor and is
instead redirected to a scavenger receptor .
cd spectra of bsa in the
presence of 60 nm anionic nps show that the secondary structure of
bsa is retained ( figure 3 ) . in comparison ,
there is a loss in -helicity for bsa in the presence of 58
nm cationic nps ( 65% to 48% , table 2 ) .
similar
results were obtained for bsa in the presence of 200 nm nps ( figure
s5 of the supporting information , table 2 ) .
the greater loss in -helicity in the presence
of the 200 nm nps is attributed to greater bsa adsorption on the larger
np . although the decrease in -helicity appears modest , it should
be noted that boiled bsa has a similar percent -helicity as
bsa incubated with carboxylate - modified nps ( 71% -helix , data
not shown ) .
this indicates both a significant change in -helicity
for bsa following exposure to cationic nps , as well as a difference
in secondary structure for bsa disrupted by heat denaturation compared
to np exposure .
changes in protein secondary structure can be accompanied
by the exposure of new peptide sequences .
while epitope exposure and
structural changes are difficult to separate , changes in secondary
structure are the driving force for both and ultimately determine
the cellular receptors used by the protein . a change in protein
secondary structure
should be associated with
changes in adsorption of the protein on the np surface .
using itc
( figure 4 ) , we observe that fewer proteins
adsorbed on the cationic , amine - modified nps ( 27 8 proteins
per np , compared to 871 21 proteins per np for anionic nps ) .
similar results were obtained for sulfate - modified polystyrene nps ,
which showed less than monolayer adsorption of bsa and disruption
of the bsa secondary structure .
the lower
binding stoichiometry is likely due to the loss of the bsa secondary
structure .
when spread out on the np surface , fewer bsa molecules
can access the surface without an energy cost .
the enthalpy of bsa binding
to anionic and cationic nps is identical ( 1.4 0.4
10 kj mol and 1.4 0.7
10 kj mol , respectively ) , which
is surprising given that the maximum bsa adsorption to the surface
of the 60 nm carboxylate - modified nps is approximately 30-fold greater
than on the 58 nm amine - modified nps .
however , the association of
bsa is much stronger on the anionic np surface ( 2.4 0.9
10 m compared with 4.0 0.5
10 m ) , which we attribute to
more energetically favorable packing of native bsa as well as some
degree of binding cooperativity .
previous itc experiments have examined
protein adsorption on nps as a function of protein species and hydrophobicity .
equilibrium association
constants and enthalpies are similar to our results , taking into consideration
the variability in itc measurements . however
, 27% coverage was observed
for carboxylate - modified nps and 63% coverage for amine - modified nps , compared to 230% and 8% , respectively , in our
experiments ( table 3 ) .
this difference could
be due to multiple factors , including differences in np diameter ,
ph , buffer , and surface modification ligand .
previous fluorescence
correlation spectroscopy measurements showed that the number of human
serum albumin proteins adsorbed onto the surface of 1015 nm
cationic and anionic gold nps were similar .
while the difference between the values we obtained with itc and
the fluorescence correlation spectroscopy measurements could be due
to np diameter or surface modification , it should also be noted that
fluorescence correlation spectroscopy is insensitive to protein conformation
and can only be used to measure the hydrodynamic diameter of nps with
and without a protein corona .
these results highlight the difficulty
of comparing results obtained with different experimental methods
as well as itc experiments under even slightly different conditions . as a complementary method to itc
, fluorescence quenching was used
to measure equilibrium association constants ( figure 5 ) . the nonlinear stern volmer plot ( figure 5b ) is indicative of a selective quenching mechanism . at low np concentrations ,
readily accessible tryptophan residues
on bsa are quenched uniformly . at higher np concentrations ,
the stronger association of
bsa on 60 nm anionic compared to 58 nm cationic nps was observed in
both the itc and fluorescence spectroscopy data , although the absolute
values differ by several orders of magnitude ( e.g. , ka = 2.4 0.9 10 m with itc versus 1.8 0.1 10 m from fluorescence spectroscopy for 60 nm anionic nps ) .
thermodynamic
parameters are highly sensitive to experimental conditions and , for
our experiments , the buffers required to optimize itc and fluorescence
spectroscopy experiments were not identical . while itc provides a
better quantitative measure of the association constant as it is a
direct , label - free measurement , the use
of multiple methods to confirm thermodynamic parameters is essential . fluorescence quenching has been used previously
to study the adsorption of bsa on gold , silver , and silver titanium dioxide nps .
equilibrium binding constants of 10 to 10 were reported for gold , 10 for silver
titanium
dioxide , and from 10 to 10 m for silver nps , depending on temperature .
the high variability in
equilibrium binding constants in the literature could be due to the
fluorescence spectroscopy method itself , in addition to the fact that
binding strength is highly sensitive to np material , size , and surface
modification .
our experiments provide
a molecular link between the structure
of the proteins that comprise the corona and the specific cellular
receptors used by the protein np complex .
we show that changes
in protein structure upon adsorption to nps determine the specific
cell surface receptor used by the protein
protein secondary structure is retained upon adsorption
to anionic nps , allowing the bsa np complex to bind to native
albumin receptors .
the denaturation of bsa following adsorption to
cationic nps directs the bsa np complexes to bind to scavenger
receptors .
these results have important implications for the in vivo
targeted delivery of nps . beyond merely confirming the presence of
a protein corona , it is critical to characterize the structure of
the corona proteins .
the diameter provided
by the supplier is used to identify the np : 93 nm carboxylate - modified
( bang s laboratories , fc02f ) , 87 nm amine - modified ( invitrogen ,
c29029 ) , 200 nm carboxylate - modified ( invitrogen , f8811 ) , 200 nm amine - modified
( invitrogen , f8764 ) , 60 nm carboxylate - modified ( bang s laboratories ,
pc02n ) , and 58 nm amine - modified ( bang s laboratories , pa02n ) .
the hydrodynamic diameter and zeta potential of the nps was measured
with a malvern zetasizer ( malvern instruments , nano - zs , table 1 ) .
nps were measured at the following concentrations :
93 nm carboxylate - modified ( 37 pm ) , 87 nm amine - modified ( 173 pm ) ,
200 nm carboxylate - modified ( 13 pm ) , 200 nm amine - modified ( 15 pm ) ,
60 nm carboxylate - modified ( 1.4 nm ) , and 58 nm amine - modified ( 1.4
nm ) .
the 60 nm carboxylate - modified nps and 58 nm amine - modified nps were
also measured in colorless mem ( invitrogen , 51200038 ) and mem supplemented
with either 10 mg ml bovine serum albumin ( bsa ,
fisher , bp1600 ) or 10% ( v / v ) fetal bovine serum ( fbs , invitrogen ,
10437028 ) . from the uv vis spectrum of fbs ,
using the extinction
coefficient of bsa ( 43,824 m cm ) , the total protein concentration in 10% ( v / v ) fbs is approximately
10 mg ml .
solutions prepared with mem were diluted
by 10% ( v / v ) for zeta potential measurements to reduce the conductivity .
for the 58 nm amine - modified nps , solutions in mem supplemented with
10% ( v / v )
fbs were filtered with a 0.2 m syringe filter to
remove aggregates formed in the presence of protein .
all experiments were carried out with
three samples , and the mean and standard deviation are reported .
60 nm carboxylate - modified ( 14
nm ) and 58 nm amine - modified ( 0.4 nm ) nps were incubated in mem supplemented
with 10 mg ml bsa or 10% ( v / v ) fbs at 4 c
for 10 min and washed four times via centrifugation ( 16000 g , 4 c , 10 min ) .
np concentrations were optimized
based on the solubility and stability of the nps in solution .
previous
studies have demonstrated that four wash steps with centrifugation
followed by resuspension in water removes all observable unbound protein
from solution .
np complex was resuspended in either
buffer containing 6% ( w / v ) sds ( new england biolabs , # b7703s ) or water .
samples were diluted with a 4x laemmli buffer ( boston bioproducts ,
bp-110r ) and boiled for 5 min before loading onto the gel .
mini - protean
gradient gels ( bio - rad , 4561094 , 420% ) were used to
separate proteins at 40 ma and 100 v along with a 5225 kda
molecular weight marker ( lonza , 50547 ) .
proteins were stained for
1 h with simply blue safe stain ( invitrogen , lc6060 ) and imaged using
a li - cor odyssey imaging system .
african
green monkey kidney epithelial
cells ( bs - c-1 , atcc ) and chinese hamster ovary cells ( cho , atcc ) were
maintained in a 37 c , 5% carbon dioxide environment and passaged
every 3 days .
bs - c-1 cells were cultured in minimum essential medium
( mem , invitrogen , 61100061 ) and cho cells in ham s f-12 ( f-12 ,
invitrogen , 21700075 ) . both were supplemented with 10% ( v / v ) fbs .
for all cell experiments , cells were grown in 35 mm glass - bottom dishes
( mattek ) . for fluorescence imaging experiments , nuclei were stained
with 27 m 4,6-diamidino-2-phenylindole dilactate ( dapi ,
invitrogen , d35671 ) at 37 c for 30 min .
cellular binding of nps was
imaged with an epifluorescence microscope ( olympus ix71 ) using a 1.20
n.a . , 60 water immersion objective ( olympus ) .
fucoidan
( sigma - aldrich , f5631 ) and polyinosinic acid ( sigma - aldrich , p4154 )
were used as competitors for scavenger receptors .
polyadenylic acid
( sigma - aldrich , p9403 ) was used as a control .
the competitor or control
molecule was incubated with cells at 4 c for 20 min in mem for
93 nm carboxylate - modified nps or in mem supplemented with 10 mg ml bsa for 87 nm amine - modified nps .
the nps were then
incubated with cells in the presence of the competitor molecule for
10 min .
cells were rinsed twice with phosphate - buffered saline with
calcium and magnesium ( pbs , invitrogen , 14040182 ) to remove unbound
nps , twice with pbs without calcium and magnesium ( invitrogen , 14190250 ) ,
and incubated in 10 mm ethylenediaminetetraacetic acid ( mallinckrodt ,
49310 - 04 ) at 37 c for 30 min to remove the adherent cells from
the mattek dishes .
cells were rinsed twice with leibovitz s
l-15 buffer ( invitrogen , 21083027 ) via centrifugation at 10000 g for 10 min , filtered with a 40 m cell strainer
( bd falcon , 352340 ) , and kept on ice for 1 h prior to analysis with
flow cytometry ( bd biosciences , lsr - ii ) .
a 488 nm laser was used to
excite the np fluorescence , and fluorescence emission was collected
on a 530/30 nm bandpass filter .
scatter plots and fluorescence histograms
were analyzed with weasel 3.0.1 ( walter and eliza hall institute of
medical research , victoria , australia ) .
cd spectra were
acquired on an olis cd spectrophotometer with the sample chamber maintained
at 20 c .
measurements were made using a 0.5 mm path length quartz
cell ( starna , 20/o - q-0.5 ) .
the bandwidth was set to 2 nm , and the
integration time was a function of the photomultiplier tube voltage .
samples were measured in 10% ( v / v ) pbs without calcium and magnesium .
bsa ( 0.098 mg ml ) was measured alone and in the presence of 60 nm
carboxylate - modified nps ( 0.4 nm ) , 58 nm amine - modified nps ( 0.4 nm ) ,
200 nm carboxylate - modified nps ( 13 pm ) , and 200 nm amine - modified
nps ( 13 pm ) .
spectra were smoothed with
a savitzy golay least - squares fitting ( digital filter = 13 ) ,
and the value at 260 nm was set to zero to account for spectral drift .
spectra were acquired in millidegrees and converted to mean residue
ellipticity using eq 1.1 the
mean residue ellipticity in units
of degrees cm dmol ( [ ] ) is
a function of the observed signal in millidegrees , [ ]obs , the average molecular weight of the protein ( mw ) , path length in
cm ( l ) , protein concentration in g l ( c ) , and the total number of amino acids ( n ) .
percent -helicity was calculated from eq 2.2the percent -helix of a protein is
a function of the mean residue ellipticity at 208 nm ( [ ]mre ) , minus the contribution from the -form and random
coil conformations at 208 nm ( 4000 ) . the observed value is compared
to the mean residue ellipticity of a pure -helix protein ( 33000 ) .
itc measurements
were made on a nano itc ( ta instruments , low volume ) at 25 c
with a constant stirring speed of 250 rpm .
for all titrations , 16
3 l injections were made with a 300 s equilibration time before
and after each injection .
all solutions were prepared in a 20 mm hepes
buffer ( ph 7.4 ) .
titration of bsa ( 75 m ) alone into hepes buffer
was subtracted injection - by - injection from bsa titrations into np
solutions .
the 60 nm carboxylate - modified nps ( 5.0 pm ) or 58 nm amine - modified
nps ( 1.4 nm ) were loaded into the sample cell .
integration of differential power plots
as a function of time gave binding curves , and the raw data was fit
with the one independent site model using nanoanalyze ( ta instruments ) .
the theoretical
monolayer coverage of bsa molecules per np was calculated using the
assumption that bsa binds end - on to the np surface with a footprint
of 3.3 10 bsa molecules per cm .
all solutions
were prepared in 10% ( v / v ) pbs without calcium and magnesium .
samples
were excited at 280 nm , and emission was collected between 250 and
500 nm using 5 nm slit widths for both excitation and emission .
bsa
( 9.8 g ml ) was measured in the presence
of nonfluorescent 60 nm carboxylate - modified and 58 nm amine - modified
nps . working np concentration ranged from 67 to 533 pm .
experiments
were repeated in triplicate , and the mean and standard deviation are
plotted for each data point .
corrected spectra are the raw spectra
with the np scatter peak and buffer contribution subtracted out and
the initial emission value at 250 nm set to zero . the stern
volmer
equation was used to calculate the equilibrium constant ( eq 3).3 the fluorescence
intensity ratio of
bsa at max in the absence ( fo ) and presence ( f ) of a
quencher is calculated and plotted versus the np quencher concentration
( [ np ] ) .
Output:
| nanoparticles used for biological
and biomedical applications encounter
a host of extracellular proteins .
these proteins rapidly adsorb onto
the nanoparticle surface , creating a protein corona .
poly(ethylene
glycol ) can reduce , but not eliminate , the nonspecific adsorption
of proteins . as a result ,
the adsorbed proteins , rather than the nanoparticle
itself , determine the cellular receptors used for binding , the internalization
mechanism , the intracellular transport pathway , and the subsequent
immune response .
using fluorescence microscopy and flow cytometry ,
we first characterize a set of polystyrene nanoparticles in which
the same adsorbed protein , bovine serum albumin , leads to binding
to two different cell surface receptors : native albumin receptors
and scavenger receptors . using a combination of circular dichroism
spectroscopy , isothermal titration calorimetry , and fluorescence spectroscopy
,
we demonstrate that the secondary structure of the adsorbed bovine
serum albumin protein controls the cellular receptors used by the
protein nanoparticle complexes .
these results show that protein
secondary structure is a key parameter in determining the cell surface
receptor used by a protein nanoparticle complex .
we expect
this link between protein structure and cellular outcomes will provide
a molecular basis for the design of nanoparticles for use in biological
and biomedical applications . |
PubmedSumm4831 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: suicide is an important public health problem both in developing and developed countries , which accounts for more than 80000 annual deaths worldwide ( 1).in 2008 , the suicide rate for the world was reported to be 11.6 per 100,000 population ( 2 ) .
however , the number of suicide cases has been rising and it is predicted to account formore than 2% of the global burden of disease by the year 2020 ( 3 ) . this is the case with suicide attempts ( sas ) that can be much more frequent and in some studies it has been reported that the prevalence of sas was 10 to 20 times higher than that of completed suicides ( 1 ) .
the median suicide rate for the countries of the eastern mediterranean region ( emr ) was estimated to be 4.90 per 100000 population , which was lower than the global rate ( 4 ) . in a systematic review of studies on suicide and suicide attempts in iran ,
the prevalence of suicide was estimated to be 9.4 in 100000 , which is much higher than the average prevalence in emr countries ( 5 ) .
however , there is a great variation in the prevalence of suicide in different parts of the country .
for instance , in hamadan province , the estimated incidence rate of suicide attempts per 100000 population was 228.6 for males and 263.1 for females ( 6 ) .
an epidemiological survey of the trend of suicide in southwest of iran between 2004 and 2009 found that the rate of suicide attempt for both genders was 53 per 100000 and 49 , 57 for men and women , respectively ( 7 ) .
moreover , the results of a study on the burden of diseases , injuries , and associated risk factors conducted in 2010 in iran showed the increasing trends of the major causes of disability - adjusted life years ( dalys ) including suicide ( 8) . more than 90% of all cases of suicides are attributed to psychological disorders such as depression and substance abuse ( 1 ) .
it has been estimated that 5% of patients with mood disorders and 6% of cases with bipolar disorders and possibly a greater proportion of patients with major depressive disorder are likely to commit suicide during their life time ( 9 ) .
however , there is some evidence that the suicidal acts are a result of an interaction between biological , genetic , psychological , social , environmental and situational factors ( 10 ) .
therefore , when investigating the epidemiology of suicide , in addition to the psychological factors , taking into account the influence of other factors , such as the cultural and socio - economic status is of a particular importance ( 3 ) .
since the possible factors that contribute to suicidal behavior can greatly vary depending on the characteristics of the population , the objective of this study was to investigate the epidemiology of suicide in sistan and baluchestan province , southeast of iran , and to identify the precipitating factors in the suicidal behavior .
this is of great importance for policy - making and developing the preventive action plans in defined populations and communities .
the study population included all suicide cases who were admitted to the emergency department of zahedan khatam - alanbia hospital between march 2010 and february 2012 .
this hospital is a referral center for toxicology , burns and other emergency services that admit patients from all the cities in the province .
we also included the suicides registered with the forensic medicine department during the same time period .
the information was collected from the hospital information system ( his ) , which is used to manage all aspects of hospital operation , such as medical and administrative activities .
the provincial forensic medicine department database was another source of information for retrieving data on suicide cases not available in the hospital his .
the study questionnaire comprised 2 parts : the first 6 questions were related to the socio - demographic characteristics of the subjects such as gender , age , education , occupation , marital status and income .
the second part included questions on history of mental and psychological disorders , factors contributing to suicidal acts , the methods used for suicide , substances used for burning , the time and place of suicide , hospitalization and outcome of the suicide attempt .
the tool designed for data collection was developed based on literature review and the questionnaires used in the similar studies conducted in iran and it was modified according to the study objectives .
an expert panel consisting of the psychiatrists , clinical psychologists and experienced nurses assessed the content validity of the questionnaire and necessary changes were made based on the feedback we received .
all completed questionnaires were reviewed by study investigators and ambiguities and gaps in data were queried .
the chi - square and fisher s exact tests were used to compare the distribution of categorical variables between different groups .
the study population included all suicide cases who were admitted to the emergency department of zahedan khatam - alanbia hospital between march 2010 and february 2012 .
this hospital is a referral center for toxicology , burns and other emergency services that admit patients from all the cities in the province .
we also included the suicides registered with the forensic medicine department during the same time period .
the information was collected from the hospital information system ( his ) , which is used to manage all aspects of hospital operation , such as medical and administrative activities .
the provincial forensic medicine department database was another source of information for retrieving data on suicide cases not available in the hospital his .
an 18-item structured questionnaire was used for data collection . the study questionnaire comprised 2 parts : the first 6 questions were related to the socio - demographic characteristics of the subjects such as gender , age , education , occupation , marital status and income .
the second part included questions on history of mental and psychological disorders , factors contributing to suicidal acts , the methods used for suicide , substances used for burning , the time and place of suicide , hospitalization and outcome of the suicide attempt .
the tool designed for data collection was developed based on literature review and the questionnaires used in the similar studies conducted in iran and it was modified according to the study objectives .
an expert panel consisting of the psychiatrists , clinical psychologists and experienced nurses assessed the content validity of the questionnaire and necessary changes were made based on the feedback we received .
all completed questionnaires were reviewed by study investigators and ambiguities and gaps in data were queried .
the chi - square and fisher s exact tests were used to compare the distribution of categorical variables between different groups .
a total of 369 suicide cases , including 240 ( 65% ) females and 129 ( 35% ) males were admitted to the emergency department of zahedan khatam - al - anbia hospital between march 2010 and february 2012 .
the greatest proportion of the cases studied were in the age group of 16 to 25 years ( 43.5% ) and those aged 34 years and older showed the lowest proportion ( i.e. 12.7% ) .
patients who finished high school studies and those with a university degree were less likely to attempt or commit suicide ( 9.5% ) while almost half the cases were found to have a primary school education .
housewives and self - employed individuals accounted for more than three quarters of the subjects investigated .
the majority of suicide patients reported to have a low or medium income and only 16% were found to have a good income .
more than one third of the cases had a history of hospitalization because of mental disorders and 62.9% were receiving outpatient treatment for psychological problems .
a total of 39 cases ( 10.9% ) were living in zahedan city and the rest of the subjects were referred from other districts to zahedan hospitals . almost half of the cases were residents of saravan and iranshahr districts while those from zabol and nikshahr districts accounted for 9.2% and 9.8% of the subjects , respectively .
the most common method of suicide was burning ( 53.4% ) followed by drug ingestion ( 23.8% ) .
kerosene was the substance commonly used for burning ( 81.4% ) . more than 90% of burning suicide cases ( i.e. 180 patients ) were those referred from other districts to the khatam - al - aanbia hospital . in zabol ,
khash , saravan and chabahar , a greater proportion of suicides were by burning , ranging from 53% to 70% and in zahedan , iranshahr and nikshahr non - burning methods dominated changing between 22% and 44% .
the majority of cases attempted suicide at home ( 88.1% ) followed by relatives ' places ( 8.1% ) and only a small proportion ( i.e. 1.4% ) of cases chose public places for suicide attempts .
half of the suicides occurred during the noon time and the cases in the morning and at night accounted for 35.8% and 14.1% of the subjects , respectively . in terms of the time of the month , suicide was more likely to occur during the first half of the month ( 62.1% versus 37.9% that took place during the second half of the month ) .
one third of suicide cases were reported during spring ( march to may ) followed by autumn ( september to november ) ( 28.7% ) and summer ( june to august ) ( 26% ) and suicide was less likely to happen during the winter ( december to february ) .
almost half of the cases were admitted to hospital for 2 - 4 days and 39.3% were hospitalized for a day or less .
overall , 49.6% of the suicide cases were fatal and 50.4% survived the suicide attempt .
unemployment and the stressful life events were reported as 7% and 6% of the causes of suicide , respectively . comparing the precipitating factors between male and female cases ( table 3 )
, showed that all factors were more common in females except for drug abuse that was more frequent in male subjects attempting suicide ( 64.6% in males versus 35.4% in female ) .
the differences in the proportion of the factors were statistically significant ( p value for fisher 's exact test < 0.0001 ) .
fatal and non - fatal suicide cases have been compared by socio - demographic and suicide attempt characteristics in table 4 .
the suicide patients who died were more likely to have a poor income as compared with those subjects who survived ( 59.3% versus 40.7% ) and a greater proportion of cases with medium or good income were among those who were discharged from hospital after a suicide attempt .
patients who committed suicide during spring were more likely to survive ( 59.1% versus 40.9% ) and a greater percentage of fatal outcomes ( 61.5% versus 38.55 ) were observed among those attempted suicides that occurred during summer time and the differences were statistically significant with a p < 0.026 . when comparing the methods used for suicide between fatal and non - fatal cases , a statistically significant difference was identified between the two groups ( p < 0.0001 ) .
more than 88% of the cases who used burning as a method of suicide succumbed , while those who used other methods such as drug ingestion or self - inflicted injury were more likely to survive the suicide attempts . data are presented as no .
the purpose of this study was to investigate the epidemiology of suicide and associated risk factors in suicide cases admitted to the emergency department of zahedan khatam - al - anbia hospital .
the results ofthis study showed that the majority of cases were young women with the low education levels , low income and more than three quarter of the cases had a history of mental disorders .
the method most frequently used for suicide was burning and the majority of cases committed suicide at home and most likely at noon time .
almost one third of the cases occurred during spring time and half of the cases were fatal .
spouse violence and dispute accounted for half of the suicide cases followed by drug abuse .
although suicide is a complex human behavior , a range of socio - demographic factors has been shown to be associated with an increased risk of suicidal behavior in different social and cultural settings .
more than 40% of suicide cases in this study were in the age group of 16 to 25 years .
this is consistent with the findings of similar studies from iran ( 6 , 11 - 13 ) and other countries ( 14 , 15 ) , in majority of which it has been reported that younger subjects account for a greater proportion of suicide cases .
study of the global patterns of mortality in young people has shown that suicide is the second leading cause of death in the 15 - 19 years age group ( 16 ) .
analysis of data from studies on suicide attempts carried out in the islamic republic of iran between 1981 to 2007 showed that the mean age of suicide attempters was 25 years ( 12 ) .
a study of suicide attempts in hamedan province reported that the suicide attempt rate was highest in the age group of 15 - 24 years with an incidence rate of 536 cases per 100000 population ( 6 ) .
similarly , more than 66.2% of the suicide cases admitted to the emergency department of a hospital were between 16 to 25 years old ( 13 ) .
the results from another study showed that the mean age of the suicide cases was 19 years for men and 24 years for women ( 11 ) .
suicidal behaviors in young people are thought to be linked to adverse life events and a wide range of risk factors have been identified ( 17 ) .
these include : social and educational disadvantages ; childhood and family adversity ; psychopathology ; individual and personal vulnerabilities ; exposure to the stressful life events and circumstances ; and social , cultural and contextual factors .
almost half of the suicide cases in our study were a result of family conflicts , with spouse violence accounting for more than a third of the total suicide events .
most common stressful life events that immediately precede the suicide attempts are the interpersonal conflicts mostly linked to relationships with spouses or partners ( 18 ) .
suicidal behaviors are one of the major contributors to the global burden of disease among women .
evidence from the who multi - country study on women 's health and domestic violence against women has shown that events such as intimate partner violence ( ipv ) , non - partner physical violence , ever being divorced , separated or widowed , childhood sexual abuse and having a mother who had experienced ivp were the most consistent risk factors for suicide attempts in women(19 ) . in a study of the socio - cultural contexts of suicide attempts among women in iran , family conflicts , marriage and love , social stigma , pressure of high expectations , and poverty
were the main issues identified as the suicide precipitating factors in women ( 20 ) .
exposure to intimate partner violence is an event that is experienced by women living in low- and middle - income countries on a daily basis , being reported by 15%-71% of women over their lifetime ( 21 ) .
there is an evidence of a consistently strong relationship between the intimate partner abuse and suicide attempts in women ( 19 ) .
another study has found that the physical violence to be associated with more than a four - fold increase in suicidal thoughts in women ( 22 ) .
surprisingly , only 27% of the women subjected to spouse violence would disclose this to anyone ( 22 ) , and they are less likely to seek medical advice ( 19 ) . a disrupted family environment and parent - adolescent conflict have been found to be associated with the suicide attempts ( 23 ) .
there is some evidence that the negative relationships with either or both parents significantly increase the risk of suicide and/or depression ( 24 ) . in our study , a total of 15% of the suicide cases were a result of parent - adolescent conflicts and family fanaticism that put them at an increased risk of suicidal behavior .
the results from a systemic review of social factors associated with suicide attempts in iran showed that the family conflicts was the most frequent cause of suicide with an average prevalence of 32% ( 25 ) .
the prevalence in the studies reviewed ranged from 55% that was reported from gilan province to 12% that was observed in khorasan razavi province .
a study of the self - poisoning suicide attempts among students showed that 21.08% of the subjects had a history of child abuse and 22.5% came from a broken family ( 26 ) . a quarrel with a family member , a relative , and/or a friend
was also found to be the most common precipitating factor ( 74.4% ) for suicide attempts by burning ( 27 ) .
another study reported that almost half of suicide attempts was a results of family conflict ( 28 ) . on the other hand ,
giving credit to the importance of the family appears to be associated with lower levels of parent - adolescent conflict , hence protecting the younger generation from suicide attempts . in comparison with
disrupted family environments , adolescents living in an atmosphere of high family cohesion and low conflict are significantly less likely to attempt suicide ( 23 ) .
this is consistent with studies from western countries ( 29 , 30 ) and also some studies from iran ( 6 , 31 - 33 ) .
an iranian study of the suicide cases from 2006 to 2010 across the country showed that the completed suicides were more likely to happen in summer and they were least prevalent in winter ( 32 ) .
however , in some studies , the clear pattern of seasonality has been identified for only suicides committed by the violent methods ( 29 ) .
as compared with females , the relationship between seasonal factors and violent suicides has been found to be stronger in male suicides ( 29 ) .
there are some evidence of the relationship between season and changes in human mood ( 34 ) .
this could be partly explained by the seasonal factors including daily sunshine and global radiation that influence the regulation of the serotonergic transmission and serotonin-1a receptor binding in limbic regions of the brain ( 35 ) .
other socio - demographic factors related to suicidal behavior include the economic constrains and educational failure . in this study ,
a greater proportion of the suicide cases had a poor or medium income and those with low income were more likely to die when attempting suicide .
this is in agreement with the results from a systemic review of studies on suicide in iran that estimated that 12% of the suicide attempts were linked to economic constrains , ranging from 4% to 40% in different studies ( 25 ) .
one fifth of cases investigated in this study had no education and the educational level of almost half of them was primary school .
this is comparable with the proportions reported in studies carried out in other parts of iran ( 13 , 36 ) . in a survey of suicide by burning in tehran , for instance ,
however , in some studies people with high school and higher educational levels dominated the suicide cases ( 11 ) .
moreover , in a systemic review of suicide studies in iran , the prevalence of educational failure among cases with suicide attempts on average was found to be 5% ( 25 ) .
overall , 18% of the suicide cases in this study were related to drug abuse .
this is in agreement with the findings from similar studies conducted in kerman and hamadan provinces that the proportions of drug abuse in the suicide cases admitted to the emergency department were16% and 16.3% , respectively ( 11 , 28 ) .
the relationship between drug abuse and suicide attempts could be partly explained by what is called " interpersonal theory " ( 37 ) . according to the theory , the repeated exposure to physically painful experiences such as injecting drugs leads to pain habituation , which is likely to entail the suicidal behavior .
harmful behaviors including suicide in people who are suffering from drug abuse is a common finding ( 38 ) .
there is some evidence that the strength of association between drug abuse and suicidal acts depends on the type of the substance abused , with prescription drug abuse showing the strongest influence , followed by inhalant and cannabis abuse ( 39 ) .
moreover , it has been identified that subjects with the recent drug use are approximately 5 times more likely to use violent suicide methods as compared with those who did not report substance abuse ( 40 ) .
it has been hypothesized that the individuals who attempt suicide differ from those who complete suicide . in the present study , we compared these two groups in terms of socio - demographic and suicide - related characteristics . in a review of suicide data for
the time period from march 2001 to march 2007 that were retrieved from health system databases of 41 iranian medical universities , the prevalence of the completed suicides was 7.3% , which is much lower than what we observed in our study ( 41 ) .
moreover , a wide range of variations in the prevalence of case fatality among suicide cases across the country has been shown , changing between 2% and 25.3% ( 11 , 13 , 28 , 42 ) . given the fact that more than 90% of the cases included in this study were those who were referred from other districts and hence more likely to suffer from life - threatening complications that made them eligible for referral to more advanced and equipped centers at the provincial level , over - representation of those cases is most likely to have resulted in more fatal cases as compared with figures from different studies across the country .
this was further substantiated by comparing burning ( the most fatal method ) with the non - burning suicide methods between the districts .
for instance , 70% and 65% of the cases referred from chabahar and saravan districts used burning for a suicide act , which was more likely to succumb in spite of referral to an advanced center .
low income , suicide attempts during summer time , and burning used as a method of suicide were more likely to be associated with fatal outcomes .
we did not identify any gender differences in terms of suicide outcome , some studies have found a significant relationship between gender and fatal suicide ( 7 ) .
the results from our study showed that suicide by burning was the most common method used in the completed suicide cases .
however , in studies from different geographical regions of iran a wide range of violent and non - violent methods are used , which seems to be influenced by the social and cultural context of the communities .
for instance , a study on the case fatality rate of the different suicide methods in ilam province showed that the most common suicide methods in fatal cases were hanging ( 75.4% ) and self - immolation ( 68.3% ) , and the least fatal methods were drug ingestion and cutting ( 42 ) .
one of the limitations of this study was representativeness of the data used for analysis , as we used the information from only one referral hospital his and forensic medicine department data .
however , this hospital is a known burn and toxicology center and the suicide cases are more likely to be admitted to this hospital and only a small fraction of cases are admitted to other hospitals .
suicide is a multi - factorial public health problem which results from an interaction between a wide range of demographic , social and cultural factors .
identifying the potential contributing factors and incorporating them into all preventive programs can help the public health authorities and policy - makers to mitigate the suicidal behaviors within communities .
Output:
| background : suicide is a growing public health problem all over the world . understanding the prevalence of suicide and its correlates is of great importance in planning programs to reduce the risk in different societies.objectives:the present study was conducted to assess the epidemiology of suicide and its associated risk factors in sistan and balouchestan province , southeast of iran.patients and methods : we investigated a total of 369 suicide cases admitted to the emergency department of zahedan khatam- al- anbia hospital between march 2010 and february 2012
. data was collected from the hospital information system ( his ) using a semi - structured questionnaire .
descriptive statistics and chi - square tests were used to identify the factors associated with suicidal behaviors.results:a greater proportion of the study subjects ( 65% ) were female .
they were more likely to be young ( 43.5% in the age group of 16 to 25 years ) and illiterate or have a primary school education ( 20.9% and 48.8% , respectively ) .
housewives and self - employed individuals and those with a low or medium income dominated the suicide cases .
the most common method of suicide was burning ( 53.4% ) followed by drug ingestion ( 23.8% ) .
one third of the suicide cases occurred during spring .
the case fatality rate was 49.6% and it was significantly associated with low income , summer time suicides , burning as a method of suicide.conclusions:this study highlights the burden of suicide and itspotential socio - demographic risk factors in sistan and blouchestan province .
this information has an implication for planning the preventive measures , policy making and future research . |
PubmedSumm4832 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: this research work was supported by the office of the national research council of thailand and the faculty of pharmacy , silpakorn university , nakhon pathom , thailand .
Output:
| eleven heavy metals in various products of moringa oleifera were analyzed to determine eleven heavy metals ( al , as , cd , cr , cu , fe , pb , mn , hg , ni , and zn ) using inductively coupled plasma - mass spectrometry . the products of m. oleifera were purchased in nakhon pathom , thailand .
all products were digested with nitric acid solution before determining the concentrations of heavy metals .
the recoveries of all heavy metals were found to be in the range of 99.89 - 103.05% .
several criteria such as linearity , limits of detection , limits of quantification , specificity , precision under repeatability conditions and intermediate precision reproducibility were evaluated .
results indicate that this method could be used in the laboratory for determination of eleven heavy metals in m. oleifera products with acceptable analytical performance .
the results of analysis showed that the highest concentrations of as , cr , hg , and mn were found in tea leaves while the highest concentrations of al , cd , cu , fe , ni , pb , and zn were found in leaf capsules .
continuous monitoring of heavy metals in m. oleifera products is crucial for consumer health . |
PubmedSumm4833 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: postcholecystectomy bilomas are relatively uncommon with a reported incidence of about 2.5% , and most often present with right upper quadrant pain and fever within seven days of the operation .
the authors report a case of a cholecystectomy performed in a 35-year - old female which resulted in a biloma , presenting 11 days postoperatively with gastric outlet obstruction .
the literature is reviewed to suggest the optimal management and treatment plans for this complication .
this patient was successfully managed with radiologic intervention for the treatment of a biloma and resulting gastric outlet obstruction after open cholecystectomy .
although uncommon , bilomas may present in an unusual manner such as with gastric outlet obstruction . as with early bilomas , they may be treated successfully with interventional radiologic techniques .
although it has been reported as occurring spontaneously with incarcerated choledocholithiasis , it is usually due to an iatrogenic injury following cholecystectomy .
the incidence of post laparoscopic cholecystectomy biloma , in the two largest series , is about 2.5% .
to our knowledge , this is the first reported case of gastric outlet obstruction secondary to a post cholecystectomy biloma .
a 35-year - old hispanic female underwent a cholecystectomy that began using laparoscopic techniques , but was converted to open cholecystectomy due to bleeding from a small branch of the cystic artery which was easily controlled after laparotomy was performed .
common bile duct , cystic duct and cystic artery were in normal anatomic location , and no anatomic abnormalities were identified . the patient was discharged four days after the operation .
she returned one week later with complaints of nausea , vomiting , as well as right and left upper quadrant pain .
there was no reported change in the color of her stools , urine or skin .
liver function tests showed elevated alkaline phosphatase , ast , alt , with normal total and conjugated bilirubin .
an abdominal ultra - sound study demonstrated large upper abdominal fluid collections bilaterally . computed tomography ( ct ) of the abdomen and pelvis showed a large fluid filled structure along the dome of the liver , consistent with a subcapsular fluid collection ( figure 1 ) .
there was also marked dilatation of the stomach secondary to kinking of the duodenum by the displaced liver and subcapsular fluid mass .
further management included an upper gastrointestinal series that revealed extrinsic compression of the proximal duodenum , creating a partial gastric outlet obstruction ( figure 2 ) .
the patient subsequently underwent percutaneous pigtail catheter drainage placed under ct guidance , which spontaneously yielded 1.5 liters of bilious fluid . a hepatobiliary iminodiacetic acid ( hida ) scan obtained one day after the ct guided drainage concluded that there was a bile leak in the region of the gallbladder fossa ( figure 3 ) .
endoscopic retrograde cholangiopancreatography ( ercp ) showed that the second portion of the duodenum was normal , with a prominent minor ampulla , and a normal sized bile duct with no apparent leak .
the patient had a sphincterotomy performed for decompression , and was subsequently discharged with catheter drainage .
ten days after discharge , the catheter became dislodged and the patient complained of recurrent pain . she was hospitalized and another ercp was performed .
it revealed a leak from a small branch of the right hepatic duct ( figure 4 ) .
postoperative computed tomographic scan of the abdomen demonstrates a fluid collection on the right side of the liver .
upper gastrointestinal series image reveals slow passage of contrast through the pylorus , consis - tent with a gastric outlet obstruction caused by inferior displacement of the liver secondary to a biloma .
ercp shows a small leak from an accessory hepatic duct ( arrow ) . during this procedure ,
postoperative biloma usually presents in a delayed fashion ( about seven days ) with right upper quadrant pain ( ruq ) and fever . the patient in this case presented with the novel finding of gastric outlet obstruction .
ct scan or ultrasound usually establishes the diagnosis of a fluid collection ; however , these tests are not specific .
this differentiation is complicated by the fact that there is usually some fluid in the gallbladder fossa 3 - 5 days post cholecystectomy .
the performance of an intraoperative cholangiogram can demonstrate aberrant anatomy , thus decreasing the likelihood of a biliary tract injury .
radionuclide scanning ( hida ) demonstrates continuity of the fluid collection with the biliary tree .
hematomas , the other major differential diagnosis , are hyperintense on both t1 and t2 images .
if the ercp does not demonstrate the leak , it may be coming from an accessory biliary duct , or a duct of luschka in the liver bed .
ercp with stent placement , percutaneous drainage , and nasobiliary drainage have been used alone or in combination .
recommend an algorithmic approach to the treatment of postoperative biloma starting with percutaneous drainage and ercp to identify the source of the leak , and subsequent sphincterotomy and stent placement if the biloma does not resolve within ten days .
these methods are effective , but not perfect , as the biloma may recur after the intervention , thus requiring a second interventional procedure .
suggest that bile leaks without associated abdominal collections should be first identified by ercp followed by sphincterotomy and/or stent placement .
these authors reserve surgery for cases of major bile duct injury when percutaneous drainage and endoscopic management fail initially . in the case presented , while a leak was observed on hida scan , ercp did not initially identify the site of injury .
percutaneous drainage evacuated the fluid collection accompanied by sphincterotomy which resulted in spontaneous resolution after several days .
ercp is appropriate to identify the site of leak with percutaneous drainage used as an initial therapeutic maneuver .
major bile duct injuries which pre - sent as bilomas and are identified by ercp may require early surgical intervention .
if the biloma does not resolve , then sphincterotomy and stent placement may result in resolution of the leak .
Output:
| background : postcholecystectomy bilomas are relatively uncommon with a reported incidence of about 2.5% , and most often present with right upper quadrant pain and fever within seven days of the operation .
there are a number of approaches to the treatment of this uncommon lesion.case report : the authors report a case of a cholecystectomy performed in a 35-year - old female which resulted in a biloma , presenting 11 days postoperatively with gastric outlet obstruction .
the literature is reviewed to suggest the optimal management and treatment plans for this complication.results:this patient was successfully managed with radiologic intervention for the treatment of a biloma and resulting gastric outlet obstruction after open cholecystectomy.conclusion:although uncommon , bilomas may present in an unusual manner such as with gastric outlet obstruction . as with early bilomas
, they may be treated successfully with interventional radiologic techniques . |
PubmedSumm4834 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: routine vision screening evaluations , typically performed at well child visits by the pediatrician or at school by a licensed heath care personnel , are a beneficial and cost - effective means to identify children that require care from an eye specialist .
young children may be unaware and/or unable to identify problems with their vision that may be visually threatening if not diagnosed and treated .
early detection and prompt treatment of ocular disorders in children are important to avoid lifelong visual impairment .
the american academy of pediatrics ( aap ) , the american association for pediatric ophthalmology and strabismus ( aapos ) , and the american academy of ophthalmology ( aao ) have all endorsed that vision assessments should begin at birth and that all children who are found to have an ocular abnormality or who fail vision assessments should be referred to a pediatric ophthalmologist or an eye - care specialist appropriately trained to treat pediatric patients .
therefore , it is critically important that parents and care takers understand the importance of vision screening and are able to recognize the different roles of pediatricians , ophthalmologists , and optometrists .
amblyopia has prevalence of 24% and is one of the most common causes of unilateral vision loss that if left untreated may ultimately lead to significant detrimental consequences in areas of educational achievement , sports participation , psychosocial well - being , and occupational selection .
it is imperative that a child with amblyopia be identified as soon as possible , as the earlier the treatment intervention can be initiated , generally the more favorable the outcome . over
75% of amblyopic children of less than seven years of age can be successfully treated .
this learning disorder usually refers to a series of difficulties with reading , although individuals have normal intelligence , available educational opportunities , and social cultural chances .
although its mechanisms have not been fully identified , it is thought to be affected by genetic and environmental factors , and a familial aggregation has been noticed .
there is a position paper endorsed by the aap , aapos , and aao which warns that vision therapy is not effective in the treatment of learning disorders .
one purpose of this study is to ascertain if parents and care takers are familiar with this statement .
a 15-question survey was designed to help determine what the general public understands in regards to vision screening in children and understanding the roles of different eye care providers .
established discussion forums on high volume websites aimed at assisting , educating , and supporting parents and caretakers by facilitating open discussion were chosen to display the questionnaire to the public .
this area incorporates the district of columbia , northern virginia , and parts of maryland and west virginia . as of the 2008 census bureau estimate ,
the population of this region was estimated to be 5,358,130 , making it the ninth largest metropolitan area in the united states .
reports have listed this area as one of the most educated and affluent metropolitan areas in the country .
data was collected using survey monkey , which is a private company in the united states that allows users to create , disseminate , and analyze web - based surveys .
questions were formatted in a combination of nine multiple choice , four true or false , one combination - free type - in & multiple choice , and one likert - scaling method question .
demographic information collected included the age distribution of respondents , the number of children , highest level of education completed , and race . see table 1 for demographic statistics of respondents .
the majority ( 70% ) was between ages 23 to 39 years old ; 40% from age 2329 , and 30% from age 3039 .
only 9% persons were greater than 49 years old . the majority ( 86% ) of respondents had at least one child .
those who had three children and more than three children were 4% and 1% , respectively .
seven people listed other ; these responses were typed in as some college , medical school , vocational , still in college , doctor of medicine , massage therapy & holistic health , and additional training and certifications .
respondents represented a variety of racial backgrounds , the majority being black or african american ( 50% ) and non - hispanic white ( 39% ) .
five percent were asian , 2% were hispanic / latino , and 4% listed other / multirace .
if respondents knew the difference between an ophthalmologist , an optician , and an optometrist , and if they could identify which of the following is a physician ( had completed medical school ) between an ophthalmologist , optician , optometrist , and a pediatrician .
a large number of respondents ( 35% ) reported that they did not know the difference between an ophthalmologist , an optician , and an optometrist ; see table 2 .
they were then asked to mark those that had completed medical school among the following ( multiple answers could be selected ) : an ophthalmologist , optician , optometrist , and a pediatrician . over ninety percent and
close to 90% checked that an ophthalmologist and pediatrician had completed medical school , respectively .
however , 7% checked that an optician had completed medical school , and one - fourth of respondents checked that an optometrist had completed medical school ; see table 2 .
inquired if ( 1 ) respondents felt all children should undergo an evaluation to detect eye and vision abnormalities during the first few months of life and ( 2 ) asked about the recommended initial visual acuity testing age .
eighty - four respondents reported that all children should undergo an evaluation to detect eye and vision abnormalities during the first few months of life ; see table 3 .
respondents were then asked what the recommended initial visual acuity testing age is ; choices were between three years of age , five years of age , seven years of age , or only if the child complains or is observed having difficulties with vision . in response to this ,
twenty - seven percent listed 5 years of age and 6% listed 7 years of age .
eight percent of respondents listed that visual acuity testing should be performed only if the child complains or is observed having difficulties with vision ; see table 3 . who should do routine pediatric screening eye exams and visual acuity testing ?
the majority of respondents ( over 50% ) reported that pediatricians should perform routine screening eye exams and visual acuity testing .
see table 4 for the percent of overall responses regarding who respondents reported should perform pediatric screenings . inquired as to where respondents felt all children who are found to have an ocular abnormality or who fail vision screening should be referred to a pediatric ophthalmologist or an eye care specialist appropriately trained to treat pediatric patients ; if so , what time frame should the child be seen .
overwhelmingly , ( 95% ) respondents believed that all children should be referred to a pediatric ophthalmologist or an eye care specialist appropriately trained to treat pediatric patients if they fail a vision screening ; see table 5 .
there was a difference in regards to what should happen next after a vision screening has failed .
the majority ( 76% ) reported that the child should undergo a mandatory comprehensive eye exam by a licensed health care provider as soon as possible .
however 5% reported the child should wait six months then have another mandatory vision screening and close
see table 5 for the percent of overall responses as to what respondents believed should happen next after vision screenings have failed . when asked was the following response true or false : overzealous prescribing of spectacles to infants and small children can be potentially harmful .
however , 11% reported this statement was false , and over 30% admitted that they were not sure ; see table 6 .
the majority ( 90% ) reported that the best chance for treatment success in amblyopia is before age 10 .
however , 1% reported before age 16 , and close to 10% believed that amblyopia could be treated at any age ; see table 7 .
respondents were asked how they felt about the following statement : upon entry into kindergarten , the parents or guardians of a young child must present proof of the child having passed a vision screening within the previous twelve months ; there were varied responses .
forty percent strongly agreed with this statement , 42% somewhat agreed , 15% somewhat disagreed and 3% strongly disagreed ; see table 7 . asked if learning disabilities ( such as dyslexia ) can be effectively treated with vision therapy .
responses were divided with slightly more persons reporting that this statement was false ; see table 8 .
respondents in our study were a relatively well - educated group with over ninety percent completing a college degree .
the survey was posted on established discussion forums on high volume websites aimed at assisting , educating , and supporting parents and caretakers by facilitating open discussion .
therefore , in order to discover the survey link , one had to be an active participant in the discussion group .
surprisingly , over one - third of respondents admittedly did not know the difference between an ophthalmologist , optician , and an optometrist ; furthermore , a significant percentage of respondents thought that an optician and optometrist receive medical school training .
sixteen percent of persons did not believe that vision assessments should begin at the first months of life which is in contradiction to current recommendations .
about 40% incorrectly identified the correct preferred practice pattern of recommended visual acuity testing age .
eight percent of respondents listed that visual acuity testing should be performed only if the child complains or is observed having difficulties with vision .
there was a large discrepancy in who should perform routine pediatric eye exams , although the majority ( over 50% ) reported that pediatricians should perform routine screening eye exams and visual acuity testing .
most respondents reported that if a child fails a vision screening , they should see an eye care specialist , but there was not a uniform opinion as to when they should see the eye care specialist . the majority ( 76% ) reported that the child should undergo a mandatory comprehensive eye exam by a licensed health care provider as soon as possible if they failed a vision screening ; however , 5% reported the child should wait six months then have another mandatory vision , screening , and close to 20% thought it should be up to the parent with no mandatory regulations .
over forty percent either did not believe or were unsure that overzealous prescribing of glasses to children can be harmful .
the majority ( 90% ) understood that amblyopia should be treated at least before age 10 ; although 9% thought amblyopia could be treated at any age .
currently , there is not a uniform vision screening law in the united states ; screening regulations differ from state to state across the country .
however , there are proposed screening guidelines and recommendations that are endorsed by the aap , aapos , and aao .
there is a significant lack of understanding of the current vision screening recommendations , difference between eye care professionals , and the importance of early treatment of amblyopia .
many parents do not understand the potential detrimental consequences of delayed care in the event their child fails a vision screening .
steps should be taken to further educate the general public of the difference between eye care professionals and to promote a better understanding of the current vision screening recommendations and the importance of early treatment of amblyopia with a goal that parents will understand the importance of vision screening and the need for prompt followup if the vision screen is abnormal .
vision screening evaluations is a cost - effective means to identify problems . children may be unable to express problems with vision that may be visually threatening .
early detection and prompt treatment of ocular disorders are important to avoid lifelong visual impairment .
this study identifies the lack of understanding among parents regarding vision screening recommendations , difference between eye professionals , and the importance of early treatment of amblyopia .
Output:
| objective . to ascertain if parents are familiar with current recommendations on pediatric vision screening and to assess their knowledge of the roles that pediatricians , ophthalmologists and optometrists have in this screening process
. methods .
a survey was targeted at parents to determine what the general public understands regarding vision screening .
results .
the survey was conducted from january may 2010 .
one hundred fifty six persons responded .
over one - third did not know the difference between eye care specialists .
many believed opticians and optometrists receive medical school training . over forty percent incorrectly identified the recommended visual acuity testing age .
a large discrepancy existed regarding who should perform pediatric eye exams .
most agreed a failed screening warranted follow - up , but there was not a uniform opinion as to when to seek care .
the majority of respondents understood amblyopia should be treated at least before age ten ; although nine percent believed amblyopia could be treated at any age .
discussion .
there is a significant lack of understanding of the current screening recommendations , difference between eye care professionals , and the importance of early treatment of amblyopia . conclusions .
many parents do not understand the potential detrimental consequences of delayed care in the event their child fails a vision screening . |
PubmedSumm4835 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: human
cytomegalovirus ( hcmv ) is one of the prevalent opportunistic pathogen that causes a wide spectrum of clinical manifestations ( 1 ) .
this virus is regarded as the main morbidity and mortality cause in immune suppressed patients ( ie ; organ transplant recipients , human immunodeficiency virus ( hiv ) patient ) ( 2 ) . newborns with congenital infection
have a mortality rate of about 5 percent , and neurologic morbidity occurs in 50 to 60 percent of survivors ( 3 ) . in spite of the fact that cmv is a widespread pathogenin the human population , prevention of its disease is rather difficult .
although several vaccine approaches have been developed , none have yet been put into routine clinical practice .
the cell - mediated immune response is necessary in the recovery of infections ( 4 ) .
the best way to protect females before the onset of puberty is a cmv vaccine that stimulates cellular and humoral immune response .
this would reduce the risk of congenital cmv infection in the fetus and newborn ( 5 ) . in previous studies ,
many peptides had been reported that had been used as vaccine against cmv . the most abundant tegument protein ( pp65 protein )
is a major target of the cytotoxic t - cell ( 6 ) . besides , the most abundant envelope protein ( the glycoprotein b , gb ) is a major target of the humoral immunity ( 1 , 3 ) .
it seems that the development of a suitable vaccine for cmv , synchronously using epitopes specific for the immune dominant protein derived from these proteins , are the best choice .
a major limitation for using vaccines to induce protective immune responses against cmv infection is related to achieving efficient uptake and processing antigen - presenting cells ( apcs ) .
one way to overcome this problem is the use of the fc - fusion peptides in which one or more antigenic peptides are fused into the fc domain of immunoglobulin ( ig ) .
fusion of peptides to fc domain can increase harvesting and delivering them to the t lymphocyte , which is critical for protection against cmv .
the most effective method of antigen uptake in apcs such as macrophages and dendritic cells ( dcs ) is receptor - mediated uptake .
for this reason , dcs have several types of fc receptors ( fcr ) that bind the fc domain of igg molecules ( 7 ) .
therefore , to facilitate the binding of peptide to apc , fc receptor was added to desired fusion peptide . in recent decade , pichia pastoris was used as a useful expression system in vaccine development ( 8) . in this study , a cocktail peptide vaccine using pp65 , and gbwas designed against cytomegalovirus infection .
cloning and expression of this cocktail peptide vaccine fused with fc domain of mouse igg2a in p. pastoris was reported .
these epitopes were gb431 - 450 , gb471 - 490 and gb571 - 590 ( 9 ) for gb protein ( gen bank access number gi : 138192 ) and pp65361 - 376 ( 10 ) , pp340 - 355 ( 11 ) , and pp65417 - 427 ( 12 ) for pp65 protein ( gen bank access number gi : 130714 ) .
finally , the fc fragment of mouse igg2a ( gen bank access number gi : 51835 ) ( 7 ) was fused to c - terminal of cocktail epitopes .
sequences optimization and colon simulating in p. pastoris were checked by dna 2.0 , genscript and genius softwares .
ppicza expression vector carries -factor signal sequence ( -mf ) to drive fusion peptide secretion .
besides , this vector contains the zeocin resistance gene , shble , which is used for selection of escherichia coli and p. pastoris recombinants .
also , a c - terminal polyhistidine ( 6xhis ) tag was added to c - myc in order for fusion peptide to be detected by dot blot assay .
this strain was cultured at 37 c in lb ( luria broth ) medium supplied with ampicillin .
ppicza was used as shuttle vector for expression of fusion peptide , and the p. pastorisgs115 strain ( invitrogen , usa ) was used as an expression host .
the yeast cells were grown at 30 c on ypd ( yeast extract peptone dextrose ) medium ( 1% yeast extract , 2%bac to - peptone 2% glucose ) and ypds ( yeast extract peptone dextrose medium with sorbitol ) ( 1% yeast extract , 2% peptone , 2% glucose , 1 m sorbitol ) supplemented with 100 g / ml zeocin when necessary .
inclusion of sorbitol in ypd plates stabilizes electroporated cells as they appear to be somewhat osmotically sensitive .
restriction enzymes used for cloning were purchased from promega and used in accordance with manufacturer s recommendations . in order to amplify this synthetic fusion sequence ,
the presence of desired segment was confirmed by double digestion with related restriction enzymes and sequencing .
after minipreparation of pgh containing fusion sequence and double digestion , gel extraction and purification of desired segment were carried out by commercial kit according to manufacturer s recommendations ( 5 prime , germany ) .
this segment was cloned into ppicza shuttle vector under control of aox1 promoter , and the resulting vectors were called ppicza - cmv .
the construction of vector was confirmed by restriction digestion , pcr with aox1 and -factor primers , which amplified entire recombinant fusion peptide sequence .
pcr was performed with the primers 3aox1 5-gcaaatggcattctgacatcc-3 , and -factor , 5-tactattgccagcattgctgc-3 .
temperature profile was one cycle in 94 c for 3 min followed by 30 cycles in 94 c for 1 min , 55 c for 1 min , and 72 c for 2.30 min and finally 72c for 1 min .
stable integration into the aoxi ( aldehyde oxidase 1 ) of p. pastoris was achieved after linearization of the 5 g ppicza - cmv peptide expression vectors with saci .
after colony selection on ypds media supplemented with 100 g / ml zeocin , the recombinant p. pastoris cells were subjected to bmgy ( buffered glycerol - complex medium ) medium for fusion peptide expression . in this step , a total of 10 colonies were obtained and subsequently screened for methanol utilization phenotype . to remove inhibitory effect of other carbon sources ,
the recombinant p. pastoris strain gs115 was cultured in bmgy medium ( containing 1% yeast extract , 2% peptone , 100 mm potassium phosphate ph 6 , 1.34% yeast nitrogen base , 4 x 10 - 5% biotin and 1% glycerol ) .
after acquiring bmgy turbidity to od600 = 1.5 , the cells were harvested through centrifuge . in order to induct aox1 ,
the product in question was transferred into the bmmy medium ( the same as bmgy medium but with 0.5% methanol instead of 1% glycerol ) . in this system ,
the inducer was 0.5% methanol , which was added into the medium from day 2 up to day 7 . to confirm the expression of pp65-gb - fc
sds - page was performed in a 10% ( w / v ) polyacrylamide gel . as a control ,
these epitopes were gb431 - 450 , gb471 - 490 and gb571 - 590 ( 9 ) for gb protein ( gen bank access number gi : 138192 ) and pp65361 - 376 ( 10 ) , pp340 - 355 ( 11 ) , and pp65417 - 427 ( 12 ) for pp65 protein ( gen bank access number gi : 130714 ) .
finally , the fc fragment of mouse igg2a ( gen bank access number gi : 51835 ) ( 7 ) was fused to c - terminal of cocktail epitopes .
sequences optimization and colon simulating in p. pastoris were checked by dna 2.0 , genscript and genius softwares .
ppicza expression vector carries -factor signal sequence ( -mf ) to drive fusion peptide secretion .
besides , this vector contains the zeocin resistance gene , shble , which is used for selection of escherichia coli and p. pastoris recombinants .
also , a c - terminal polyhistidine ( 6xhis ) tag was added to c - myc in order for fusion peptide to be detected by dot blot assay .
this strain was cultured at 37 c in lb ( luria broth ) medium supplied with ampicillin .
ppicza was used as shuttle vector for expression of fusion peptide , and the p. pastorisgs115 strain ( invitrogen , usa ) was used as an expression host .
the yeast cells were grown at 30 c on ypd ( yeast extract peptone dextrose ) medium ( 1% yeast extract , 2%bac to - peptone 2% glucose ) and ypds ( yeast extract peptone dextrose medium with sorbitol ) ( 1% yeast extract , 2% peptone , 2% glucose , 1 m sorbitol ) supplemented with 100 g / ml zeocin when necessary .
inclusion of sorbitol in ypd plates stabilizes electroporated cells as they appear to be somewhat osmotically sensitive .
restriction enzymes used for cloning were purchased from promega and used in accordance with manufacturer s recommendations .
in order to amplify this synthetic fusion sequence , pgh vector was transformed into jm109 e. coli strain using calcium chloride method .
the presence of desired segment was confirmed by double digestion with related restriction enzymes and sequencing .
after minipreparation of pgh containing fusion sequence and double digestion , gel extraction and purification of desired segment were carried out by commercial kit according to manufacturer s recommendations ( 5 prime , germany ) .
this segment was cloned into ppicza shuttle vector under control of aox1 promoter , and the resulting vectors were called ppicza - cmv .
the construction of vector was confirmed by restriction digestion , pcr with aox1 and -factor primers , which amplified entire recombinant fusion peptide sequence .
pcr was performed with the primers 3aox1 5-gcaaatggcattctgacatcc-3 , and -factor , 5-tactattgccagcattgctgc-3 .
temperature profile was one cycle in 94 c for 3 min followed by 30 cycles in 94 c for 1 min , 55 c for 1 min , and 72 c for 2.30 min and finally 72c for 1 min .
stable integration into the aoxi ( aldehyde oxidase 1 ) of p. pastoris was achieved after linearization of the 5 g ppicza - cmv peptide expression vectors with saci .
after colony selection on ypds media supplemented with 100 g / ml zeocin , the recombinant p. pastoris cells were subjected to bmgy ( buffered glycerol - complex medium ) medium for fusion peptide expression . in this step ,
a total of 10 colonies were obtained and subsequently screened for methanol utilization phenotype . to remove inhibitory effect of other carbon sources ,
the recombinant p. pastoris strain gs115 was cultured in bmgy medium ( containing 1% yeast extract , 2% peptone , 100 mm potassium phosphate ph 6 , 1.34% yeast nitrogen base , 4 x 10 - 5% biotin and 1% glycerol ) .
after acquiring bmgy turbidity to od600 = 1.5 , the cells were harvested through centrifuge . in order to induct aox1 ,
the product in question was transferred into the bmmy medium ( the same as bmgy medium but with 0.5% methanol instead of 1% glycerol ) . in this system ,
the inducer was 0.5% methanol , which was added into the medium from day 2 up to day 7 . to confirm the expression of pp65-gb - fc
sds - page was performed in a 10% ( w / v ) polyacrylamide gel . as a control ,
in attempting to obtain secretion of pp65-gb - fc fusion peptide at high levels in the culture medium , a cod on - optimized -mf along with the ppicza based vector was employed . in this paper ,
the aoxi promoter sequence was used to allow integration of the ppicza - cmv expression vector via homologous recombination , as well as a cod on - optimized -factor from saccharomyces cerevisiae to drive the secretion of fusion peptide ( 13 ) . in this study ,
p. pastoris strain gs115 was used as the host and the ppicza was used as an expression vector .
pp65-gb - fc segments were cloned in xhoi / xbai site of mcs ( multiple cloning site ) from ppicza ( figure 1 ) .
schematic diagram for cloning of modified pp65-gb - fc segments in ppicza ( ppicza - pp65-gb - fc ) amino acid sequences of final recombinant protein pcr ( figure 3 ) and digestion ( figure 4 ) showed that pp65-gb - fc segments were ligated with ppicza expression vector .
the pcr and restriction digestion of the recombinant plasmid ppicza - pp65-gb - fc produced a fragment with the expected length of ~1300 bp ( figure 3 ) .
dna fragments with the expected length of the target gene ( 1290 bp ) were produced in the transformed yeast clones .
line1 : 1 kb dna ladder , line 2 - 4 : 1290 bp pcr product , line 5 : negative control double restriction digestion analysis of ppicza - cmv with xhoi / xbai restriction enzymes .
in attempting to obtain secretion of pp65-gb - fc fusion peptide at high levels in the culture medium , a cod on - optimized -mf along with the ppicza based vector was employed . in this paper ,
the aoxi promoter sequence was used to allow integration of the ppicza - cmv expression vector via homologous recombination , as well as a cod on - optimized -factor from saccharomyces cerevisiae to drive the secretion of fusion peptide ( 13 ) . in this study ,
p. pastoris strain gs115 was used as the host and the ppicza was used as an expression vector .
pp65-gb - fc segments were cloned in xhoi / xbai site of mcs ( multiple cloning site ) from ppicza ( figure 1 ) .
schematic diagram for cloning of modified pp65-gb - fc segments in ppicza ( ppicza - pp65-gb - fc ) amino acid sequences of final recombinant protein
pcr ( figure 3 ) and digestion ( figure 4 ) showed that pp65-gb - fc segments were ligated with ppicza expression vector .
the pcr and restriction digestion of the recombinant plasmid ppicza - pp65-gb - fc produced a fragment with the expected length of ~1300 bp ( figure 3 ) .
dna fragments with the expected length of the target gene ( 1290 bp ) were produced in the transformed yeast clones .
line1 : 1 kb dna ladder , line 2 - 4 : 1290 bp pcr product , line 5 : negative control double restriction digestion analysis of ppicza - cmv with xhoi / xbai restriction enzymes .
line1 : 1 kb dna ladder , line 2 - 4 digested recombinant plasmid . line 5 : undigested plasmid
digestion with saci generates a fragment , which can integrate by homologous recombination into the aoxi region .
cells of p. pastoris strain gs115 were transformed with linear ( saci - digested ) form of the expression vector , ppicza - cmv .
after expression of ppicza - cmv in induction media , supernatant of the media was studied by dot blot and 10% sds - page . in dot
blot , we used antibody against c - myc epitopes in terminal segment of cassette gene ( figure 5 ) . by using the anti - cmy antibody
, it was demonstrated that a fusion peptide was present in the supernatant during the cultivation course , while no detection was observed in the control extracts . in sds - page ,
coomassie blue staining showed that six of the ten induced clones produced a fusion peptide , which was not present in the control strain and had the expected molecular weight ( ~50 kda ) for pp65-gb - fc .
fusion peptide was present in the supernatant during total course of cultivation ( 7 days ) expression of the cytomegalovirus recombinant fusion protein .
( a ) the analysis of the p. pastorisgs115/ppicza - cmv cells by 10% sds - page stained with coomassieblue revealed a protein band profile with a molecular weight of ~50 kda .
line 1 : ppicza without fusion peptide , line 2 : p. pastoris without vector .
( b)the expression of the recombinant pp65-gb : fc2a protein was analyzed by immunoblot using anti mouse igg - hrp
nowadays , development of effective , cheap and safe vaccines is one of the major challenges in medical science . in order to design effective peptide vaccines ,
identification of proper viral antigens is important for inducing protective immune response ( 14 ) .
there is little data about using p. pastoris for hcmv peptide vaccine . in this research
, it was shown that p. pastoris yeast can be successfully used as an expression system for generating cmv fusion peptide .
p. pastoris performs some posttranslational modifications such as glycosylation and refolding on heterologous eukaryotic proteins ( 13 ) .
this glycosylation can affect the stability and activation of recombinant protein that is used for studies of some aspects of recombinant protein functions ( 15 ) .
all peptides in our research were immunogenic and have been used in previous studies , separately . in this respect ,
p. pastoris cells are attractive tools to use as antigen carrier , which subsequently induces specific ctl ( cytotoxic t cell ) immune responses against viral antigens .
a recent study looks into improving the immunogenicity of the peptides based on the fast development of multi - epitopes vaccines , which showed immunological activity against bacteria and virus ( 16 ) . in this study
, we choose eight epitopes on two immunologic proteins of hcmv . in this study , emphasize was put on p. pastoris as one of the best characterized yeasts , which is also becoming increasingly important in the field of eukaryotic cell biology and gene technology . based on the metabolization of methanol ,
p. pastoris strains were divided into three distinct phenotypes : the first phenotype is wild - type , methanol utilization plus ( mut+ ) that is characterized by the presence of the alcohol oxidase 1 gene ( aox1 ) , which is responsible for 85% of the methanol utilization ; the second is methanol utilization slow phenotype ( muts ) , characterized by the absence of aox1 gene and presence of the aox2 gene , which is about 97% homologous to aox1 but much less expressed ; and the third is methanol utilization minus phenotype ( mut ) , where both aox genes are absent . among these strains ,
the mut+ strains have a greater growth rate on methanol as the sole carbon source .
expression of the cmv cocktail peptide was efficiently achieved for the first time through an easier production schedule than when an aox1inducible promoter is employed ( 17 ) . in this research
, we utilized an expression vector , ppicza , which has the aox1 gene promoter to drive peptide expression , which can be induced by adding methanol to the growth medium . in this vector ,
the native signal peptide was replaced with that of the s. cerevisiae-factor , allowing secretion of the peptide into the extracellular medium ( 18 - 20 ) .
we have shown that fusion cmv peptide can be expressed in a yeast system by dot blot and sds - page assays .
currently , there is a growing need for cmv vaccines that are capable of eliciting cell - mediated and humoral immunity .
previously , the expression of dna encoding pp52 , as a non - fusion protein , in p. pastoris had shown good level of intracellular pp52 , which has good reactivity with human sera ( 21 ) .
according to recent studies , pp65 protein recognized by cd8 t cells from the majority of cmv - infected individuals , and evidence from preclinical and clinical studies indicates that this protein is principal target of protective cellular and humoral immune response ( 17 , 22 , 23 ) . in this context
, it has been shown that pp65495 - 503 cytotoxic cd8 t - cell epitope can stimulate pp65 t - cells in healthy volunteers ( 24 ) . in this research
recently , a subunit vaccine based on cmv glycoprotein b ( gb ) formulated with mf59 adjuvant successfully terminated phase ii clinical trials ( 25 ) . also we selected three immunodominant and mhc class i restricted epitopes in gb protein and fused by -ggggs- linkers . in order to activate antigen - specific t - cells ,
antigens must be taken up by antigen presenting cells ( apcs ) , and must be consequently presented by mhc class i and ii proteins .
dendritic cells , dcs ) including fc fusion protein will improve availability of protein antigen ( 10 , 14 ) .
previous studies demonstrated that targeting of immunogenic peptide to fc on apcs can increaseits selectively uptake and induce effective protective immune response both in vitro and in vivo .
these studies indicated that fc domain of immunoglobulin ( specially igg ) to form fusion with peptide ( such as pp65 and gb from cmv in this research ) can increase the immunogenicity of fc - fused antigens and could be considered as a delivery system ( 26 , 27 ) .
recently , it was shown that fcrn - targeted mucosal immunization produced durable memory immune responses .
immunological memory is exemplified by increased levels of effector t and b cells and , functionally , by the ability to respond faster and more vigorously to a second encounter with the vaccine antigens ( 7 ) . to the best of our knowledge ,
this is the first time that the expression of hcmv - pp65-gb - fc protein was achieved in p. pastoris .
in this study , we have shown that the pp65-gb - fc can be produced at appropriate levels by p. pastoris .
current study provides a starting point for future attempt to immunological studies on this vaccine .
we believe that secretion of hcmv pp65-gb - fc in the culture media could help downstream processing .
although further experiments are needed to determine immunogenicity of this cocktail peptide , the data outlined here underline that this vaccine could be a promising candidate for the development of a novel peptide vaccine .
Output:
| objective(s):human cytomegalovirus ( hcmv ) remains a major morbidity and mortality cause in immuno suppressed patients .
therefore , significant effort has been made towards the development of a vaccine . in this study ,
the expression of the pp65 and gb fusion peptides and fc domain of mouse igg2a as a novel delivery system for selective uptake of antigens by antigen - presenting cells ( apcs ) in pichia pastoris yeast system were studied.materials and method : in this study , four immune dominant sequences in pp65 protein and 3 immuno dominant sequences in gb protein were selected according to literature review .
peptide linker -ggggs- was used for construction of fusion peptide .
this fusion peptide was cloned in the ppicza expression vector and transfected into p. pastoris host cells.results:dot blot and sodium dodecyl sulfate polyacrylamide gel electrophoresis ( sds - page ) techniques showed that a high level of pp65-gb - fc fusion peptide was expressed.conclusion:this cmv pp65-gb - fc fusion peptide could be a promising candidate for the development of a novel peptide vaccine . |
PubmedSumm4836 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the sample population included 18 to 45 year old subjects living in tabriz , north - west of iran in 2009 .
a sample size of 400 subjects was estimated prior to the study according to the cochrane formula considering p as 0.04 , d as 0.02 , and as 0.05 . a two stage cluster sampling method with a probability
postal codes were extracted by the cooperation of the east azerbaijan provincial health center ( department ) providing an annually updated sampling framework . at the first clustering stage ,
a presumed 200 households were selected followed by equal sized samples according to gender at the second stage .
then , the researchers evaluated one male and one female subject in each of the selected households through conner s adult adhd rating scale ( self- report ) . in non - cooperating cases ,
the subjects with adhd index higher than 70 in the self - report questionnaire of conner s adult adhd rating scale were initially evaluated for childhood adhd symptoms ; and if positive , the adhd portion of k - sads questionnaire about childhood was fulfilled ; and if certified by one more family member knowing about his / her childhood , the subject was selected .
then , the psychiatric interview was performed for all selected individuals according to the dsm - iv - tr criteria and wender utah ; and those who had definite symptoms were diagnosed to have adult adhd .
the participants included 400 population subjects ( 200 men and 200 women ) with an age range of 18 to 45 years living in urban tabriz , north - west of iran in 2009 .
the inclusion criteria were defined as follows : an age range of 18 - 45 , lack of severe mental and somatic disability , willingness and consent to participate in the study .
conner s adult adhd rating scale was used for screening the purpose followed by a clinical diagnosis made through psychiatry interview based on dsm - iv .
the conners adult adhd rating scale ( caars ) has widely been used to screen and follow up patients ; and its validity and reliability are shown to be in accordance with dsm - iv .
it has multiple indices including attention deficit index ( subscale a ) , hyperactivity - impulsivity index ( subscale b ) , adhd total symptoms index ( subscale c ) and adhd index ( subscale d ) .
subscale c is the sum of a and b subscales . in the original reference manual of the caars
, it is clarified that which questions belong to specified subscales ; and with adding the scores of each subscale questions , scores of each subscale was determined .
this questionnaire had been translated to persian by clinical psychiatry research center ( cprc ) in tabriz and validated by amiri et al .
the reliability and feasibility of the persian version of this diagnostic instrument were already determined as fair to good for most diagnostic categories ( kappa > 0.6 ) . and has just recently been used by the authors referring also to the previous studies with an overall internal consistency of the conner s adult adhd rating scale by cronbach s alpha being equal to 0.83 ( 14 ) . in this study ,
the internal consistency of the scale was also assessed as a measure of reliability by cronbaches being equal to 0.83 .
the descriptive statistics including frequency , relative frequency , means and standard deviations were used to depict the current situation of adult adhd and describe the demographic status of the understudy population .
chi - square and fisher s exact tests were used to determine the association of demographic categorical variables and occurrence of adult adhd .
independent t - test was used to compare the numeric scale variables such as age of smoking initiation in the two groups ( adult adhd and normal population ) .
this study was approved by the regional committee of ethics in tabriz university of medical sciences .
the study protocol was approved and publicly defended as a thesis project for a degree of specialty in psychiatry in tabriz university of medical sciences .
the participants included 400 population subjects ( 200 men and 200 women ) with an age range of 18 to 45 years living in urban tabriz , north - west of iran in 2009 .
the inclusion criteria were defined as follows : an age range of 18 - 45 , lack of severe mental and somatic disability , willingness and consent to participate in the study .
conner s adult adhd rating scale was used for screening the purpose followed by a clinical diagnosis made through psychiatry interview based on dsm - iv .
the conners adult adhd rating scale ( caars ) has widely been used to screen and follow up patients ; and its validity and reliability are shown to be in accordance with dsm - iv .
it has multiple indices including attention deficit index ( subscale a ) , hyperactivity - impulsivity index ( subscale b ) , adhd total symptoms index ( subscale c ) and adhd index ( subscale d ) .
subscale c is the sum of a and b subscales . in the original reference manual of the caars
, it is clarified that which questions belong to specified subscales ; and with adding the scores of each subscale questions , scores of each subscale was determined .
this questionnaire had been translated to persian by clinical psychiatry research center ( cprc ) in tabriz and validated by amiri et al .
the reliability and feasibility of the persian version of this diagnostic instrument were already determined as fair to good for most diagnostic categories ( kappa > 0.6 ) . and has just recently been used by the authors referring also to the previous studies with an overall internal consistency of the conner s adult adhd rating scale by cronbach s alpha being equal to 0.83 ( 14 ) . in this study ,
the internal consistency of the scale was also assessed as a measure of reliability by cronbaches being equal to 0.83 .
the descriptive statistics including frequency , relative frequency , means and standard deviations were used to depict the current situation of adult adhd and describe the demographic status of the understudy population .
chi - square and fisher s exact tests were used to determine the association of demographic categorical variables and occurrence of adult adhd .
independent t - test was used to compare the numeric scale variables such as age of smoking initiation in the two groups ( adult adhd and normal population ) .
this study was approved by the regional committee of ethics in tabriz university of medical sciences .
the study protocol was approved and publicly defended as a thesis project for a degree of specialty in psychiatry in tabriz university of medical sciences .
twenty - two among 400 selected subjects ( 5.5% ) had adhd index higher than 70 points including six females ( 27.3% ) and 16 males ( 72.7% ) .
the interview showed that 15 subjects ( 3.8% ) had adult adhd according to the dsm - iv - tr criteria and wender utah .
the mean age was 33.40 7.67 and 32.19 7.74 in adult adhd and normal subjects .
the adult adhd prevalence in the general population according to the age strata was six ( 3.2% ) in 18 - 30-year - old subjects , seven ( 5% ) in 31 - 40-year - old subjects , and two ( 2.7% ) in 41 - 45-year - old subjects .
also , the prevalence of adult adhd was 5.5% ( 11 subjects ) in men and 2% ( four subjects ) in women . according to the results obtained from fisher exact test , the sex ratio was not different between those with and without adult adhd ( table 1 ) . also , according to the results obtained from chi - square test , the frequency distribution of age , marital status , birth order , educational level and occupational status were not different between subjects with and without adult adhd ( table 1 ) .
the frequency distribution of history of psychiatric treatment , alcohol drinking , and smoking did not differ between subjects with and without adult adhd according to fisher exact test ( table 2 ) . according to table 3
, the results of the t - test test showed that the mean age of smoking initiation did not differ between the subjects with and without adult adhd .
this study which was conducted to determine the prevalence of adult adhd in tabriz showed that 3.8% among 400 participants aged 18 to 45 years had adhd which was determined according to dsm - iv - tr criteria and wender utah .
this prevalence is similar to that of western countries . in the national comorbidity survey replication
, 4.4% of 3199 subjects aged 18 to 44 years met the dsm - iv criteria for adhd ( 8) . in another report , the prevalence rate of 3.4% was reported among 18 to 44 year old subjects ( 13 ) .
also , in a study conducted on outpatients with non - psychotic psychiatric illnesses , the prevalence of adhd was 16.8% and it was 5.3% among healthy participant ( 15 ) . in a study conducted in hungary among 3529 adults aged 18 to 60 years , adult adhd was more common in men and in adults younger than 40 years of age .
the prevalence was 2.3% in males and 0.91% in females ; 2.02% in the < or = 40 year old group and 0.70% in the > 40 year old group based on dsm - iv diagnostic criteria ( 16 ) .
similar prevalence of adult adhd in western countries and iran demonstrates the weak effect of sociocultural factors in this disorder . in a study
it was showed that the heritability of adhd in adults is estimated around 30% in men and women .
all familial transmission is explained by genetic inheritance ; there is no support for the hypothesis that cultural transmission from parents to offspring is important ( 17 ) .
this prevalence rate of adult adhd requires designing and managing general health . in different studies ,
the prevalence of adhd in boys has been reported to be more than girls ( 18 , 19 , 20 ) .
nonetheless , as the results of our study indicate , gender has a weak impact on adult adhd as well as non - significant prevalence in men ( 5.5% vs. 2% percent ) .
however , some studies have reported higher prevalence among men ( 8 , 13 ) . according to our findings ,
the prevalence of adult adhd was not different in the age strata , which is similar to the reports of some other studies ( 1 , 9 ) and opposite to some others ( 13 ) .
one study had reported higher prevalence of adhd in lower ages ( 11 ) . in some studies ,
the prevalence of adult adhd was not reported to differ according to marital status ( 1 , 13 ) as in our study ( 1 , 13 ) , but some others have reported significantly higher prevalence among divorced or previously married patients ( 7 , 8 , 21 ) .
another study showed a higher prevalence of adult adhd in widowed / divorced/ separated and single patients ( 11 ) .
however , due to the effect of adult adhd on intimate relationships leading to less stability and higher divorce rate , the judgment about the effect of this disorder on marital status may need longer follow ups .
the lack of association between adult adhd and educational level was similar to some studies ( 1 , 9 ) and opposite to some others showing higher prevalence of adult adhd in illiterate subjects or those with low literacy ( 11 , 13 and 21 ) .
employment status was not associated with the prevalence of adult adhd , but in previous studies unemployed subjects have had higher prevalence of adult adhd ( 8 , 11 , 21 ) .
also , a study on workers has shown lower prevalence of adult adhd among expert workers ( 1 ) .
previous studies did not evaluate the association of adult adhd and birth order ; the results obtained in our study showed no association in this aspect .
this may be explained by the fact that when a person enters adulthood and integrates with the public , the effect of birth order will be diminished despite its initial effect on personality development in childhood .
however , in previous studies , patients with adult adhd seeked treatment less than the normal adults ( 8 , 13 ) , but in our study the number of psychiatrist visits was similar between normal and adult adhd subjects .
this may be due to different factors such as poor insight , psychiatric disorders stigma , or lack of access to treatment .
however , the findings of this study highlighted the importance of increasing our knowledge about the general population .
also , it is suggested that the contributing factors for lack of treatment seeking among adult adhd patients be evaluated in the future studies .
another part of our study showed the self - report of alcohol use and smoking and revealed that the mean age of smoking initiation was not different between the subjects with and without adult adhd .
this finding is the opposite of those findings reported by previous studies about smoking ( 22 ) and alcohol use ( 23 , 24 ) , which showed the substance abuse as the outcome and comorbidity of adhd . with respect to the association of smoking and substance use with adult adhd
, it may be noted that this is a type of self - administration treatment for adhd ( 25 , 26 ) . in our study , few normal and adult adhd subjects were reported to use alcohol , and this may be due to the fact that alcohol use is illegal and stigmatic in iran . since the self - report of alcohol and substance use in islamic countries , would bias the results and regarding small sample size and type of questions , it may not be judged . however , in our study , the sample size was calculated to be 400 , but the 3.8% prevalence rate of adult adhd is required to be replicated with a larger sample population to increase the reliability of the correlational analysis .
limitations : the main limitation of this study was its moderate sample size allowing for 2% precision .
however , the results are yielding considering it to be among the first prevalence studies conducted in iran about adult adhd .
the prevalence of adult adhd in tabriz ( with one million and three - hundred thousand population ) residents aged 18 to 45 years was 3.8% ( 5.5% in men and 2% in women ) according to dsm - iv - tr criteria and wender utah .
the prevalence of adhd was not associated with age , marital status , birth order , educational level , career status , alcohol use and smoking .
however , other studies have reported the effect of psychosocial factors on the prevalence of adult adhd ( 8 , 11 , 21 ) , but it was not observed in our study .
our findings about the contributions of adult adhd were important in some aspects ; these findings may be due to iranian sociocultural effect , and also research factors such as inclusion criteria and sample size .
performing complementary studies about the contributors of adult adhd and psychiatric comorbidities in iran and the other middle east countries would result in more definite recognition of psychosocial contributors of adult adhd .
considering the high prevalence of adhd in adults and the importance of on time diagnosis and treatment of this disorder , further studies are needed to determine the definite prevalence in the whole country .
since many patients are hidden cases receiving no treatment and may develop side effects of the disease in their life , providing information for the public and exclusive training for the professionals are needed in this field . more special trainings for general practitioners to diagnose and refer the patients for treatment would decrease the under - treatment cases .
furthermore , early prognosis and treatment of patients may decrease burden of disease , such as costs due to accidents , substance abuse , career and education leave and other problems .
Output:
| objectiveattention deficit hyperactivity disorder in adults ( adult adhd ) is gaining more attention nowadays .
nevertheless , very few studies have addressed this issue in iran .
the present study was conducted to determine the prevalence of adult adhd in tabriz , north - west of iran.methodsfour hundred urban inhabitants of tabriz- with an age range of 18 to 45 years were selected through the probability proportional to size cluster sampling in 2009 .
the screening was performed by conner s adult adhd rating scale , and the definite diagnosis of adult adhd was performed via clinical interview according to dsm - iv - tr and wender utah criteria.resultsthe prevalence of adult adhd was estimated to be 3.8% .
men when compared with women were more likely to have adhd ( 5.5 % in men versus 2 % in women ) .
marital status , birth order , educational level and occupational status showed no significant association with adult adhd .
history of psychiatric treatment , alcohol drinking and smoking had similar relative frequency in subjects with and without adult adhd.conclusionthe prevalence of adult adhd in this region of iran seems to be substantially higher than expected or treated .
this would require more attention to be drawn by health sector managers in order to improve the knowledge of the general population and the knowledge of the health care professionals about the disorder . |
PubmedSumm4837 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: congenital midline nasal masses are rare developmental anomalies estimated to occur in one out of every 20,000 - 40,000 births .
a nasal dermoid cyst ( ndc ) typically presents as a midline mass located anywhere from the glabella to columella .
the majority of ndc 's are diagnosed in infancy and early childhood , but in some cases a lesion may not be noticed until complications occur .
tessier craniofacial clefts may involve entire soft tissue and skeletal elements throughout the course of the cleft , resulting in a distorted craniofacial growth pattern and altered potential for normal growth .
the tessier number 0 cleft patient may present with minimal notching in the lip , vermilion and nose , and a minimally bifid nose .
the bifid nose deformity is an indicator of tessier 's 0 cleft with various degrees of skeletal problems .
we report a rare case of tessier 's 0 cleft with presence of midline ndc within the groove of the bifid nose in a 4-year - old female child .
a 4-year - old female child was referred to department of oral and maxillofacial surgery with a chief complaint of swelling on the nose since 1 year which had increased in size from past 2 months .
there was no previous history of facial trauma , infection , or surgery and familial inheritance .
further , clinical evaluation revealed a swelling on the nasal dorsum and a well - defined groove between two alar domes causing increase in columellar width .
the anterior edge of nasal septum was thick and separated in the shape of a
y , contributing to a bifid appearance of nose and there was presence of a midline punctum over the swelling .
ct scan axial view showed a soft tissue swelling overlying glabella and in between nasal septum with no evidence of intracranial extension . taking all of these findings into consideration ,
all the laboratory tests were in normal ranges and treatment was planned in two stages , excision of the dermoid cyst initially and rhinoplasty in the second stage . under general anesthesia , using a midline vertical incision on dorsum of the nose , cystic lining was exposed and a tract was found extending from punctum to a cystic cavity overlying the nasal bridge .
the entire cystic mass was excised and layered closure was done using 3 - 0 polyglactin and 6 - 0 prolene sutures .
histopathological examination revealed that the cyst is lined by keratinizing squamous epithelium with attached pilosebaceous structures suggestive of dermoid cyst [ figures 16 ] .
the surgical wound healed uneventfully and no recurrence was found during the follow - up period .
frontal view photograph showing swelling on dorsum of the nose and mild depression in midline .
note the presence of a punctum at dorsum of the nose ( ellipse ) worms eye view showing swelling on dorsum of the nose and mild depression in the midline .
note the increased width of columella lateral view showing convexity of swelling over dorsum of the nose axial computed tomography ( ct ) scan view showing the dermoid cyst lining within the confines of nasal septum ( ellipse ) intraoperative photograph showing the cyst after exposure surgical specimen of excised dermoid cyst
they are often associated with a sinus tract , and their extent varies . in particular
, they may remain confined to the surface , involve deep , local tissues , or even extend into intracranial compartment .
patients with midline nasal masses require magnetic resonance imaging ( mri ) or ct imaging to assess the lesion and determine possible intracranial extension .
craniofacial clefts were classified by tessier in 1973 based on his personal experience yielded by clinical , radiologic , and surgical observations .
the exact incidence is not known , but estimates range from 1.4 to 4.9 per 100,000 live births .
these clefts are found along the lines of fusion of different processes responsible for development of face during the first 8 weeks of life .
tessier craniofacial clefts may involve entire soft tissue and skeletal elements throughout the course of cleft , resulting in a distorted craniofacial growth pattern and altered potential for normal growth . the number 0 cleft results from failure of the two medial nasal processes to fuse in the midline .
an incomplete median cleft may occur as an isolated entity or as part of syndromes such as oral - facial - digital ( ofd ) syndrome .
the bifid nose is a malformation that falls within a spectrum of tessier number 0 cleft , occurring directly in the midline of the lip and nose .
the columella and nasal tip are typically bifid and broadened , with a midline depression or groove .
the nose appears shortened in the vertical dimension . in our case , it was a mild tessier 's 0 cleft involving nose without orbital hypertelorism .
many different approaches have been advocated for the removal of nasal dermoids , ranging from a simple extracranial excision to complex procedures in which intracranial excision and nasal reconstruction are required .
incision and drainage , aspiration , curettage , and subtotal excision fail to eradicate the cyst , resulting in recurrence .
the cutaneous punctum is removed in continuity with the cyst by making an elliptical incision around the sinus opening .
other approaches ; such as transverse incision , lateral rhinotomy , external rhinoplasty , inverted - u incision , and degloving procedures ; have also been advocated .
failure to diagnose and excise nasal dermoid properly can result in progressive enlargement , skeletal distortion , infection , meningitis , and intracranial abscess .
we advise a complete evaluation and neurosurgical consultation if any clinical or radiographic indication of intracranial involvement is found . from a surgical point of view for managing tessier 's 0 cleft ,
when planning to treat number 0 cleft , the surgeon must assess severity of the cleft . in more severe cases , when the nasal dorsum is affected and duplication of the septum occurs , resection of the excess tissue over the nasal dorsum , and closing in the midline may be performed .
a z - plasty and broken - line scars are performed only if it is necessary to provide significant soft tissue nasal length , avoiding nonanatomic correction .
some authors have surgically managed the patients with resection of dorsal nasal skin , reshaping of cartilaginous structures , and using bicoronal approach in severe cases .
they have proposed performing lateral osteotomies even in children . however , this may have some deleterious effects on nasal growth and it is better to postpone the lateral osteotomy until postadolescent period .
the combined extraoral and intraoral approach enables a clear exposure of all nasal and lateral maxillary structure and especially in relation with the cleft region . for this reason , repair of bifid nose
may be accomplished without previously described skin excision and wide dissections , yielding a better healing . besides lengthening the columella with this incision involving the only nasal sill area , modified forked flap enables exposure of the nose as well . in conclusion ,
tessier 's 0 cleft with presence of midline ndc within the groove of bifid nose is a very rare occurrence .
successful management of the midline ndcs along with tessier 's 0 cleft requires a thorough preoperative evaluation followed by a meticulous excision of dermoid cyst with appropriate planned surgical technique , later for correction of nasal deformity .
Output:
| this is a rare anomaly of midline nasal dermoid cyst ( ndc ) along with tessier 's 0 cleft .
midline ndcs present most commonly result from aberrant embryological development , and most commonly give rise to bifid nasal deformity resulting in midline cleft of the nose .
craniofacial clefts are among the most disfiguring of all facial anomalies .
they exist in a multitude of patterns and with varying degrees of severity .
the bifid nose deformity is generally an indicator of tessier number 0 cleft .
we present a rare combination of midline ndc with a mild tessier 's 0 cleft in a 4-year - old female child who was surgically treated with wide emphasis given on its diagnosis and other treatment modalities . |
PubmedSumm4838 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the domesticated silkworm , bombyx mori , which has been reared by humans for more than 5000 years , is an agriculturally important insect and has economically important values in sericulture .
in addition , the silkworm is a key model of the lepidoptera , a group of holometabolous insects .
bombyx mori nucleopolyhedrovirus ( bmnpv ) is an exclusive pathogen of the silkworm , frequently causing serious economic damage to sericulture production .
the infection cycle of bmnpv is mediated by two phenotypically different viral phenotypes : the occlusion - derived virus and the second virion phenotype , the budded virus .
the genome of bmnpv has been completely sequenced and the pathogenesis of systemic bmnpv infection has been largely investigated .
evidence has shown that npv infection typically results in a global shutoff of insect gene expression , and protein synthesis in host cells begins at about 1218 hours after infection .
had demonstrated that the activation of mitogen - activated protein kinases ( mapk ) signaling pathways was required for efficient infection by bmnpv .
recently , a major emphasis in silkworm research has been given to develop npv resistant varieties by transgenesis .
however , studies on antiviral mechanism in insects are still in their infancy , and the defense mechanisms at an early stage of viral infection need to be investigated .
recently , rna - sequencing ( rna - seq ) , based on deep sequencing technology , is a powerful tool for transcriptome analyses .
rna - seq has revealed novel genes and transcripts , tissue - specific alternative splicing , and genomic structural variations [ 10 , 11 ] . in recent years
, rna - seq has been employed to investigate the molecular mechanisms of numerous physiological events in the silkworm [ 12 , 13 ] .
performed transcriptome analysis of the brain of the silkworm bombyx mori infected with bmnpv and revealed that differentially expressed genes ( degs ) involved in synaptic transmission , circadian rhythms , and the serotonin receptor signaling pathway of bombyx mori were related to the locomotor activity of bombyx mori following bmnpv infection . in the current study ,
the fat bodies from two silkworm strains of bombyx mori , qiufeng and qiufengn , were used for identifying the complexity of the antiviral mechanism in silkworm .
the qiufengn strain is identified to be highly resistant to bmnpv infection in our previous study ( data not shown ) . besides
, rna - seq technology was applied to analyze the transcription profile between the qiufeng strain and qiufengn strain following bmnpv infection .
the purpose of this study was to decipher transcriptomic changes and related genes with potential functions against bmnpv infection and to increase the understanding of the enhanced virus resistance of silkworm on the transcriptomic level .
the silkworm bombyx mori strains , qiufeng and qiufengn ( a disease - resistant variety ) , were maintained in our laboratory and reared using fresh mulberry leaves under laboratory conditions at 27 1c with 7085% relative humidity and a photoperiod of 12 h light/12 h dark .
the fifth instar larvae were harvested after the 4th ecdysis and were used for the experiments .
fifty newly molted silkworm larvae of the 5th instar from each of the strains ( qiufeng and qiufengn ) were deprived of food 2 h before infection . for infection , the silkworms
were orally inoculated with 7 l of bmnpv suspension ( 2 10 polyhedra / ml ) .
the fat bodies of these 2 strains were collected at 48 h after infection , respectively .
specially , the samples from qiufeng and qiufengn in this study were named as t01 and t02 , respectively .
the samples were isolated on ice and placed immediately in liquid nitrogen and frozen at 70c until use .
total rna was extracted from each sample according to the manufacturer 's instructions using trizol ls ( invitrogen , ca , usa ) , as previously described .
the rna was then treated with rnase - free dnase i in order to remove genomic dna contamination .
the purity and quality of the rna were determined by assessing the absorbance ratio od260/280 ( 1.92.0 ) using nanodrop nd-1000 spectrophotometer ( nanodrop , wilmington , de ) . besides , the rna was quantified with a qubit 2.0 fluorometer ( invitrogen corporation , carlsbad , ca , usa ) in accordance with the manufacturer 's instructions .
the integrity of the rna samples was verified using an agilent 2100 bioanalyzer ( agilent , santa clara , ca , usa ) with rna integrity number ( rin ) values over 8.0 .
libraries construction and the rna - seq were carried out by the biomarker biotechnology corporation ( beijing , china ) .
briefly , the poly(a ) mrnas were enriched from total rna with oligo(dt ) magnetic beads and then the enriched mrnas were fragmented by using fragmentation buffer . using these cleaved mrna fragments as templates ,
the second cdna strand was then synthesized with buffer , rnase h , dntps , and dna polymerase i. thereafter , the double - stranded cdna fragments were purified with agencount ampure xp beads ( beckman coulter , brea , ca , usa ) and resolved with elution buffer ( eb ) for end repair and the addition of poly(a ) .
the suitable size of fragments was selected and purified by ampure xp beads ( beckman coulter , brea , ca , usa ) , and then the purified cdna templates were enriched through pcr amplification . after the library was constructed , the agilent 2100 bioanalyzer ( agilent , santa clara , ca , usa ) and the qubit 2.0 fluorometer ( invitrogen corporation , carlsbad , ca , usa ) were used to calculate the molar concentration and confirm the insert size .
the cdna libraries were sequenced on an illumina hiseq 2500 instrument ( illumina inc . , san diego , ca , usa ) that generated paired - end reads of 125-bp .
after removing the adaptor sequences and those reads with unknown nucleotides of more than 5% ( n bases ) or those low - quality reads ( more than 50% of low - quality bases with q - value 5 in a single read ) , the clean reads were obtained after being filtered from the raw reads .
the cleaned rna - seq reads were then mapped to the silkworm genome sequence derived from the silkdb database ( http://silkworm.swu.edu.cn/silkdb/ ) using the software tophat2 .
the transcript levels were quantified using the fragments per kilobase of exon per million fragments mapped ( fpkm ) .
a threshold of fpkm 0.1 was set to ensure that the genes were expressed in these two groups .
based on the alignment results of cleaned rna - seq reads being mapped to the reference sequence using the software tophat2 , samtools software was applied to perform single nucleotide polymorphism ( snp ) calling .
the filtering threshold for high quality snps was set as follows : ( 1 ) the alignment score of tophat2 was no less than 50 ; ( 2 ) the interval of called snps was more than 5 bases ; ( 3 ) the quality score was no less than 2 ; ( 4 ) the sequencing depth was 5x and 100x . furthermore , the snps of the two strains were compared .
the ratio of transition and transversion was calculated via analyzing each type of dna substitution .
the as events contain several typical types , including alternative 5 splice site , alternative 3 splice site , intron retention ( ir ) , exon skipping ( es ) , alternative last exon , alternative first exon , and mutually exclusive exons . in this study
, the cufflinks software was employed to annotate all novel as events that occur in qiufengn and qiufeng strain based on the intron - containing mapped data .
the new genes were identified via discarding the sequences encoding less than 50 amino acids and the sequence containing only one intron .
the assembled unigenes were annotated based on sequence comparability with previously identified genes with descriptions . for assignments of the predicted gene descriptions ,
a blastx alignment ( e value < 1.00e 05 ) was carried out between our assembled unigenes and the protein databases such as ncbi nonredundant protein ( nr ) database ( http://www.ncbi.nlm.nih.gov/ ) , the kyoto encyclopedia of genes and genomes ( kegg ) pathway database ( http://www.genome.jp/kegg/ ) , swiss - prot protein database ( http://web.expasy.org/docs/swiss-prot_guideline.html ) , and the cluster of orthologous groups ( cog ) database ( http://www.ncbi.nlm.nih.gov/cog/ ) .
the best aligning results that had the highest sequence similarity with our unigenes were used to decide the sequence direction of unigenes and determine their functional annotations .
differential gene expression analysis was carried out to compare the qiufengn and qiufeng libraries using ebseq which is developed with empirical bayesian approach in rna - seq data comparing two or more biological conditions .
the false discovery rate ( fdr ) was applied to determine the p value thresholds via benjamini - hochberg method .
the fold change for each transcript between these 2 samples was calculated as the ratio of the fpkm values . in this study , the criteria of a fold change ( fc ) 2 and a fdr
heat maps of the significant genes were generated with the heatmap.2 package in r. besides , a blastx alignment ( e value < 1.00e 05 ) was performed between the identified degs and the protein databases like nr database ( http://www.ncbi.nlm.nih.gov/ ) , kegg pathway database ( http://www.genome.jp/kegg/ ) , swiss - prot protein database ( http://web.expasy.org/docs/swiss-prot_guideline.html ) , and the cog database ( http://www.ncbi.nlm.nih.gov/cog/ ) .
moreover , go and kegg pathway enrichment analyses for these degs were conducted using hypergeometric tests with the assembled reference transcriptome set as the background . for the enrichment analyses ,
a p value of < 0.05 was chosen as the threshold to determine the significant enrichment . besides
, the tool of topgo was applied to improve the specificity and discovery sensitivity by considering the interrelationships of the identified go terms .
additionally , the sequences of degs were subjected to the cog database ( http://www.ncbi.nlm.nih.gov/cog/ ) and the corresponding cog annotation results were extracted .
to understand and monitor the changes in gene expression in silkworm disease - resistant strain ( qiufengn ) , fat bodies from bmnpv - infected qiufengn and bmnpv - infected qiufeng were used to build 2 libraries for transcriptome sequencing . after filtering , a total of 14.78 gb clean data ( more than 7.15 gb for t01 and t02 , resp . )
the quality score ( q - score ) of > 30 ( q30 ) and guanine - cytosine ( gc ) percentages of the two groups were 88.00% and 45.41% and 88.81% and 46.41% , respectively ( table 1 ) .
besides , the ratios of the unique mapped reads that accounted for the mapped reads in these two groups ( t01 and t02 ) were 68.53% and 76.29% , respectively .
in addition , the results showed that the present sequencing data were completely saturated and were adequate for the follow - up analysis ( figure 1(a ) ) .
snps were discovered by mapping filtered reads to the reference sequences for further application of the rna - seq data . as summarized in table 2 ,
a total of 78,408 snps were identified in the qiufeng strain of silkworm after quality control and filtration , including 44,121 genic snps and 34,287 intergenic snps . on the other hand ,
a total of 56,786 snps were identified in qiufengn strain , consisting of 34,858 genic snps and 21,928 intergenic snps .
the proportions of transition substitutions were 63.22% compared with a smaller proportion ( 36.78% ) of transversion with regard to the qiufeng strain . while the proportion of transition substitutions was 64.46% , the proportion of transversion substitutions was 35.54% in the qiufengn strain
furthermore , 15.28% snps were heterozygous in the qiufeng strain and 23.56% were heterozygous in the qiufengn strain .
the mean number of snps per kilobase in the orf region for the two strains was shown in figure 1(b ) . to identify the differences in novel as events ratios between the qiufengn and qiufeng strains ,
the cufflinks software was applied to calculate the changes in the relative splice abundances . in all
, we found that a total of 7,874 novel simple as events that fell into six different categories were identified in qiufengn strain , including 3,107 es events , 481 ir events , 625 alternative 5 splice site events , 749 alternative 3 splice site events , 860 alternative last exon events , and 2,052 alternative first exon events . on the other hand ,
total 5937 novel as events that fell into these six different categories were identified in qiufeng strain , including 2,257 es events , 313 ir events , 504 alternative 5 splice site events , 602 alternative 3 splice site events , 705 alternative last exon events , and 1,556 alternative first exon events .
we found that , in these two strains , the use of alternative 5 splice sites is a little more frequent than the use of alternative 3 splice sites .
in addition , our mapped data showed that es and alternative first exon were common events compared with other as events in these two strains .
sequence similarity search was carried out based on blastx ( cut - off e value 10 ) searches against 5 public databases : nr database , go database , kegg database , swiss - prot protein database , and cog database .
the results indicated that , out of 1200 unique sequences , 1053 could be annotated with known proteins in nr database as reference .
the unigenes obtaining gene descriptions from kegg database were 255 . in all , 1053 of the assembled unigene sequences showed homology to available known sequences , while unigenes without hits ( 147 , 12.20% ) might represent new genes or errors in the assembly procedure .
the difference in levels of degs between qiufengn and qiufeng strains was calculated according to rpkm value of the obtained unigenes . under the criteria of fc
2 and fdr < 0.01 , a total of 1,728 degs were identified in qiufengn sample compared with qiufeng sample , of which 242 genes were upregulated and 1,540 were downregulated .
the heat map and ma plot of degs were shown in figures 2(a ) and 2(b ) .
these results demonstrated the overall difference in transcriptional expression level of degs between qiufengn and qiufeng strains .
in addition , a total of 1,706 degs could be annotated based on searches against 5 public databases : nr , go , kegg , swiss - prot protein database , and cog database .
thereinto , 458 , 903 , 366 , 1,006 , and 1,706 degs could be annotated with known proteins in cog , go , kegg , swiss - prot , and nr database as reference , respectively .
the degs were assigned to different go categories in terms of cellular component ( cc ) , molecular function ( mf ) , and biological process ( bp ) to determine their functional classifications ( figure 3 ) .
go functional annotation of the 1,728 degs indicated that 724 degs were enriched in mf ontology , 590 degs were enriched in cc ontology , and 734 degs were enriched in bp ontology . in general , 19 , 18 , and 20 catalogs of cc , mf , and
the majority of the identified degs were assigned to the cell , organelle , and membrane in the cc category .
besides , the results showed that the degs were significantly concerned with binding and catalytic activity in the mf category .
additionally , we found that , in the category of bp , the majority of the degs were significantly involved in single - organism process , cellular process , and metabolic process .
in addition , the results of topgo tool analysis showed that the degs were significantly related with structural constituent of pupal chitin - based cuticle , disaccharide transport , and membrane ( table 3 ) . on the other hand
, the results of kegg enrichment analysis indicated that a total of 201 annotated degs were assigned into 97 pathways .
as shown in figure 4(a ) , the pathways were mainly classified into 5 categories , namely , metabolism , genetic information processing , cellular processes , environmental information processing , and organismal systems . besides , we found that the most representative pathway related to metabolism was oxidative phosphorylation ( figure 4(a ) ) .
on the other hand , figure 4(b ) showed that the oxidative phosphorylation , phagosome , citrate cycle ( tca cycle ) , arginine and proline metabolism , and pyruvate metabolism pathways were most significantly enriched . to further analyze the completeness of the transcriptome library and evaluate the effectiveness of annotations , cog analysis of the degs
was carried out , which could provide more information about the potential functions of genes .
the results indicated that the degs were classified into 25 functional categories ( figure 5 ) . among those categories ,
the cluster of general function prediction only was the largest group , followed by amino acid transport and metabolism and carbohydrate transport and metabolism .
the resistance mechanisms of bombyx mori against bmnpv remain obscure . in the present study ,
rna - seq technology was applied to profile the transcriptome of qiufengn as well as qiufeng strains and approximately 14.78 gb clean data ( more than 7.15 gb for qiufengn and qiufeng , resp . )
a total of 78,408 snps were identified in the qiufeng strain of silkworm and 56,786 snps were identified in qiufengn strain . besides , novel as events were found in these 2 strains .
in addition , 1,728 degs ( 242 upregulated and 1,540 downregulated ) were identified in the qiufengn strain compared with the samples of qiufeng strain .
analyses of go categories revealed that these degs were mainly involved in go terms related to membrane , metabolism , binding and catalytic activity , cellular processes , and organismal systems , such as oxidative phosphorylation and tca cycle .
pathway analysis with kegg annotation showed that the highest levels of gene representation were found in oxidative phosphorylation , phagosome , tca cycle , arginine and proline metabolism , and pyruvate metabolism .
additionally , cog analysis indicated that degs were associated with amino acid transport and metabolism and signal transduction mechanisms . in this study , we identified a total of 78,408 snps in the qiufeng strain of silkworm after quality control and filtration , including 44,121 genic snps and 34,287 intergenic snps .
by contrast , 56,786 snps were identified in qiufengn strain , consisting of 34,858 genic snps and 21,928 intergenic snps .
these results indicated that the complex regulatory machinery was involved in bombyx mori following bmnpv infection . on the other hand ,
1,728 degs were identified in the qiufengn strain ( resistant to infection ) compared with the samples of qiufeng strain ( susceptible to infection ) , indicating that a relatively large number of genes were involved in antiviral mechanisms in silkworm .
small quantities of ros are spontaneously formed as byproducts of redox processes under normal conditions such as oxidative phosphorylation in the mitochondria .
the findings of gaikwad et al . demonstrated that oxidative stress was increased due to d - galactose in d - galactose treated larvae of silkworm . besides
, evidence has shown that cellular organelles which are surrounded with lipid membranes could be damaged due to lipid peroxidation , a result of oxidative stress . in this study , we found that degs identified between qiufeng strain and qiufengn strain were concerned with various go terms and pathways such as organelle and membrane , and oxidative phosphorylation , which indicated that oxidative stress might be related to the defensive function of silkworm following bmnpv infection . on the other hand ,
multiple metabolism - related functions were enriched by degs identified in this study , including pyruvate metabolism , tca cycle , and arginine and proline metabolism .
xu et al . revealed that many metabolic activities of the midgut like carbohydrate metabolism , the tca cycle , and oxidative phosphorylation were probably affected during the wandering stage of bombyx mori silkworm . in line with the previous study , we suggested that many metabolic activities such as oxidative phosphorylation were affected and had biological relevance for the antiviral mechanisms of silkworm .
moreover , degs were identified to be related with the environmental information processing , such as phosphatidylinositol signaling pathway .
degs related to this pathway were as follows : bgibmga002122 ; bgibmga003299 ; bgibmga007232 ; bgibmga012694 ; bgibmga012695 .
ample evidence has shown that phosphatidylinositol signaling pathway is significantly related to immune response [ 28 , 29 ] . in addition , several immune - responsive genes such as serpin-5 were probably involved in the host 's antiviral mechanisms of bombyx mori following infection . in this study ,
cog analysis also revealed degs related signal transduction mechanisms . collectively , understanding the physiological functions of these degs involved in signaling pathway will require further characterization in order to determine their roles in immunity or other processes .
we identified that a rather larger number of degs were involved in some functional categories , indicating a series of major pathological changes in the silkworm following infection and several functions were related to the antiviral mechanisms of silkworm .
oxidative stress might be related to the defensive function of silkworm following bmnpv infection . in addition , many metabolic activities such as oxidative phosphorylation were affected and had biological relevance for the antiviral mechanisms of silkworm . moreover , understanding the physiological functions of these degs involved in signaling pathway will require further characterization in order to determine their roles in immunity or other processes .
these findings provide new research directions that may deepen our understanding of virus resistance of silkworm on the molecular level . because there are some false positive rates in rna - seq data , further experimental verifications like real - time pcr are needed .
Output:
| purpose . to decipher transcriptomic changes and related genes with potential functions against bombyx mori nucleopolyhedrovirus infection and to increase the understanding of the enhanced virus resistance of silkworm on the transcriptomic level . methods .
we assembled and annotated transcriptomes of the qiufeng ( susceptible to infection ) and qiufengn ( resistant to infection ) strains and performed comparative analysis in order to decipher transcriptomic changes and related genes with potential functions against bmnpv infection .
results . a total of 78,408 snps were identified in the qiufeng strain of silkworm and 56,786 snps were identified in qiufengn strain . besides , novel as events were found in these 2 strains .
in addition , 1,728 degs were identified in the qiufengn strain compared with qiufeng strain .
these degs were involved in go terms related to membrane , metabolism , binding and catalytic activity , cellular processes , and organismal systems .
the highest levels of gene representation were found in oxidative phosphorylation , phagosome , tca cycle , arginine and proline metabolism , and pyruvate metabolism .
additionally , cog analysis indicated that degs were involved in amino acid transport and metabolism and carbohydrate transport and metabolism . conclusion .
we identified a series of major pathological changes in silkworm following infection and several functions were related to the antiviral mechanisms of silkworm . |
PubmedSumm4839 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: esthetic considerations and dental appearance have become very important for children and adolescents , who are therefore strongly motivated to seek orthodontic treatment.1 the number of children and adolescents seeking orthodontic treatment has dramatically increased over the past few decades ; however , not all of these patients have true orthodontic problems.2 the patient s perception , parents perceptions , and orthodontist s assessment all influence the need for orthodontic treatment in children and adolescents .
several studies have shown that there is no link between actual need for treatment as assessed by orthodontists and perceptive need as evaluated by patients or their parents , unless the condition is symptomatic.36 with the increased demand for orthodontic treatment , free health services need a quantifiable method of assigning resources.7 accordingly , several orthodontic treatment need indices have been developed to help to estimate treatment need and improve consistency in treatment provision,7 such as the index of orthodontic treatment need ( iotn);8 the dental aesthetic index;9 the index of complexity , outcome and need;10 and the peer assessment rating index.11 these scale - based indices are used to evaluate the severity of malocclusion and orthodontic treatment need . however
, each method has its limitations : most treatment need indices do not assess the prognosis of untreated malocclusions and related symptoms , and these indices may need revalidation overtime.7,12 the iotn , introduced by brook and shaw in 1989 , consists of two components , the aesthetic component and the dental health component ( dhc).8 the iotn has been comprehensively compared with other treatment need indices and has been found to be accurate , valid , and reproducible , with high sensitivity and specificity.1315 past studies have used various indices to investigate orthodontic treatment need in different populations .
the iotn is most frequently used , especially among researchers in the middle and far east .
based on the dhc of the iotn , a lower percentage of treatment need has been reported among children in egypt ( 19.8%),16 india ( 21%),17 saudi arabia ( 22.4%),18 kuwait ( 28%),19 and jordan ( 28%)20 than among iranian ( 36.1%),21 turkish ( 38.8%),22 pakistani ( 40%),23 malaysian ( 47.9%),24 and chinese ( 52%)25 populations .
orthodontic treatment is expensive , with many factors influencing its cost , such as case difficulty , length of treatment , insurance coverage , and clinic location , among others.26 in saudi arabia , governmental institutions , including the ministry of health , military hospitals , and academic institutions , provide free orthodontic treatment to the public .
this free service potentially allows patients with little treatment need to be treated , displacing others with greater need .
consequently , this system can generate waiting lists extending for many years , even for patients with severe malocclusion and mandatory treatment need .
it has been shown that severe malocclusion affects the quality of life of saudi children.27,28 at the same time , providing free orthodontic treatment can result in a heavy work load for public health care providers.4 in 2006 , hassan4 examined orthodontic treatment need according to the dhc of the iotn among adults who were referred for orthodontic treatment at king abdulaziz university ( kau ) in jeddah , saudi arabia , and compared that need with that of patients at private dental clinics.4 he found that the proportion of patients with little to no treatment need was significantly higher at kau clinics than at private clinics .
in contrast , the proportion of patients with great treatment need was significantly higher at private clinics than at kau clinics.4 in countries with publicly funded orthodontic services , orthodontic treatment priority is determined by the severity of malocclusion and the need for treatment . since its development in 1990 , the iotn has been used by the national health service in the uk to limit access to orthodontic care ; since 2006 , the iotn has defined which patients will receive national health service treatment in primary care.29 in finland , publicly funded dental treatment , including orthodontic treatment , has been provided to residents up to 18 years of age .
the finnish national board of health recommends the ten - grade treatment priority index to select patients for orthodontic treatment.30,31 in saudi arabia , there are no national regulations guiding the extent of public orthodontic care , and no rationing of access to care according to the severity of malocclusion has been implemented .
providing free , high - quality orthodontic services in saudi arabia , such as the services provided at the college of dentistry at king saud university ( ksu ) , as well as estimating the resources and workforce necessary to provide these services , requires careful evaluation of the true need for orthodontic treatment in this country .
therefore , the objective of this retrospective study was to use the dhc of the iotn to assess and compare the severity of malocclusion and orthodontic treatment need among young saudis receiving free treatment at public orthodontic clinics versus those paying for treatment at private dental clinics .
at an alpha of 0.05 with a maximum difference of 0.4 , and with an estimated standard deviation of one with a power of 0.85 , the necessary sample size was estimated to be at least 114 study subjects in each group . after study approval was obtained from the ethical committee of the college of dentistry research center at ksu , the preorthodontic records ( orthodontic files , pretreatment study models , and panoramic radiographs ) of 300 orthodontically treated patients aged 1321 years were studied .
patient consent was not required by the ethical committee of the college of dentistry research centre at ksu as patient data were kept unidentified .
one hundred sixty - five orthodontic records were collected from the orthodontic department at the college of dentistry at ksu , the oldest and largest public university in riyadh .
ksu houses a large orthodontic department in the college of dentistry with more than 20 orthodontists .
one hundred thirty - five orthodontic records were collected from five randomly selected private orthodontic clinics in different administrative areas in riyadh .
lists of orthodontically treated patients from 2013 through 2015 were obtained and patients who fulfilled the inclusion criteria were selected .
the following inclusion criteria were used : saudi patients aged 1321 years with preorthodontic records , patients currently under orthodontic treatment by orthodontists , patients with orthodontic records of good quality , patients treated with fixed appliances , and those with no history of previous orthodontic treatment .
the study models were examined to determine the severity of malocclusion and orthodontic treatment need based on the dhc of the iotn.8 the dhc is classified into five grades ranging from grade 1 ( no treatment need ) to grade 5 ( extreme treatment need ) .
two examiners were trained and calibrated by an expert orthodontist to use the dhc of the iotn at the college of dentistry , ksu .
data from study models were collected using the acronym mocdo ( missing teeth , overjet , crossbite , displacement of contact points , overbite ) to identify the most severe occlusal trait of each patient .
panoramic radiographs were examined to confirm the presence of hypodontia , supernumerary teeth , and impactions .
the data were analyzed with statistical package for social sciences 20 software ( ibm corporation , armonk , ny , usa ) .
the incidence of each occlusal trait and the dhc of the iotn grade were calculated . the final overall score for iotn category from grade 1 to grade 5
treatment need was categorized as no or little need ( grades 1 and 2 ) , borderline need ( grade 3 ) , or treatment required ( grades 4 and 5 ) .
the sample was divided into two age groups ( 16 years and > 16 years ) .
we compared the severity of malocclusion and orthodontic treatment need at the two types of dental practice and between age groups and sexes using the chi - square test .
p - values < 0.05 were considered significant . a kappa test was used to confirm intra- and interexaminer reliability .
kappa testing also showed good inter - examiner reliability , with a value of 0.84 .
approximately 58% of the sample was 16 years of age ( mean , 15.92.7 years ) .
the sample included 179 study models from female patients ( 59.7% ) and 121 from male patients ( 40.3% ) .
there were no significant differences in the distribution of age or sex between the practices ( p>0.05 ) .
the most common orthodontic problem was displacement ( 96% ) , followed by increased overjet ( 64.7% ) , class ii or iii molar relationship ( 64% ) , crossbite ( 36% ) , overbite ( 36% ) , and open bite ( 31% ) .
approximately 12.3% of the sample had congenitally missing teeth and 13.7% had retained deciduous teeth ; however , impaction was relatively uncommon ( 8.3% ) .
the incidence of cleft lip and palate was 3.3% . the distribution and severity of orthodontic problems among patients attending each type of practice
approximately 77% of patients treated at ksu clinics had class ii or iii malocclusion , compared with 48% of patients at private clinics ; this difference was statistically significant ( p<0.0001 ) .
a significant difference was also found in the severity of tooth displacement among treated patients between the practice types ( p<0.0001 ) .
approximately 61% of patients treated at private clinics had slight tooth displacement , compared with 23.3% of patients treated at ksu clinics .
in addition , significantly more patients with eruption - associated problems , such as hypodontia , retained deciduous teeth , impactions , and cleft lip and palate , were treated at ksu clinics than at private clinics ( p<0.0001 ) .
similarly , a significantly higher percentage of patients treated at ksu clinics had severe open bite ( 21.7% ) , compared with only 6.1% of patients treated at private clinics ( p=0.002 ) .
in contrast , there were no differences between practices in the percentages of patients with increased overjet , crossbite , or over bite , regardless of severity ( p>0.05 ) .
the distribution of orthodontic problems according to orthodontic treatment need is shown in table 3 .
most of the orthodontic problems were recorded in patients with great need of orthodontic treatment ; however , open bite , increased overjet , and increased overbite were most commonly observed . among the patients ,
13% had no or slight treatment need , 18.3% had moderate to borderline need , and 68.7% had great treatment need .
comparison of dhc grades between the ksu group and the private group revealed a significant difference in treatment need ( p=0.003 ) ( figure 1 ) .
seventy - seven percent of patients treated at ksu clinics were in great need of orthodontic treatment , compared with 58.5% of patients treated at private clinics .
the percentage of patients with little to no treatment need ( 17% ) or borderline treatment need ( 24.4% ) was higher in the private group than in the ksu group ( 9.7% and 13.3% , respectively ) ( figure 1 ) . in the current study
, there was a significant difference in treatment need among male patients treated at ksu versus those treated at private clinics ( p<0.0001 ) ( figure 2 ) .
most male patients with no , little , or borderline treatment need were treated at private dental clinics , while male patients with great treatment need were treated at ksu clinics .
similarly , most younger patients with no , little , or borderline treatment need were treated at private dental clinics , whereas young patients with great treatment need were treated at ksu dental clinics ( p<0.0001 ) ( figure 3 ) .
demand for orthodontic treatment is expanding as awareness has increased in the growing population of saudi arabia.32 however , several studies have indicated that patients overestimate their own treatment needs compared with the evaluation of orthodontists.3,4 the clinical skills of orthodontists allow much more accurate and comprehensive assessment of a patient s presenting condition than the patient s self - assessment.33 in the current study , the need for orthodontic treatment was evaluated based on orthodontic assessment , with the assumption that all patients perceived themselves as needing orthodontic treatment .
the iotn was used in this study because it is valid , quick , reproducible , and easy to use .
however , the iotn is mainly designed for permanent teeth and its application in patients with mixed dentition may require modification.34 the iotn is an excellent tool when used by experts in orthodontic research ; however , a long training period is required before an examiner can use the index reliably .
the modified iotn appears to overcome the training and reliability problems that often accompany the use of orthodontic indices by nonspecialists in oral health surveys.35 although widely used to grade several common occlusal traits , the iotn has some limitations .
for example , it does not assess the skeletal components of malocclusion and does not account for facial features , deformity , or soft - tissue conditions.36 in addition , there is no correlation between the iotn grade of a presenting malocclusion and functional or quality - of - life improvement after treatment , and some of the functional indications for orthognathic treatment are not included.37 the index of orthognathic functional treatment need was developed to overcome some of these limitations.37,38 approximately 60% of patients in the present study were females . in general , female patients seek orthodontic treatment more than male patients , a difference that reflects the greater concern about facial and dental appearance among females.39 in addition , this sex difference might be attributed to the earlier growth and development , and also greater self - consciousness of females compared with males.2 more than half of the patients were younger than 16 years of age , which may indicate that younger adolescents are more concerned about their appearance,39 or might be related to greater parental influence on their younger children , whereas older children might decide for themselves whether to pursue treatment .
similar occlusal discrepancies were reported in a previous study of patients referred for orthodontic treatment at kau.4 in a study of referred pakistani patients , overjet , followed by crowding , were the most common occlusal traits associated with increased severity of malocclusion.40 the main occlusal traits found in patients who had a great need for orthodontic treatment were open bite , increased overjet , and overbite .
comparable findings were reported among brazilian patients with great need for orthodontic treatment.41 further , it was reported that the most common occlusal traits among saudi children requiring orthodontic treatment were tooth displacement , increased overjet , and deep bite.28 malocclusions characterized by open bite , severe overjet , and overbite can interfere with social relationships ; facial appearance is considered the main reason for seeking orthodontic treatment.1 we found that orthodontic patients treated at ksu clinics had more severe malocclusions , such as severe displacement , class ii and iii molar relationship , open bite , and problems associated with eruption , than the patients treated at private clinics .
this difference could be related to different selection criteria for orthodontic treatment , or to the presence of different dental specialties at the dental college , which results in referral of difficult cases to its orthodontic clinics , whereas private patients usually refer themselves for treatment . in addition , this difference could be attributed to people s trust and confidence in the orthodontic treatment provided at ksu by qualified and skillful orthodontists accustomed to dealing with difficult situations .
furthermore , as ksu is a large teaching institution , it applies new treatment strategies based on recent research , making it an attractive choice for people with severe malocclusion seeking orthodontic treatment .
regardless of the severity of overbite , crossbite , or overjet , orthodontic patients with these malocclusions were treated in similar percentages at both practice types , because such problems are recognized by patients or their parents , who seek orthodontic treatment in any clinical setting .
in addition , occlusal conditions such as increased overjet , tooth displacement , and increased overbite have a higher psychosocial impact than other conditions.42 in our study , almost 70% of orthodontic patients had great treatment need .
a comparable 71.6% of patients were reported to need orthodontic treatment in a previous study of patients referred to kau.4 a higher percentage ( 83.2% ) of great treatment need was reported among referred turkish children.22 however , a lower percentage ( 52.5% ) was reported among saudi children who were about to undergo orthodontic treatment.28 in addition , 47.1% of referred pakistani patients were clinically assessed as needing orthodontic treatment.40 these differences in orthodontic treatment need among orthodontically referred and treated individuals might be attributed to variability in the perceptions of patients or referring dentists , who may assess malocclusion with different prioritization of esthetic factors versus quantifiable treatment need . although the majority of patients in the present study required treatment , a difference in patients distribution between ksu and private clinics was found .
approximately 77% of orthodontic patients treated at ksu clinics had great treatment need , compared with 58.5% at private clinics .
this difference mainly results from differences in the severity of malocclusion in the sample population .
patients with great treatment need often require a multidisciplinary approach with various hospital services that can only be provided at large institutions such as ksu .
approximately 42% of orthodontic patients treated at private clinics had no , little , or borderline treatment need , compared with 23% of patients at ksu clinics .
the desire of patients or their parents to receive treatment leads them to pay for treatment of conditions that have little treatment need .
these results contradict those of hassan , who found in 2006 that the proportion of patients with little to no treatment need was significantly higher at kau clinics than at private clinics , whereas the proportion of patients with great treatment need was significantly higher at private clinics than at kau clinics.4 hassan s study included patients referred for orthodontic treatment , whereas our study included orthodontically treated patients .
the majority of male patients with no , little , or borderline treatment need were treated at private clinics , whereas male patients with great need were treated at ksu clinics .
this difference might be related to the fact that most male patients with little need were not accepted for treatment at ksu clinics and instead sought treatment at private clinics .
similarly , the majority of younger patients with no , little , or borderline treatment need were treated at private clinics , whereas younger patients with great need were treated at ksu clinics .
younger patients might convince their parents to seek and pay for orthodontic treatment at private clinics , even when there is little need for treatment .
although most adolescents treated at ksu clinics were in great need of treatment , a considerable proportion ( 23% ) with no , little , or borderline treatment need were also treated .
the free treatment provided at ksu clinics allows anyone to seek treatment , regardless of the severity of malocclusion .
the treatment of patients with little treatment need might be related to sociopsychological patient needs .
patient perception concerning orthodontic treatment should not be ignored , and orthodontists should focus their attention beyond orthodontic mechanotherapy to the more subjective aspects of a patient s discomfort and attitude toward treatment.43 while the orthodontist prioritizes function and occlusion , the patient might perceive other factors to be equally important in initiating treatment.44 although public clinics are tasked with providing care both to patients with true orthodontic treatment need and to those with needs that are more sociopsychological than functional , the long waiting lists for orthodontic treatment at ksu clinics indicate that the resources for orthodontic treatment are insufficient to accommodate the demand for services . therefore , patient selection is necessary to ensure that treatment is provided to patients who need it the most , with consideration of the patient s self - perceived need .
national rules and regulations guiding the provision of public orthodontic services should be imposed and implemented based on evaluations such as occlusal indices .
orthodontic need assessment is not only important for treatment priority screening , but also useful for clinical intervention , dental - based programs , resource planning , and third - party funding.2 experience with the use of such indices in other countries suggests that they play a valuable role in resource distribution and preparation , and result in more consistency in patient recognition and treatment referral.45 accordingly , we recommend the use of the dhc of the iotn as a screening tool to evaluate the waiting lists of patients seeking orthodontic treatment at ksu clinics .
our study had some limitations , including missing data for some suitable patients and restricted access to the private clinics and patients records , which limited the sample size .
in addition , because this study was based on a limited sample and was collected from a single public academic institution , the results can not be generalized to all orthodontically treated patients receiving care at public clinics .
young saudi patients receiving free treatment at public orthodontic clinics at ksu had more severe malocclusion and greater need of orthodontic treatment than the patients paying for treatment at private orthodontic clinics .
Output:
| objectiveto assess and compare the severity of malocclusion and orthodontic treatment need among young saudis receiving free treatment at public dental practices versus those paying for treatment at private practices.materials and methodsthis retrospective study evaluated the records of 300 patients ( 179 females , 121 males ; age 1321 years ) treated at orthodontic clinics from 2013 through 2015 .
the public sample was selected from orthodontic clinics at the college of dentistry , king saud university ( ksu ) ; the private sample was selected from five private orthodontic clinics in riyadh , saudi arabia .
the records were examined for the severity of malocclusion and for orthodontic treatment need using the dental health component of the index of orthodontic treatment need .
the prevalence of each occlusal discrepancy and the dental health component grade were recorded .
the severity of malocclusion and orthodontic treatment need were compared between practice types , age groups , and sexes with the chi - square test.resultsdisplacement , increased overjet , and class ii and iii malocclusion were the most common orthodontic problems in this study .
patients attending public clinics at ksu generally had more severe malocclusion than the patients attending private clinics .
seventy - seven percent of orthodontically treated patients at ksu clinics were in great need of treatment , compared with 58.5% of patients treated at private clinics ( p=0.003 ) . among the patients with great treatment
need , approximately 62% of male patients and 70% of patients 16 years of age were treated at ksu clinics , compared with 38% and 48% , respectively , treated at private clinics ( p<0.0001).conclusionyoung saudis receiving free orthodontic treatment at public clinics at ksu had more severe malocclusion with greater need of orthodontic treatment than the patients paying for treatment at private clinics . |
PubmedSumm4840 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: cerebral white matter injury ( wmi ) is recognized as the most common form of injury to the developing brain of neonates , especially survivors of preterm birth1 ) .
although multiple factors are involved in brain injury , both infection and inflammation are well - established risks factors for wmi in the preterm population234 ) .
the major period of vulnerability for wmi occurs prior to the onset of myelination ( 2332 gestational weeks)5 ) .
preterm neonates are at high risk of severe and/or multiple bacterial infections between birth and hospital discharge6 ) . for these reasons ,
several studies have sought to demonstrate a relationship between infection / inflammation and wmi in preterm neonates as well as to elucidate the underlying mechanisms47 ) .
however , infection / inflammation - associated brain injury does not occur exclusively in preterm neonates but is also seen in term neonates .
the risk of cerebral palsy is increased by 2 to 12 fold in term neonates with antenatal choriomanionitis8910 ) . nevertheless , the principal anatomic substrate of infection / inflammation - associated cerebral injury in term neonates is not known . in this regard , recent reports of neonatal seizures associated with rotavirus infection in term neonates suggest several new and surprising perspectives111213 ) .
first , infection / inflammation might induce wmi in term - neonates as well as preterm neonates .
second , wmi might be caused not only by bacterial but also by viral infections .
third , the developing brain can be damaged by afebrile infections outside the central nervous system ( cns ) . although further studies are needed to establish the relationship between rotavirus infection and wmi in term neonates , these recent reports111213 ) underscore the need for a paradigm shift recognizing the following : ( 1 ) that common viral infections can induce wmi in term neonates without direct viral invasion , and ( 2 ) that rotavirus is a common cause of neonatal seizures in term neonates . in this paper
we then discuss the clinical characteristics and prognosis of term neonates with rotavirus - associated wmi and compare both with the features of 2 other viral infections , parechovirus and enterovirus .
finally , we suggest further directions of research into rotavirus - associated wmi in the developing brain .
rotavirus is the most common cause of gastroenteritis - associated seizures in infants and young children14 ) .
although neonates are vulnerable to seizures as well as rotavirus infection , the connection between the two in this age group has been overlooked for many years .
only a few studies have examined the association between rotavirus infection and neurological symptoms in newborns15161718 ) .
rotavirus infection has been suggested as possible cause of ' fifth day fits ' in 1990s by herrmann et al.15 ) .
they15 ) observed an epidemic occurrence of 21 cases of ' fifth day fits ' . after a coincidental detection of rotavirus in the stools of several cases of fifth day fits , they tested the stools of 19 fifth - day fitters and 30 matched controls15 ) .
rotavirus was detected in 18 of the 19 neonates ( 95% ) with ' fifth day fits ' compared with only 12 of the 30 matched controls ( 40% ) ( p<0.01)15 ) . before proceeding with the main topic of this review ,
rotavirus - associated wmi in newborns , we first need to consider the entity of ' fifth day fits ' .
the term was introduced in the 1980s to describe an epidemic of neonatal seizures that occurred during the 1970s1920 ) . '
fifth day fits ' are defined as the onset of seizures between the fourth and sixth days of life in otherwise apparently healthy full - term infants20 ) .
the newborns are neurologically normal at the onset of the convulsion but become drowsy and hypotonic for several days thereafter19 ) .
although the long - term prognosis was not defined in the original reports , these patients were assessed as normal at the time of their discharge from the hospital21 ) .
acute zinc deficiency and feeding type were suggested as causes of fifth day fits , but neither was convincingly confirmed2223 ) .
environmental factors were also proposed as the etiology because the prevalence of this syndrome was periodically variable .
in newborns , they became an important issue following an outbreak in a neonatal care unit in mid-1970s242526 ) .
the contemporary , epidemic - like occurrence of ' fifth day fits ' and rotavirus infection in newborns lent support to the suggestion of herrmann et al.15 ) however , the association between rotavirus and ' fifth day fits ' has not been replicated . around the same time with herrmann et al.15 ) , an association between rotavirus infection and bradycardia - apnea episodes has been reported.16 ) the incidence of bradycardia - apnea episodes was higher in neonates with than without rotavirus infection ( 33% vs. 8% , p<0.05)16 ) .
bradycardia - apnea episodes were significantly more common in term than in preterm newborns16 ) .
however , unfortunately , they16 ) did not report when symptom onset occurred nor did they address the numerous central and peripheral causes that may induce apnea in newborns .
a few years later , a study in south africa17 ) yielded results that conflicted with the previous 2 studies1516 ) . retrospective and prospective analyses found no association between rotavirus infection and the neurological symptoms of newborns17 ) .
however , the demographic characteristics of the patients were unclear , and significant selection bias was suspected17 ) .
however , recent studies11121318 ) that included neuroimaging again suggested rotavirus as a cause of neonatal seizures or wmi .
recent studies11121318 ) of wmi in neonatal seizures and the potential involvement of rotavirus infection are summarized in table 1 .
verboon - maciolek et al.18 ) firstly suggested rotavirus as a cause of cerebral injury in newborns based on the cranial ultrasonography and magnetic resonance imaging ( mri ) findings of five preterm and three term infants who developed seizures or apnea during rotavirus infection .
clinical signs during the first week of life were noted in 2 of the 3 full - term infants18 ) . in preterm infants ,
the symptoms became evident during the late preterm period ( 3436 weeks of postgestation)18 ) .
cranial ultrasonography demonstrated mild to severe periventricular echogenicity coinciding with illness related to rotavirus infection and subsequent cystic evolution in 6 patients18 ) . among these 6 patients ,
diffuse high signal intensity attributable to a cystic lesion in the white matter was seen on mri in four preterm newborns18 ) .
the other 2 term infants showed focal diffusion - weighted mri changes at disease onset and focal white matter cysts on repeat mri18 ) .
systemic infection was proven in only 2 patients based on a positive polymerase chain reaction test of the cerebrospinal fluid ( csf ) and/or blood18 ) .
neuroimaging was normal in preterm newborns in weekly cranial ultrasonography before rotavirus infection , and no other causes for seizures / wmi ( including human parechovirus , enterovirus , and herpes simplex virus ) were detected18 ) .
the researchers18 ) therefore suggested an association between rotavirus enteritis and wmi indistinguishable from that in late onset cystic - periventricular leukomalacia ( pvl ) .
the most impressive finding of verboon - maciolek et al.18 ) was that rotavirus apparently induces diffuse wmi with cystic evolution in the developing brain without direct invasion of the cns .
the adverse neurological sequelae of cystic pvl highlight the need for additional studies to confirm their findings .
three recent reports from korea111213 ) lend support to the role of rotavirus infection in wmi .
the main findings of these three studies111213 ) were similar and can be summarized as follows : ( 1 ) neonates presenting with seizures characterized by a distinctive diffusion - weighted imaging ( dwi ) pattern had a high positive rate of rotavirus infection .
( 2 ) patients with this dwi pattern were apparently healthy term infants who presented with similar clinical features and suffered seizures between days 4 and 6 of life .
( 4 ) rotavirus was detected only in stool specimens , not in blood and csf specimens .
( 5 ) the presence of other viral pathogens , especially human parechovirus and enterovirus , was not proven .
( 7 ) cystic evolution and neurological sequelae were observed in some of the patients .
the pattern of wmi was evident on dwi , which showed extensive and symmetrical restricted diffusion in the periventricular white matter and along entire fiber tracts , including the corpus callosum ( fig .
this pattern was also seen in the full - term infants evaluated by verboon - maciolek et al.18 ) .
most findings of verboon - maciolek et al.18 ) were similar to those reported from korea111213 ) , but there were also several differences between the studies .
first , preterm newborns were excluded from the three korean studies111213 ) , perhaps because it is difficult to perform mri in preterm neonates at the time of illness for reasons such as the clinical condition of the patients or technical limitations at the evaluating centers . according to verboon - maciolek et al.18 ) , outcomes were worse in preterm than in full - term neonates , but this remains to be confirmed .
second , the sample size was larger in each of the three studies from korea111213 ) than in the study of verboon - maciolek et al.18 ) . a 5-year single center retrospective study from korea by yeom et al.11 ) showed that rotavirus infection was identified in 17 neonates with the aforementioned dwi pattern .
other 2 studies1213 ) from same single tertiary center reported that total 32 infants with this dwi pattern had rotavirus in their stool specimens for 5 consecutive years .
by contrast , verboon - maciolek et al.18 ) reported on only eight patients from four hospitals for 6 years .
the difference in patient number may be explained by the different patient criteria for testing rotavirus and the sensitivity of dwi in the detection of acute edema .
all eight patients in the study of verboon - maciolek et al.18 ) had symptoms compatible with rotavirus gastroenteritis .
however , in all three korean studies111213 ) , a screening test for rotavirus was routinely performed and almost all patients were found to be asymptomatic for rotavirus infection .
thus , if only patients with gastroenteritis symptoms had been tested for rotavirus , a relationship between the two would not have been found111213 ) .
verboon - maciolek et al.18 ) used ultrasound in their evaluations of preterm neonates . however , the sensitivity of dwi to the acute phase of edema is superior to that of ultrasound and conventional mri , especially in the immature brain27 ) .
conventional mri techniques are insensitive to acute edema in the newborn brain due to the lack of myelination in neonates28 ) .
dwi with corresponding apparent diffusion coefficient maps can detect acute edema earlier and more clearly28 ) . according to yeom et al.11 ) , if dwi had not been performed , the unique pattern of wmi might not have been recognized because only subtle signal changes were detected in most of their patients evaluated by conventional mri techniques ( fig .
although the long - term neurological sequelae have yet to be defined , rotavirus - associated wmi may not always be benign .
cystic evolution was observed in 27%75% of patients with rotavirus - associated wmi ( fig .
verboon - maciolek et al.18 ) reported adverse outcomes , including epilepsy and cerebral palsy , in four of their 8 patients .
lee et al.12 ) detected mild neurological deficits , including speech or motor delay , in four of the 13 patients included in their study .
the factors associated with poor prognosis have yet to be identified ; however , they may include rotavirus infection or coinfection with enterovirus in preterm infants1318 ) .
the clinical features of the patients with rotavirus - associated wmi who were described in recent reports11121318 ) are surprisingly similar to those of patients with the largely forgotten clinical entity of ' fifth day fits ' . in an examination at median 4.6 years , developmental abnormalities
were observed in more than half of the patients with ' fifth day fits'21 ) .
the pattern of wmi seen in rotavirus infections is not unique and is , in fact , strikingly similar to that seen in neonatal enterovirus and parechovirus encephalitis11293031323334 ) . in all 3 infections ,
the major findings on cerebral imaging are diffuse high signal intensity in the white matter on t2-weighted sequences and restricted diffusion in the periventricular white matter , corpus callosum , and deep white matter . however , the signal changes seen on conventional mri sequence are more subtle in the wmi of rotavirus infections than in the wmi related to enterovirus and parechovirus infections3034 ) .
a predilection for cystic evolution in the frontal lobes is another common feature1112183031 ) , as is the timing of wmi susceptibility following viral infection . despite the broad range in the onset of these viral illnesses ,
thus , it seems that the white matter is susceptible to viral infection during the late preterm to full - term period and the final common pathway to virus - induced wmi may not differ among rotavirus , enterovirus , and parechovirus .
however , there are differences in the clinical characteristics of the patients infected with the different viruses .
as mentioned above , rotavirus - associated wmi characteristically occurs around the fifth day of life in full - term neonates . by contrast
, the onset of illness is more heterogeneous in full - term neonates with enterovirus and parechovirus infections : 213 days and 149 days , respectively30313235 ) .
the most notable difference between infections with rotavirus vs. the other viruses is the clinical presentation of the respective patients .
sepsis - like illness , including fever and rash , is observed in most cases of enteroviral and parechviral meningoencephalitis303132 ) , whereas neither fever / rash nor symptoms of gastroenteritis are seen in most neonatal patients with rotavirus - associated wmi1113 ) . in cases of rotavirus infection
, virus was not detected in the csf111213 ) , whereas it is usually detected in the csf of neonates infected with enterovirus and parechovirus3031333435 ) .
in addition , csf pleocytosis was not observed in rotavirus infection but was present in some cases of enterovirus infection1130 ) .
the similarities and differences in wmi induced by the three viruses are summarized in table 2 .
the activation of brain microglia is the principal initiating event in systemic infection / inflammation leading to wmi36 ) . the activated microglia release compounds such as reactive oxygen and nitrogen species and cytokines , all of which are toxic to the premyelinating oligodendrocytes ( pre - ols ) in white matter36 ) .
pre - ols are highly vulnerable to free radical attack and to glutamate - induced excitotoxicity36 ) .
this is the mechanism underlying pre - ol injury in systemic infection / inflammation , and it results in the acute loss of pre - ol , pre - ol maturation arrest , and/or abnormal myelination36 ) . in wmi caused by enterovirus and parechovirus ,
the single - stranded ribonucleic acid of enterovirus and parechovirus may activate the microglia via the activation of intracellular toll - like receptors ( tlr ) 7 and 8 , resulting in wmi37 ) .
in addition , tlr8 localizes to neurons and axons , and its activation results in the inhibition of axonal outgrowth and neuronal apoptosis without cns inflammation38 ) .
the latter hypothesis could explain the rare finding of csf pleocytosis in cases of wmi induced by parechovirus37 ) .
rotavirus , by contrast , is unlikely to penetrate the brain in cases of wmi in newborns1118 ) .
thus , at least in these patients , wmi caused by rotavirus can not be explained by either of the 2 aforementioned mechanisms , and how rotavirus leads to wmi in neonates remains unclear .
because rotavirus infection is common in neonatal care units , recent studies11121318 ) demonstrating rotavirus - induced wmi would be of great concern to pediatricians . according to these studies111213 ) , rotavirus is one of the most common causes of neonatal seizures .
furthermore , they11121318 ) suggest a new paradigm of viral infection : infection with a common virus can induce wmi in term neonates even without direct invasion .
however , the causal link between rotavirus infection and wmi in neonates remains to be validated in prospective cohort studies .
if rotavirus infection indeed induces wmi in neonates , the long - term prognosis of these patients determined . despite the lack of evidence , an enterotoxin of rotavirus ( nsp4 ) has been considered as cause of the neurological complications of rotavirus39 ) .
variability in nsp4 across rotavirus strains may be a key determinant of pathogenicity29 ) . or
neonates who had suffered from antenatal subclinical chorioamnionitis may be vulnerable to wmi by postnatal rotavirus infection .
the relationship between rotavirus infection and wmi strongly suggests the use of sequential neuroimaging in all rotavirus - infected newborns with neurological manifestations
. neonates with neurological symptoms should be tested for rotavirus infection and evaluated using mri including dwi .
however , it might be a new aspect of ' fifth day fits ' , what we knew but forgot for long time .
Output:
| that rotavirus infection can cause neurological symptoms in young children has been well established .
however , it is surprising why rotavirus infection has been overlooked as a cause of neonatal seizures for many years , despite significant research interest in neonatal rotavirus infection .
neonates are the age group most vulnerable to seizures , which are typically attributed to a wide range of causes . by contrast , because rotavirus infection is usually asymptomatic , it has been difficult to identify an association between this virus and neonatal seizures .
the conventional wisdom has been that , although neonates are commonly infected with rotavirus , neurological complications are rare in this age . however , recent studies using diffusion - weighted imaging ( dwi ) have suggested a connection between rotavirus infection and neonatal seizures and that rotavirus infection can induce diffuse white matter injury without direct invasion of the central nervous system .
the clinical features of white matter injury in rotavirus - infected neonates include the onset of seizures at days 46 of life in apparently healthy term infants .
the recent findings seem to contradict the conventional wisdom .
however , white matter injury might not be a completely new aspect of rotavirus infection in neonates , considering the forgotten clinical entity of neonatal seizures , ' fifth day fits ' . with increased use of dwi in neonatal seizures
, we are just starting to understand connection between viral infection and white matter injury in neonates . in this review
, we discuss the historical aspects of rotavirus infection and neonatal seizures . we also present the clinical features of white matter injury in neonatal rotavirus infection . |
PubmedSumm4841 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the conceptual emphasis of addressing the issues of the tooth or orofacial structures along with the concerns of the person involved has been the basis for providing health care in dentistry .
dental education and practice have been acknowledged as one of the most challenging , demanding , and stressful fields.1 - 4 many studies have identified that stress is involved at every stage in a dentist s career . hence , the dental students are expected to acquire diverse competencies such as academic and clinical competencies and interpersonal skills.1,5 - 10 further , the dentist has to be competent to understand the influence of the behavior of the patient so as to apply unique individualized approach while treating the patients.11 it is evident that healthcare professionals including dentists , hospital staff , and patients all bring important emotions to the workplace .
research focused on emotional intelligence ( ei ) over the past two decades has suggested that this might significantly determine whether these emotions enhance the practice or lead to interpersonal conflicts.12 ei , a conceptual framework is currently viewed as a form of pure intelligence of cognitive ability that translates psychological knowledge into terms that are useable by people not professionally trained in psychology , like dentists.11,12 india , an emerging economic global icon is known for its unity in diversity . demographically , being the second largest nation we have nearly 300 dental schools wherein students from different economic and social backgrounds are choosing dentistry as their career . hence , assessing the ei of these budding dentists is valid .
however , the scarcity of studies undertaken related to ei especially , in a culturally diverse and magnanimous indian society prompted us to embark on a study of this nature .
a cross - sectional , self - administered , structured questionnaire survey in english was conducted to assess ei of all the undergraduate students in drs sudha and nageswara rao siddhartha institute of dental sciences , gannavaram , india .
all the undergraduate students from second , third , and final year bds students and interns aged 19 - 25 years , were invited to participate in the study .
first - year students could not be included as the admission for the current academic year was not done when this study was being carried out .
the structured questionnaire was adapted from sterrett s ei questionnaire.13 it consisted of 30 questions , 5 each to assess the self - awareness , empathy , self - confidence , motivation , social control , and self - competency .
all the participants were asked to answer each question , anything between virtually never to virtually always using the rating scale 1 - 5 ( table 1 ) .
the ratings for each category were added in a template to obtain the total score for that specific facet of ei based on 5-point likert scale scoring from 1 to 5 ( virtually never = 1 to virtually always = 5 ) .
the minimum and a maximum score for each domain were 5 and 25 , respectively .
the ei score was derived by summing up the score obtained for all the domain ; the maximum and minimum total scores being 150 and 30 , respectively .
scores between 16 and 20 was considered for average ei ; scores below 15 and 10 were considered for poor ei and very poor ei , respectively .
average ei meant that there is a need for improvement in that domain while poor and very poor ei required immediate intervention .
the collected data were analyzed using statistical software spss version 20 ( chicago , inc . ) .
the mean , median , and mode for various responses between the groups were compared .
a cross - sectional , self - administered , structured questionnaire survey in english was conducted to assess ei of all the undergraduate students in drs sudha and nageswara rao siddhartha institute of dental sciences , gannavaram , india .
all the undergraduate students from second , third , and final year bds students and interns aged 19 - 25 years , were invited to participate in the study .
first - year students could not be included as the admission for the current academic year was not done when this study was being carried out .
the structured questionnaire was adapted from sterrett s ei questionnaire.13 it consisted of 30 questions , 5 each to assess the self - awareness , empathy , self - confidence , motivation , social control , and self - competency .
all the participants were asked to answer each question , anything between virtually never to virtually always using the rating scale 1 - 5 ( table 1 ) .
the ratings for each category were added in a template to obtain the total score for that specific facet of ei based on 5-point likert scale scoring from 1 to 5 ( virtually never = 1 to virtually always = 5 ) .
the minimum and a maximum score for each domain were 5 and 25 , respectively .
the ei score was derived by summing up the score obtained for all the domain ; the maximum and minimum total scores being 150 and 30 , respectively .
scores between 16 and 20 was considered for average ei ; scores below 15 and 10 were considered for poor ei and very poor ei , respectively .
average ei meant that there is a need for improvement in that domain while poor and very poor ei required immediate intervention .
the collected data were analyzed using statistical software spss version 20 ( chicago , inc . ) .
the mean , median , and mode for various responses between the groups were compared .
the distribution of the participants is described in table 2 . of 186 undergraduate students ,
28 were males and 158 females ; all of them aged between 19 and 25 years .
the proportions of the participants by gender appeared to reflect the overall student population choosing bds as their profession .
further , 130 of them were 20 - 22 years old ( 20 years-41 participants , 21 years-44 participants , 22 years participants ) .
table 3 describes the mean , median , standard deviation ; minimum and maximum score for each component of ei , as well as that of the overall score of ei .
of all the variables self - awareness was found to be more than the others with the mean and median scores were 18.2 ( 0.420 ) and 18.5 , respectively .
self - confidence , self - control , empathy , and motivation were found to be approximately the same among all the individuals .
however , social competency was found to be the lowest of all with mean 15.81 ( 0.342 ) and median 16 .
when the overall ei was estimated , the highest score was 144 and lowest was 68 with the mean 101.93 ( 5.56 ) and median 101 .
when the total score obtained by each individual were analyzed ( table 4 ) only 11.55% of the participants had good ei with scores above 20 in all domains while a majority of 54.02% proved to have average ei .
the same pattern of scoring has been observed when each component of ei was analyzed .
many researchers have attempted to define ei since then and have used various terms to describe such as emotional literacy , the emotional quotient , personal intelligence , social intelligence , and interpersonal intelligence.14 in a broader sense , it comprised of those skills that enables an individual to create value for oneself and others.14 the increasing complexities of the curriculum in education from schooling to graduation and beyond will always be challenging to every individual and hence ei can be considered to influence many aspects of daily life .
ei is increasingly made reference to in medicine and other healthcare disciplines where it is suggested it is important for professional mental health as well as effective practice.14,15 salovey and mayer introduced this concept of ei over decade ago and is described as a type of social intelligence that involves the ability to monitor one s own and other s emotions , to discriminate among them , and to use this information to guide one s thinking and actions.14,15 in a broad spectrum of skills that enables an individual to create value for oneself and others .
dental education has been asserted as one of the most challenging , demanding , and stressful fields of study , as dental students are expected to acquire diverse competencies such as academic and clinical along with the interpersonal skills.1,16 the stressful nature of the dental profession and the factors involved have been well - documented.1,16 assessment of ei is an important factor in determining students adjustment and educational achievements .
it is believed that ei may explain differences in the quality of intrapersonal and interpersonal relationships and contribute to job performance and management effectiveness and predict success.14 recent studies have proven that the students with high ei can cope up to the stress and perform better in the academics.15,17 - 20 india being known for the cultural diversity , it is valid to assess the ei across the country , as many students from different backgrounds are choosing dentistry . with the surge in the number of dental colleges ,
the scenario pertaining to dentistry has changed in india and the dentist to population ratio has come down to 1:10,000 in urban and 1:20,000 in the rural parts of the nation.21 however , in india dental students are not assessed for their ei before their admission or they undergo any specific education in this regard .
the quality of the future dental workforce will be in jeopardy as ei of the students choosing dentistry every year , is unknown .
only a few studies have been done and the available data is sparse.12 with this background , the present the study was undertaken so as to establish a baseline data about the ei of the students choosing dentistry as their career , in this part of the country . of the 186 participants ,
this is in accordance with the trend in most of the colleges in india , as most of the females are choosing dentistry as their career.15,21 - 23 it has been observed that dentistry has been attractive to women as their stature in the society is better financially and professionally.23 a structured questionnaire adapted from sterrett s ei questionnaire , * and the scoring was done using 5-point likert scoring scale as it is most widely accepted worldwide .
the ei of all the participants was assessed by evaluating the six facets of ei : self - awareness , self - confidence , self - control , empathy , motivation , and social competency .
self - awareness means having a deep understanding to one s emotions , strengths , weaknesses , needs , and drives .
self - confidence is a positive and balanced attitude having to do with the self dimension .
it consists of a basic belief that we can do what is needed to produce the desired outcome .
self - control is dealing well with stress , controlling emotional moods or outbursts without over control .
empathetic individuals are also effective in retaining talent because they are able to develop a personal rapport with others .
a positive attitude in the social dimension is motivation , one of the key facets of ei and of leadership .
appropriate behavior in the social dimension leads to social competency . to develop such social skills ,
we must focus on other people , rather than on what we are experiencing or want to say.14 when both mean and median of each of the 5 domains of ei were evaluated , the values obtained were consistent with each other . this could be attributed to the fact that the most of the scores obtained were analogous .
when each domain was evaluated in the present study , few had scored above 20 ; while the majority of the students obtained average scores ( 16 - 20 ) followed by poor ( 11 - 15 ) and very poor ( below 10 ) .
the same trend was when the overall scores were considered , 11.55% had good ei , 54.02% had average ei .
this was in congruence with other studies.14,24 our study was a self - reported assessment and reflected the ei of students in our institution .
the observations of the present study can not be deemed to be applicable to the students studying in other colleges in the same region as well as across the country . as ei was assessed based on the self - reported scale ,
this type of studies can be accurate only when the individual s self - concept is precise .
the results of the study are prone for response bias as students can tend to either exaggerate or fake their responses .
previous study has suggested that this limitation can be overcome when peer assessment and self - reporting responses are evaluated together.12
our study was a self - reported assessment and reflected the ei of students in our institution .
the observations of the present study can not be deemed to be applicable to the students studying in other colleges in the same region as well as across the country . as ei was assessed based on the self - reported scale ,
this type of studies can be accurate only when the individual s self - concept is precise .
the results of the study are prone for response bias as students can tend to either exaggerate or fake their responses .
previous study has suggested that this limitation can be overcome when peer assessment and self - reporting responses are evaluated together.12
this study was carried out to obtain the baseline data on ei of the undergraduate students in this part of the country .
only 11.55% of the students had good ei and most of them need definite intervention to improve their ei .
further research has to be carried out to design a valid mean to assess ei which can be relevant to the indian scenarioei of the students have to be assessed in the formative years such as in school , so that appropriate measures can be taken to improve if neededei of the candidate has to be considered as important during the admission process to professional courses as they are more stressful and challenging .
only then , one can safeguard the standards that are mandatory for dentistry and other professional courses .
further research has to be carried out to design a valid mean to assess ei which can be relevant to the indian scenario ei of the students have to be assessed in the formative years such as in school , so that appropriate measures can be taken to improve if needed ei of the candidate has to be considered as important during the admission process to professional courses as they are more stressful and challenging .
only then , one can safeguard the standards that are mandatory for dentistry and other professional courses .
Output:
| background : emotional intelligence ( ei ) is a measure of pure intelligence of cognitive ability that translates psychological knowledge into terms that are useable by people not professionally trained in psychology , like dentists.materials and methods : a cross - sectional , self - administered , structured questionnaire survey in english was distributed among 186 undergraduate students to assess their ei .
it consisted of 30 questions , 5 each to assess the self - awareness , empathy , self - confidence , motivation , social control , and self - competency .
all the participants were asked to answer each question , anything between virtually never to virtually always using the rating scale 1-5.results:the collected data were analyzed using statistical software spss version 20 ( chicago , inc . ) .
the mean , median , and mode for various responses between the groups were compared .
only 11.55% of the participants had good ei with scores above 20 in all domains , while a majority of 54.02% proved to have average ei .
a mere 2.05% showed to have very poor ei and 28.84% demonstrated poor ei.conclusions:the study showed that only 11.55% had a good ei and a major percentage of the students require immediate intervention to improve their ei . |
PubmedSumm4842 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: a randomized split mouth - controlled clinical study was conducted to evaluate the effectiveness of curcumin strip in the treatment of chronic periodontitis compared to srp alone .
the study - related procedures were explained to the patients before they signed an informed consent form .
a total of twenty subjects of age 3555 years and 15 subjects with chronic periodontitis , each with bilateral 56 mm probing pocket depth ( ppd ) , were recruited from the outpatient department of periodontics , j.k.k .
patients who received treatment with any form of antibiotics / anti - inflammatory drugs in the last 3 months , smokers , and with history of systemic diseases , pregnancy , lactation , and drug allergies were excluded from this study .
a composition of 0.2% curcumin was loaded onto the guided tissue regeneration ( gtr ) membrane ( heali guide
preoperative probing depth was measured and gcf sample was collected preoperatively as shown in figures 2 and 3 respectively .
0.2% loaded curcumin strip preoperative ( probing pocket depth mm ) gingival crevicular fluid collection .
( a ) control group , ( b ) test group
healthy group : it consists of 5 sites in which no bleeding on probing , no pocket depth ( healthy group)group i : it consists of 15 sites , in which srp was done ( control group)group ii : it consists of 15 sites , in which srp was followed by the placement of curcumin strip inside the pocket ( srp + curcumin strip ) ( test group ) as shown in figure 4 .
healthy group : it consists of 5 sites in which no bleeding on probing , no pocket depth ( healthy group ) group i : it consists of 15 sites , in which srp was done ( control group ) group ii : it consists of 15 sites , in which srp was followed by the placement of curcumin strip inside the pocket ( srp + curcumin strip ) ( test group ) as shown in figure 4 .
curcumin strip placement gcf collection was done using micropipettes preoperatively and postoperatively after 21 days as shown in figure 3 .
the sod activity was assessed using enzyme - linked immunosorbent assay as shown in figures 6 and 7 .
the clinical parameters such as plaque index ( pi ) , gingival index ( gi ) , and sulcus bleeding index ( sbi ) were assessed at baseline and on the 21 day .
healthy group : it consists of 5 sites in which no bleeding on probing , no pocket depth ( healthy group)group i : it consists of 15 sites , in which srp was done ( control group)group ii : it consists of 15 sites , in which srp was followed by the placement of curcumin strip inside the pocket ( srp + curcumin strip ) ( test group ) as shown in figure 4 .
healthy group : it consists of 5 sites in which no bleeding on probing , no pocket depth ( healthy group ) group i : it consists of 15 sites , in which srp was done ( control group ) group ii : it consists of 15 sites , in which srp was followed by the placement of curcumin strip inside the pocket ( srp + curcumin strip ) ( test group ) as shown in figure 4 .
curcumin strip placement gcf collection was done using micropipettes preoperatively and postoperatively after 21 days as shown in figure 3 .
the sod activity was assessed using enzyme - linked immunosorbent assay as shown in figures 6 and 7 .
the clinical parameters such as plaque index ( pi ) , gingival index ( gi ) , and sulcus bleeding index ( sbi ) were assessed at baseline and on the 21 day .
the results obtained were analyzed statistically , and comparisons were made within each group using paired and unpaired student 's t - test using ( ibm corp . released 2010 .
armonk , ny : ibm corp ) . a value of p < 0.05 was considered as the level of significance .
the in vitro release of curcumin from the collagen membrane was over 24 h as shown in graph 1 .
the in vitro release of curcumin from the collagen membrane over 24 h the pi , gi , and sbi scores at baseline was 1.862 0.539 , 1.885 0.595 , 2.027 0.444 , respectively , and after 21 days , pi , gi , and sbi scores were reduced to 1.170 0.192 , 1.160 0.239 , 1.186 0.212 , respectively , as shown in table 1 and graph 2 .
comparison of the pi , gi , and sbi scores between baseline and after 21 days shows a statistically significant difference with a p < 0.05 in both test and control groups
. comparison of clinical parameters at baseline and after 21 days comparison of mean changes in clinical parameters at baseline and on the 21 day the ppd in group i at baseline was 5.0 0.0 mm , and the ppd after 21 days reduced to 2.467 0.833 mm .
the ppd in group ii at baseline was 5.0 0.0 mm , and the ppd after 21 days reduced to 2.400 0.828 mm .
comparison of the ppd in groups i and ii shows that statistically , there is no significant difference with a p > 0.05 as shown in table 2 and graph 3 .
comparison of probing pocket depth between group i and group ii intergroup comparison of mean changes of probing pocket depth in groups i and ii in the healthy group , the mean concentration of sod levels was 12.264 2.130 . in the control group , at baseline , the sod level was 1.448 0.625 and 21 days after treatment sod level improved to 9.366 2.609 . in the test group ,
the sod level at baseline was 1.618 0.746 and 21 days after treatment sod level improved to 11.649 2.884 as shown in table 3 and graph 4 .
comparison of sod levels postoperatively in both groups showed that there is a statistically significant difference with a p < 0.05 .
periodontal disease is a multifactorial disease caused by microbial flora , which is present in the subgingival plaque .
these bacterial species result in the production of various cytokines and also causes an increase in number and activity of polymorphonucleocytes ( pmns ) .
curcumin is a yellow pigment from c. longa and is a major component of turmeric .
the desirable preventive or putative therapeutic properties of curcumin have also been considered to be associated with its antioxidant , anti - inflammatory , antimicrobial , and chemopreventive properties .
the anti - inflammatory effect of curcumin is most likely mediated through its ability to inhibit cyclooxygenase-2 , lipoxygenase , and inducible nitric oxide synthase .
curcumin may function indirectly as an antioxidant either by inhibiting the activity of inflammatory enzymes or by enhancing the synthesis of glutathione , an important intracellular antioxidant .
curcumin also acts as a free radical scavenger and antioxidant by inhibiting lipid peroxidation and oxidative dna damage .
currently , there is a growing interest in the linkage between antioxidants and periodontal disease .
a significant antioxidant enzyme within mammalian tissues is sod , which catalyzes the dismutation of o2 to h2o2 and o2 .
efficacy of 0.2% curcumin loaded onto the gtr membrane in strip form adjunct to srp was evaluated in the present study . according to franz diffusion method ,
maximum release of drug from strip used in this study was within 24 h. in our present study , the clinical parameters such as pi , gi , and sbi scores were reduced from baseline to 21 day in both test and the control groups .
the mean ppd was significantly reduced on the 21 day compared to the baseline in both test and control groups .
the results were in accordance with the study conducted by behal et al . in 2011 , who demonstrated ppd reduction following placement of 2% turmeric gel , when compared to srp alone .
gcf samples were taken at baseline and after srp ( 21 day ) . in the healthy group ,
sod levels were 12.264 2.130 . in the control group , at baseline , sod level was found to be 1.448 0.625 and improved to 9.366 2.609 on the 21 day following periodontal therapy , which shows statistically significant differences before and after treatment in accordance with karim et al .
sod level at baseline in the test group was 1.618 0.746 and improved to 11.649 2.884 on the 21 day following periodontal therapy .
on comparison of sod levels , group ii showed statistically significant difference comparing to group i. the sod levels seem to be nearing to the healthy group when curcumin strip was used as an adjunct to srp .
from this study , all the clinical parameters were significantly reduced in test and control sites .
furthermore , sod levels were significantly improved in test sites when compared with control sites .
thus , the present study concluded that curcumin strip can be effectively used as an adjunct to srp in treatment of chronic periodontitis and serves as antioxidant in subgingival environment .
although the study has positive outcome for particular antioxidant , elaborate studies are needed to prove the efficacy of curcumin strip in other antioxidants and also with reference to areas such as proper concentration and release system .
Output:
| aim : curcumin has proven properties such as anti - inflammatory , antioxidant , antimicrobial , and it also accelerates wound healing . the purpose of this study was to investigate the level of superoxide dismutase ( sod ) enzyme , in gingival crevicular fluid ( gcf ) , and the impact of nonsurgical treatment on the antioxidant profile using 0.2% curcumin strip as local drug delivery.materials and methods : a total of twenty subjects of age 3555 years and 15 subjects with chronic periodontitis , each with bilateral 56 mm probing pocket depth , were selected for this study .
healthy group consists of 5 sites in which no bleeding on probing , no pocket depth .
group i it consists of 15 sites with chronic periodontitis , in which scaling and root planing ( srp ) was done ( control group ) .
group ii
it consists of 15 sites , in which srp followed by the placement of curcumin strip inside the pocket ( srp + curcumin strip ) ( test group ) .
gcf collection was done preoperatively and postoperatively after 21 days .
the sod activity was assessed using enzyme - linked immunosorbent assay.results:in this study , all the clinical parameters were significantly reduced in test and control sites .
further , sod levels were significantly improved in test sites when compared with control sites.conclusion:thus , the present study concluded that curcumin strip can be effectively used as an adjunct to srp in treatment of chronic periodontitis and serves as antioxidant in subgingival environment . |
PubmedSumm4843 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: repeat
expansion disorders are caused by mutations in dna where
repeats in certain genes become expanded .
once the repeats are transcribed ,
mrna ( mrna ) folds into a hairpin with repeating internal loop motifs ,
which can be translated into toxic proteins or sequester proteins
and cause disease .
one hypothesis is that formation
of non - b - form conformations by the repetitive dna sequences , such
as hairpins , is the reason for the expansion during dna replication
and repair . in the expansions of cag repeats , which are typically
found in the coding regions of mrnas such as huntingtin ( htt ) , androgen
receptor ( ar ) , spinocerebellar ataxia ( sca ) , and atrophin-1 ( atn1 )
genes ,
the transcripts are translated into toxic polyglutamine ( polyq ) proteins , resulting in huntington s disease
( hd ) , spinal and bulbar muscular atrophy ( sbma ) , spinocerebellar ataxia
type 1 ( sca1 ) , and dentatorubral - pallidoluysian atrophy ( drpla ) , respectively .
furthermore , it has been shown recently that rna cag repeat expansions can sequester proteins and contribute to neurodegeneration .
another genetic disorder , friedreich s ataxia ( frda ) , is
caused by expansion of gaa repeats .
a common heritable
form of mental retardation , fragile x - associated tremor ataxia syndrome
( fxtas ) , is caused by expansion of the cgg segment from 50 to 200
repeats in the 5-untranslated region ( utr ) of the fragile
x mental retardation 1 ( fmr1 ) gene .
once the fmr1 gene is transcribed into mrna , the expanded cgg repeats fold into a hairpin structure with repeating
11 gg internal loops that sequester and inactivate sam68 protein .
myotonic dystrophy ( dm ) is another genetic disease that is the
most common adult - onset form of muscular dystrophy .
dm is a neuromuscular
disorder that is characterized by muscle weakness and slow relaxation
of muscles after contraction .
it is caused by expansion
of ctg and cctg repeats in dna , with ctg leading to
myotonic dystrophy type 1 ( dm1 ) and cctg to type 2 ( dm2 ) . in both
dm1 and dm2 ,
once the trinucleotide ctg in the 3-utr of the
dystrophia myotonica protein kinase ( dmpk ) gene and
the tetranucleotide cctg repeats in the zinc - finger 9 ( znf9 ) gene are transcribed , the cug and ccug repeats fold into rna hairpins with repeating 11
uu and 22 cu / uc internal loop motifs , respectively , attracting muscleblind - like 1 ( mbnl1 ) or cytoplasmic multiprotein complexes that cause ,
for example , muscle chloride channel dysfunction and abnormal regulation of insulin receptors . because the expanded rna repeats are in the noncoding regions
the diseases are caused by rna gain - of - function . even though the disease mechanisms described
above are the most well established ones , expanded rna repeats might
play other roles in the cell . as an example , expanded repeats in utrs
are translated via a repeat associated non - atg translation .
the crystal structures of model rna molecules
containing cug repeats have been determined
before by different groups
using x - ray diffraction methods .
in addition , an nmr structure
of a single copy of the dm1 motif was characterized that displayed
an overall a - form structure . even though
all these structures show 11 uu internal loops in anti
anti conformations , large amplitude motions
in rna internal loops could not be investigated with the current experimental
methods .
the conformations that rna cug repeats
adopt upon protein or small molecule binding require a better understanding
of these motions .
helical stacking unstacking and syn anti transformation of uridines
in 11 uu base pairs are two such important large scale motions
that have significance in small molecule
various
groups have designed and published small molecules and ligands targeting
rna cug repeats , but at present there is no experimental structure available that
reports the atomistic details of a small molecule bound to rna cug repeats .
thus , the structural and thermodynamic properties
of 11 uu base pairs in rna cug repeats
are of significant interest , since they may provide insight into the
conformations that these repeats adopt upon interaction with proteins
or small molecules .
we recently analyzed the
properties of 11 aa internal loops
seen in rna cag repeat expansions .
the crystal
structure of a model rna with three cag repeats ,
r[5uugggc(cag)3gucc]2 , was found to exhibit terminal 11
aa base pairs in syn
the terminal
aa base pairs interact with dangling uridine bases , stabilizing the syn anti conformational state .
the
results basically indicated that a dynamic base pair such as 11
aa internal loops could transform to another conformation upon interacting
with a molecule .
thus , we utilized umbrella sampling md simulations
to predict the 2d free energy surface for 11 aa internal loops
to investigate the potential stable conformations and transformation
pathways . in line with the experimental
results ,
anti and syn anti conformations as global
and local minima , respectively . furthermore
, several stable local
minima states in both anti anti and syn anti conformations
were found for 11 aa internal loops .
the results indicated that
the stable 11 rna internal loop conformations could be exploited
for small molecule binding .
indeed , we analyzed the binding mechanism
of a substituted naphthyridine ( c-2 ) to rna 11 uu internal loops ,
which inhibits binding of mbnl1 to rna cug
repeat expansions .
similar results were seen when we analyzed 6-n-5-hexynoate
kanamycin alkyne ( k - alkyne ) binding to 22 cu / uc internal loops
in rna ccug repeats , which is a lead small
molecule targeting rna causing dm2 .
hence ,
atomistic details of the structure and dynamics of rna internal loops
as well as the transformation pathways extracted from the predicted
free energy profiles can yield insights that might be used to understand
and develop drugs that will target rna repeat expansions .
although
there are no structures reported for mbnl1 bound to cug repeats , it is thought that the zinc finger 3 and 4 domains ( zn3/4 )
of mbnl1 have some functional roles in the binding process .
thus , the present investigations could also
shed light on this pathogenic interaction . in the present contribution ,
structural and thermodynamic properties
of 11 uu rna internal loops are predicted using regular and
umbrella sampling md simulations in explicit solvent with an amber
force field , which includes a torsional revision for rna .
we also exploited the discrete path sampling
( dps ) method to investigate the energy landscape of the 11 uu
internal loop in rna cug repeats .
three systems
were considered : 3cug3syw ( r[5uugggc(cug)3gucc]2 ) , 3cuginf ( r[5c(cug)3g]2 ) , and 1cug ( r[5ccgcugcgg]2 ) . 3cug3syw and 3cuginf were used to predict the dynamic properties of 11
uu base pairs .
in particular , 3cuginf was designed
to simulate 11 uu rna internal loops in an infinitely long linear
rna system , while 3cug3syw is an already solved crystal
structure with pdb accession code 3syw .
1cug
was designed to predict the 2d free energy surfaces of 11 rna
uu internal loops using umbrella sampling md calculations .
similar
to our previous rna cag repeat study , one of the reaction coordinates was chosen as
the torsion ( rotation around the glycosidic bond ) in order
to mimic the orientation of the uridine base with respect to sugar ,
while the other reaction coordinate was a pseudotorsion ( )
mimicking base flipping ( base stacking unstacking ) .
two 2d
potentials of mean force ( pmf ) surfaces , ( 1, )
and ( 1,2 ) , were calculated for
the 11 uu base pairs .
our results indicate that 11 uu
rna internal loops are dynamic and favor the anti anti conformation but have several local
minima in the 2d pmf profiles displaying both anti anti and syn anti conformations . the 2d ( 1, )
pmf exhibits three pathways for the syn anti anti anti transformation , one of which dominates in temperature jump md simulations .
these results were verified using dps calculations , which showed that
in the dominant kinetic pathway the uridine flips out via the major
groove , followed by a rotation around to produce a syn anti transformation . in line
with previous studies , the 2d ( 1,2 ) pmf as well as regular md simulations displayed 11 uu base
pairs in 2 , 1 , and 0 anti anti hydrogen - bond conformations .
similar to the 11 aa base pairs
studied before , a na binding
pocket was discovered near the 11 uu base pair , stabilizing
the syn anti conformation .
furthermore , md simulations of 3cug3syw showed 22
gc / cg regions flanked by 11 uu base pairs to have stable but
distorted forms , which indicates flexibility .
the present results
reveal atomistic details of the structure and
thermodynamics of 11 uu base pairs in rna cug repeat expansions that are inaccessible with current experimental
methods .
this insight should help us to design better compounds targeting
rna cug repeats in future work .
1cug
( figure 1a ) was employed
to predict the 2d free energy surfaces of 11 uu base pairs using
umbrella sampling calculations .
3cug3syw ( figure 1b ) was considered
to model the structural properties of a crystal structure ( pdb accession
code 3syw ) , which has three consecutive cug repeats .
finally , 3cuginf ( figure 1c ) should provide insight into the dynamics
of 11 uu base pairs in an infinitely long linear rna system .
the initial structure of 1cug was built from the already solved
nmr structure ( pdb accession code 2l8u ) .
a homology
model of 3cuginf was built from the crystal structure
data of 3syw(38 ) with uu base pairs in either anti anti or syn anti conformations .
two initial structures
were created for 3cuginf ; one where all 11
uu base pairs were in anti anti conformations ( 3cuginf / anti anti ) and another where the middle uu base pair ( u6u17 ) was in syn anti ( 3cuginf / syn anti ) .
this was done in order to investigate potential syn anti anti anti transformations . for the initial structure of 3cug3syw ,
data from the crystal structure 3syw(38 ) was used , including dangling uridine residues , which were
utilized experimentally to crystallize the system . as shown in figure 1b , the dangling uridine
residues were kept in the structure in order to mimic the original
system as far as possible . the leap module of amber md package was used to neutralize all the systems with
na and/or cl ions and to solvate with tip3p water molecules . in 3cuginf , 10 extra cl and na ions were randomly included in the systems .
the
1cug and 3cug3syw were designed to have truncated
octahedral boxes , while 3cuginf was designed to have
a cubic box that created an infinitely long rna system ( figure 1c ) .
the 1cug , 3cuginf , and 3cug3syw systems had 4025 , 2265 ,
and 10766 water molecules , respectively .
once equilibrated , these
systems had 0.67 , 0.21 , and 0.18 mm na concentrations ,
respectively .
we also designed another 3cuginf system ,
which was neutralized with 20 na ions , had the middle
uu basepair in syn
anti conformation ,
and was solvated with 4333 water molecules to yield a na concentration of 0.24 mm .
two sets of md simulations for this system
were run . the amber force field with
revised and / torsional parameters were used in both regular
and umbrella sampling md simulations , as these revised parameters
have been shown to improve the predictions .
model
rna sequences and initial structures used in regular and
umbrella sampling md simulations . for illustrative purposes ,
the opaque region of c represents the unit cell , while
transparent regions represent the neighboring cells to illustrate
the design of the infinitely long rna system .
each system was first
minimized and equilibrated in two steps ( see also table s1 ) .
after equilibration , constant pressure dynamics with isotropic positional
scaling was used in all the production runs .
the reference pressure
was set to 1 atm with a pressure relaxation time of 2 ps .
an atom - based long - range hard cutoff of
8.0 was used .
as described above , two independent md calculations were
run on 3cuginf , 3cuginf / anti anti and 3cuginf / syn anti , with total md
simulation times of 500 and 606 ns , respectively , with a 1 fs time
step .
the temperatures of all md simulations were kept at
300 k. the pmemd module in amber12 was
used to run the md simulations .
the
reaction coordinates
shown in figure 2 ,
which we previously utilized to study rna 11 aa base pairs , were used to build the 2d pmf surfaces for rna
11 uu internal loops .
two different 2d potential of mean force
( pmf ) surfaces , ( 1 vs ) and ( 1 vs 2 ) , were calculated for 11 uu
base pairs using the model system 1cug ( figure 1a ) .
nucleic acid bases can rotate around
glycosidic bonds ( rotation around torsional angle ) , which
are responsible for the syn and anti base orientations with respect to sugar ( figure 2a ) .
while purine residues prefer both syn and anti orientations , pyrimidine residues
mostly prefer anti .
hence , one of the reaction coordinates
was chosen to be the torsional rotation .
the second reaction
coordinate was chosen to imitate base stacking unstacking ,
where the center - of - mass pseudodihedral angle ( ) was defined
to mimic this motion ( figure 2b ) . in order to build each 2d pmf surface ,
initial structures
with different ( 1, ) and ( 1,2 ) combinations were created for the model system
1cug ( see section s1 in the supporting information for the details ) .
reaction coordinates utilized to build the 2d pmf surfaces
for
rna 11 uu base pairs . in a
, the torsional angle highlighted
in red is ( o4c1n1c2 )
responsible for the syn anti transformation . in order to investigate the base stacking
unstacking , pseudodihedral angles , 1 and 2 , defined by the center - of - masses ( coms ) of four atom groups
in b
due to the relatively
large energy barriers we did not see any syn anti transformations in the md simulations of 3cug3syw and 3cuginf ( except for one case , which
had low na concentration ) .
thus , we studied the structural
properties of 11 uu base pairs with respect to temperature using
1cug .
two systems were considered : one where the 11 uu
base pair is in an anti anti conformation ( = 200 and 1 = 40 )
and another where it is in a syn anti conformation ( = 40 and 1 = 350 ) .
for each case , 10 independent md simulations were run where the temperature
was increased from 300 to 400 k by 5 k for each 1 ns md time interval .
once the temperature reached 400 k , another 19 ns md was run in each
case .
we should note that this particular calculation is somewhat similar
to simulated annealing protocol and was done to force the system to
overcome the energy barriers responsible of syn anti transformation .
because 400 k is higher than the boiling
point , a full md would not mean much .
we utilized
umbrella sampling md simulations to predict the 1d pmf profiles of
a , g , u , and c mononucleosides along the torsional axis ( figure 2a ) .
the procedure
is similar to the umbrella sampling simulations described above , except
that only the individual mononucleosides were solvated with 738 tip3p
water molecules and simulated .
torsional angles were incremented by 10 that created 36 umbrella
sampling windows for each system .
after minimization and 1 ns equilibration ,
each window was simulated for 5 ns .
the torsions in the umbrella
sampling md simulations were restrained in a square bottom well with
parabolic sides and 30 kcal/(mol rad ) force constants .
the discrete path sampling method ( dps ) has previously been used to study the energy landscapes
for a diverse range of atomic and molecular systems . in particular , this approach has proved to be effective in exploring
landscapes that feature broken ergodicity , leading to multiple relaxation time scales .
dps is based on geometry
optimization techniques and is efficient in sampling rare
event dynamics , which are typically inaccessible in conventional
unbiased simulation methods . in the present work
we have used dps to explore the energy landscape of the rna cug repeats , to supplement our results from unbiased molecular
dynamics and umbrella sampling simulations ( see section s2 in the supporting information for the details ) .
dps simulations were seeded from conformations corresponding to the
major basins on the 2d pmf of the single cug repeat , choosing a diverse range of pseudotorsion and torsion
values .
these conformations were locally minimized using a modified
version of the lbfgs algorithm , to build
an initial database of minima .
geometry optimizations were deemed
to have converged when the root - mean - square gradient fell below 10 kcal mol .
connection attempts were made between these minima in a
pairwise fashion , starting from the highest energy minimum in the
database to the lowest .
once sufficient connections were found , a
disconnectivity graph analysis revealed that syn anti and anti
anti states of the uridine base pairs were likely to emerge as competing
funnels on the energy landscape .
the stationary point databases were
further expanded by refining the discrete paths between the syn anti and anti
anti end points , using systematic applications
of the shortcut barrier and untrap schemes , which have been described
in detail in previous work and are available
within our pathsample code .
dps simulations
were deemed to have converged sufficiently when the rate constants
corresponding to the syn
anti anti anti conformational
transition were stable to within an order of magnitude . the final
stationary point database consisted of 21927 minima and 25467 transition
states .
free energies were estimated from the database by employing
the harmonic superposition approximation . here , the molecular partition function is approximated as a sum
over harmonic vibrational densities of states corresponding to the
catchment basins of each minimum .
the ptraj module of amber12 was used
for dihedral , root - mean - square deviation ( rmsd ) ,
and cluster analyses . the weighted histogram analysis method ( wham )
in the wham
analysis , the last 1.5 ns data of each umbrella sampling simulation
was used , and periodicity was turned on in both dimensions .
x3dna was used to extract global structural properties
of 3cug3syw from the md trajectory .
the rate constants corresponding
to the conformational transitions between the syn anti and anti anti states were calculated from the stationary point database
using a graph transformation method , as described in a previous work .
the estimates for the rate constants at 300
k were obtained using a self - consistent regrouping scheme , which recursively lumps minima separated by
free energy barriers below a threshold into one macrostate .
this is
an attractive approach , as the free energy surface then becomes a
function of the experimental observation time , due to the lumping
of minima separated by low barriers .
furthermore ,
this method alleviates any bias arising due to the choice of original
end points , as they are expanded into ensembles of structures that
are assumed to be in local equilibrium on the time scale of the rate - determining
step of interest .
the potential
and free energy
landscapes were visualized in the form of disconnectivity graphs .
the disconnectivity graph provides a powerful yet simple representation
of the energy landscapes and is free of potential artifacts that can
arise from low dimensional projections onto selected order parameters .
this representation retains all of the kinetic information in the
database and thus provides a way to rigorously test the validity of
the reaction coordinates employed in our 2d umbrella sampling simulations
( see section s3 in the supporting information for the details ) .
,
we found that the md trajectories for 3cug3syw and
3cuginf show stable 11 uu base pairs both in anti anti and syn anti conformations . except for one case
( 3cuginf with low na concentration ) ,
no syn
this result was attributed to the high energy barriers observed in
umbrella sampling and dps calculations , which predicted three syn
temperature
jump md simulations were performed , which revealed that one of the
pathways predicted by umbrella sampling and dps calculations dominates
the syn
we use different colors to represent each stable 11 uu base
pair conformation to highlight the transformations ( figure 3 ) .
conformational states
of 11 uu base pairs seen in md trajectories
of 3cug3syw and 3cuginf .
color notation
was used to represent each state to make visualization of rmsd plots
( vide infra ) easier .
black ( a ) , red ( b ) , and cyan ( c ) represent anti anti conformations with 2 ,
1 , and 0 hydrogen - bond .
green ( d ) , blue ( e ) , yellow ( f ) , and orange
( g ) are used for syn
anti uu conformations , the system is symmetric . as a result ,
there are two conformations each in a and b representing the same
state .
the initial
structure of 3cug3syw solved by x - ray diffraction
with 2.20 resolution is shown in figure 1b .
the system
contains three consecutive rna cug repeats
with two dangling uridines which were included experimentally to facilitate
crystallization .
we analyzed the global structural properties of 3cug3syw and compared them to the published crystal structure .
furthermore , the conformational preference of each 11 uu base
pair , as well as the 22 cg / gc base pairs flanked by two neighboring
11 uu base pairs ( figure 4 ) , along with the dynamics of dangling uridines , were analyzed .
rmsd s ( in ) of u8u33 , g9c10/g31c32 , u11u30 , g12c13/g28c29 , and u14u27 are plotted
with respect to the stable conformations shown in figures 3 and 5 .
anti conformations with stable forms represented by black ,
red , and cyan ( figure 3a c , and movie s1 ) . in the rmsd
analysis of the 11 uu base pairs ( u8u33 ,
u11u30 , and u14u27 ) ,
conformational states with rmsd greater than 1 represent symmetry
related versions of the states .
as noted in figure 3 , uu base pairs in states colored black and
red have two identical conformations representing 2 and 1 hydrogen - bond
states , respectively .
the plots were created in this form to display
the transformations of 11 uu base pairs during the trajectory .
note also that the stable gc / cg conformation represented by magenta
only forms when the flanking 11 uu base pairs are both in the
2 hydrogen - bond and opposite symmetry states ( black ) ( see movie s2 ) .
the main difference between the 3syw crystal structure and the 3cug3syw structure is that the former
is an almost frozen system while the latter is a system equilibrated
at 300 k and thus includes dynamics .
the minor ( mgw ) and major groove
widths ( mgw ) in the crystal structure of 3syw are around 15 and 16 , respectively
( figure s1 ) .
analysis of the md trajectory
shows that the mgw fluctuates around the crystal structure value ( figure s1 ) , which is globally in an a - form conformation .
on the other hand
the expanded mgw suggests that the inclusion of 11
uu internal loops gives flexibility to the system . to understand the
flexibility of each region in the rna duplex
, we analyzed the rmsd
of 3cug3syw with respect
to the crystal structure . in the analysis ,
the sequence was broken
down into 2 and 5 base pair segments so that we could investigate
which regions in the rna were responsible for the flexible behavior
( figure s2 ) .
the results show that the
regions including uu base pairs are more flexible than the other regions
in 3syw ( figure s2 ) .
globally , the central region , which
includes 3 cug repeats , is more flexible than
the terminal regions , which includes watson crick gc and wobble
gu base pairs ( figure s2 ) . this result
is expected because individual fluctuations of 11 uu internal
loops will accumulate and yield global flexible regions as seen in 3syw .
it is noteworthy ,
however , that the overexpanded mgw might be a force field artifact .
even though it is known that rna internal loops introduce flexibility
into the system , the overexpanded mgw might be due to an improper
description of base stacking and/or backbone torsions .
cluster analyses of
the md trajectory show three unique anti anti conformations for the 11 uu base pairs , in line
with the previous experimental results , which represent 2 , 1 , and 0 hydrogen - bond states , colored black ,
red , and cyan , respectively , in the rmsd plots ( figures 3 and 4 ) . during the
1 s md simulation
anti anti anti transformations numerous times ( figure 4 and movie s1 ) .
hydrogen - bond analyses indicate that the 11 uu base pairs populate
the 2 , 1 , and 0 hydrogen - bond states with probabilities 43% , 41% ,
and 16% , respectively .
furthermore , in the regions where the 22
gc / cg base - pairs are in canonical watson crick forms the black
red transformations are very fast because the conformational
states are very similar to each other ( figures 3a , b and 4 ) .
the 0
hydrogen - bond state ( cyan ) seems to act like an intermediate state
and is less stable than to the 1 ( red ) and 2 ( black ) hydrogen - bond
states .
hence , the dynamic behavior of the 11 uu base pairs
yields flexible regions in the rna structure described above ( figure s2 ) .
the structure of 3cug3syw ( figure 1b ) is not as rigid as an infinitely
long rna .
thus , the effects of its flexibility will appear in weak
regions of 3cug3syw .
the 11 uu base pairs will
be the first to acquire this flexibility , as noted above .
the next
weakest regions are 22 gc / cg base - pairs flanked by these uu
base - pairs . even though the gc base pairs in these regions are in
watson
crick forms , they will not be as rigid as in regular
rna stem regions due to the flanking uu base pairs .
indeed , our
analysis shows that 22 gc / cg regions flanked by uu base - pairs
are flexible and can have a stable noncanonical conformation ( figures 4 and 5c and movie s2 ) . in the rmsd analysis
of g9c10/g31c32 and
g12c13/g28c29 the magenta color
represents this stable noncanonical conformation ( figure 5c ) , which persists for as long
as 200 ns , as is apparent during 420 and 610 ns intervals in the md
simulation ( magenta color in figure 4 ) .
note , however , that this stable noncanonical gc / cg
conformation only forms when the flanking 11 uu base pairs are
both in stable 2 hydrogen - bond and opposite symmetry states ( black )
( figure 4 and movie s2 ) . in this noncanonical gc / cg form
, each
gc base pair loses two watson crick hydrogen - bonds , while forming
an attractive electrostatic interaction between the nh2 group of guanine and the 2-oh group of the ribose
of its watson
the results indicate that if the flanking
base pairs ( in this case the 11 uu ) transform to energetically
favorable states they can distort the repeating 22 gc / cg regions
( movie s2 ) .
this particular phenomenon
is one of the reasons why we observe an overexpanded mgw in the md
trajectory ( figure s1 ) . as described above ,
the particular distorted gc / cg conformation shown in figure 5 forms when the flanking uu
base pairs are in 2 hydrogen - bond states ( figure 4 ) .
the overexpression of the 2 hydrogen - bond
states might be a force field artifact , which could indirectly cause
the overexpanded mgw we observed ( figure s1 ) .
therefore , caution is required when analyzing the results , even
though we are using an improved rna force field .
( b ) one of the gc base pairs is distorted and loses a hydrogen - bond .
in this form
, the nh2 group of guanine forms an
attractive electrostatic interaction with the 2-oh group of
cytidine .
( c ) both gc base pairs are distorted and lose one hydrogen - bond
each .
both gc base pair conformations are in the distorted gc form
described in b. the distortions happen only when the flanking 11
uu base pairs are both in the 2 hydrogen - bond but opposite symmetry
states ( see movie s2 ) . as noted
above
, the rna sequence shown in figure 1b includes dangling uridines , which were
used experimentally to help crystallize the system .
the initial conformations of the dangling uridine ends
are shown in figures 1b and 6a .
at later times , however , they transform
to a stable state where u2 and u21 are both
unstacked , while u1 and u20 are stacked on top
of the guanine of the terminal gc base pairs ( g3c38 and g22c19 ) ( figure 6c ) . in this form ,
both u1 and
u20 have flipped upside down sugars ( figure 6c ) , as seen previously in nmr and md analyses
of the single - stranded rna structure gacc .
although the crystal structure of 3syw has the dangling
uridine ends being inserted into the rna major grooves , this does
not mean that they will remain there when the system is equilibrated
at room temperature .
indeed , the md simulation of 3cug3syw shows the dangling uridine ends in very different conformations ,
where stacking interactions play an important role in the final conformations
( figure 6c ) . once the
dangling uridine ends transformed to this final stable conformation
( figure 6c ) they stayed
there for the rest of the md simulation ( see supporting information ) .
however , we should note that this particular
result might be a force field artifact caused by the improper description
of the backbone , the nonbonded interactions , or solvent molecules .
chen and garcia recently showed that the van der waals parameters
of adenine base atoms required revision , and a similar revision might be required for uridine .
conformational
transformation of the dangling uridine bases ( from
the md trajectory of 3cug3syw ) .
( a ) initial state
where dangling uridines are bent toward the rna major groove .
( c ) final
stable state where uridine ( u1 and u20 ) is flipped
upside down and stacked over the rna terminal base pair , while the
other uridine ( u2 and u19 ) is unstacked . for
residue numbering see figure 1b . in dm1 ,
hence ,
the system in figure 1c was designed specifically to study the behavior of 11 uu
base pairs in an infinitely long linear rna system with continuous
cug repeats .
because a full turn of an a - form
rna duplex requires 11 basepairs , we designed the system shown
in figure 1c , such
that the rna duplex is along the z - axis , has 11 basepairs ,
and stacks perfectly with the neighboring rna duplexes when periodic
boundary conditions are turned on .
no restraints ( either positional
or torsional ) were imposed on the rna duplex ; stacking interactions
between the neighboring gc base pairs keep the system in a linear
form automatically .
this trick , which we previously applied to rna
ccug repeats to investigate the dynamic properties
of cu / uc internal loops , allows us to
design an infinitely long linear rna duplex ( see movie s3 ) .
although r(3cuginf ) is not a perfect
rna cug repeat expansion , it is rather a linear
rna duplex having three continuous cug repeats
and then a ggcc / ccgg tetramer region ( see figure 1c ) .
if we leave off the end - fraying
effects in the finite duplexes , this does give the same structural
properties of finite duplexes .
ultimately the periodic trick will
break down when the length of the structure is longer than the persistence
length .
force the rna duplex to stay in a linear form due to the stacking
of the neighboring rna duplexes and , hence , study the behavior of
11 uu base pairs in a linear rna geometry ( see supporting information ) .
two md simulations were run ; one
where the initial conformations of all the uu base pairs were anti
anti ( 3cuginf / anti anti ) and another
where the initial conformations of u3u20 and
u9u14 were anti anti and u6u17 was syn
we further completed two independent
md simulations on 3cuginf / syn anti , which had low na concentration ( 0.24 mm ) . a 500 ns md simulation was run for this system .
anti and stayed in this form during the
md simulation ( figure 7 ) .
similar to the results seen for 3cug3syw , three
11 uu base pair conformations are observed in the md trajectory
representing 2 , 1 , and 0 hydrogen - bond states ( figures 3 and 7 ) . even though
no anti anti syn anti transformations are seen ,
numerous anti anti anti anti transformations are observed
( figure 7 ) .
a hydrogen - bond
analysis indicates that the 11 uu base pairs in 3cuginf / anti anti populate
states with 2 , 1 , and 0 hydrogen - bonds with probabilities 33% , 60% ,
and 7% , respectively .
the reason for the increase in the 1 hydrogen - bond
state compared to 3cug3syw is due to the rigidity
of the 22 gc / cg regions flanked by 11 uu base - pairs in
3cuginf .
structurally , the 2 ( black ) and 1 ( red )
hydrogen - bond states are alike , while the 0 ( cyan ) hydrogen - bond state
acts like an intermediate ( figure 3a c ) .
thus , the black red transformations
will be fast if no large distortions occur in the 22 gc / cg regions .
in 3cug3syw , because 22 gc / cg regions are flexible
the 11 uu base pairs have a higher probability of transforming
to the stable 2 hydrogen - bond states . on the other hand , analyses
showed that the conformations of the 22 gc / cg regions in 3cuginf / anti
the results indicate that the 22 gc / cg regions in 3cuginf / anti anti are
structurally more rigid than the ones in 3cug3syw . as a result
, it is harder for the 11 uu base - pairs to transform
to a stable 2 hydrogen - bond state without distorting the 22
gc / cg regions in 3cuginf / anti anti .
rmsd analysis of 11 uu base pairs seen in the 3cuginf / anti anti md simulation
( see figure 1c for
residue numbering ) .
the color
scheme described in figure 3 was used to display the conformational transformations .
note
that black and red conformations ( figure 3 ) represent 2- and 1-hydrogen - bond states ,
which can be described by two symmetric orientations ( figure 3a , b ) .
as described above , the initial conformation was designed
to have the middle uu base pair ( u6u17 ) in a syn
anti conformation and the terminal
uu base pairs ( u3u20 and u9u14 ) in anti anti .
figure 8 shows the rmsd and na binding
analyses for this system . except for one case , which had low na concentration ,
anti anti anti transformations were seen for u3u20 and u9u14 , where 2 , 1 , and 0 hydrogen - bond
states were occupied with probabilities 47% , 48% , and 5% , respectively .
however , u6u17 , which stayed in the syn anti conformation , exhibited
only 1 and 0 hydrogen - bond states with probabilities 93% and 7% , respectively .
the green and blue conformations shown in figure 3 display 1 hydrogen - bond state when the 11
uu base pair has a syn anti conformation .
even though no syn anti anti anti transformation was observed for u6u17 in this
system we see that there are at least four times where u6 , which is in the syn conformation , unstacked from
the helical axis , colored orange in the rmsd plot ( figures 3 g and 8) . in this orange state
( figure 3 g ) , u6 is unstacked from the helical axis
via the minor groove but does not complete the syn anti transformation ( movie s4 ) .
one reason for not observing the syn anti transformation is the na binding pocket seen near u6 ( figure 9 ) .
the transformation of u6 from
a stacked state ( green , blue , and yellow colored states displayed
in figure 3 ) to an
unstacked state ( orange ) only happens when the na binding
pocket is not occupied by a na ion ( movie s4 ) .
however , this state was short - lived because na ions were found to rapidly occupy the binding pocket even
after u6 tried to unstack and then stabilize the syn anti uu conformation by bringing
back u6 to the stacked conformation ( see md simulation
times 205 , 360 , 420 , and 545 ns
in figure 8) . as a
result , no syn anti transformation
was observed .
rmsd of 11 uu base pairs and na binding
to the
pocket seen in 3cuginf / syn anti md simulations ( see figure 1c for residue numbering ) .
the initial structures
of the terminal uu base pairs , u3u20 and u9u14 , were anti
a na binding pocket was observed
near u6 when it was in the syn conformation
( figure 9 ) . in the
na binding analysis
different colors represent different
na ions in the system where the distance between each
ion and the center - of - mass ( com ) of the three atoms shown in figure 9 ( o2p
and o2 of u6 , and n7 of g7 ) were calculated .
note that when the binding pocket was not occupied
by a na ion , u6 tried to unstack from the helical
axis and transformed to the orange state ( figure 3 g ) .
however , this state was short - lived ,
and no syn anti transformation
was observed ( movie s4 ) .
na binding pocket was observed near u6 when
it was in the syn orientation .
when occupied by a
na ion , there are three attractive electrostatic interactions .
as shown in figure 8 , these interactions stabilize the syn anti uu orientation .
when no na ion was present
in the pocket , u6 unstacked via the minor groove ( movie s4 ) .
a full syn anti transformation , however , was not observed , due to the
rapid occupation of the pocket by na ions .
this can be
seen in the rmsd analyses of u6u17 ( figure 8) where the orange
colored state has a short lifetime . in order to investigate further the role of na ions
,
we designed another 3cuginf system , which had a low
na ion concentration .
in the first set , we observed a syn anti transformation within 60 ns ( figure s3 ) .
this transformation happened right
after the loss of a na ion from the binding pocket ( figure s3 ) . in the second
set , however , we did
not observe any syn anti transformation within 200 ns ( figure s4 ) . during the md simulation of the second set , the na binding pocket was occupied by different na ions
anti uu conformation
is intrinsically stable and is further stabilized by na ions through the na binding pocket .
the md results for 3cug3syw and 3cuginf have provided details of
the dynamics of each system . except for
one case ( 3cuginf with low na concentration )
anti anti anti transformation
for 11 uu base pairs . to further explore this result
, we utilized
umbrella sampling md simulations to build two 2d pmf surfaces , ( 1, ) and ( 1,2 ) ( variables
defined in figure 2 ) , to extract the transformation pathways for 11 uu base pairs
as well as other potentially stable uu conformations .
note , however ,
that the calculated 2d pmf surfaces are approximations to the true
multidimensional energy landscapes .
for example , in the analysis we
assumed that the flanking gc basepairs will not be distorted during
base stacking unstacking .
it is possible that the flanking
gc basepairs might stack on top of each other once the uridines are
fully unstacked from the helical axis .
the choice of pseudodihedral shown in figure 2b was made after
careful analysis , where we tried other reaction coordinates to mimic
base stacking unstacking .
the use of pseudodihedrals to study
base flipping in nucleic acids was previously done by us and others .
figure 10 shows
the 2d ( 1, ) pmf surface predicted by umbrella
sampling calculations
for 11 uu base pairs .
there is excellent overlap of the ( 1, ) distributions calculated for each umbrella sampling
run ( figures s5 and s6 ) .
anti anti anti transformations : p1 , where
uridine unstacks via the minor groove in order to make the syn anti transformation , p2 , where
uridine follows a direct transformation from syn anti , while stacked within the rna helical axis , and p3 ,
where uridine unstacks via the major groove to perform the syn anti transformation .
these
pathways are similar to the ones predicted for rna cag repeats , but details of the free energy landscape ( figure s7 ) are different .
energy barriers in the 2d ( 1, )
pmf surface predicted for 11 aa base pairs are roughly 2 to
4 kcal / mol lower than for the 11 uu base pairs considered in figure 10 ( see also figure s7 ) .
this result is expected because adenosine
mononucleoside is known to prefer 40% syn and 60% anti , while cytidine is known to
prefer over 90% anti , which results in different energy barriers ( figure s7 ) .
2d ( 1, ) pmf surface predicted
for 11
uu base pairs by umbrella sampling calculations .
the results include
11 minima , where ( g ) is the global minimum conformation ( anti anti ) .
energy barriers , such
as the ones seen in b e and j g transformations ,
might be the reason why we could not see any syn anti anti anti transformation in regular md simulations at 300 k. see figure s7 for a comparison with the results previously
obtained for 11 aa base pairs .
figure 11 shows the
2d ( 1,2 ) pmf surface predicted
by umbrella sampling calculations for 11 uu base pairs ( for
details of the reaction coordinates see figure 2b ) .
the overlap of the ( 1,2 ) distributions calculated for each umbrella
sampling run is shown in figure s8 .
this
particular analysis was performed to investigate the correlation of
stacking unstacking of each base in a 11 uu base pair .
note , however , that the initial conformations of the 11 uu base
pairs are anti anti .
thus ,
the effect of syn anti transformations
is omitted in this analysis .
first we note that the 2d pmf surface
is symmetric , which is expected for 11 uu base pairs in the
rna cug ( figure 11 ) .
second , we find that unstacking of each
uridine is negatively correlated . hence , when one of the uridines
starts to unstack the other uridine in the 11 uu base pair tends
to stay in the helical axis .
this result is illustrated in figure 11 with double - ended
arrows , here emphasizing the channels directing the stacking and unstacking
for each uridine .
third , the results indicate the lowest free energy
states describing the different stacked 11 uu base pair conformations .
states a and b in figure 11 represent a mix of 2 and 1 hydrogen - bond conformations , while
state c represents a mix of 1 and 0 hydrogen - bond .
as described before ,
the conformations of 2 and 1 hydrogen - bond uu base pairs are almost
identical and , therefore , overlap in figure 11 .
a detailed hydrogen - bond analysis is displayed
in figure s9 . in the 2d ( 1,2 ) pmf surface , regions around ( 1 = 40 , 2 = 70 ) and ( 1 = 70 , 2 = 40 ) represent 2 hydrogen - bond conformations , while the
other regions of states a and b shown in figure 11 represent 1 hydrogen - bond conformations
( figure s9 ) .
the a b , a
c , and b c transformations displayed in figure 11 were also observed in the
md simulations of 3cug3syw and 3cuginf ( figures 4 and 7 ) .
2d ( 1,2 ) pmf surface
predicted
for 11 uu base pairs by umbrella sampling calculations .
double - ended
arrows indicate the channels directing the stacking and unstacking
of uridine in a 11 uu base pair .
a
and b represent a mix of 2 and 1 hydrogen - bond states , while c represents
a mix of 1 and 0 hydrogen - bond states ( see figure s9 for hydrogen - bond analyses ) . as described above , the syn and anti are two important rna conformations .
even though the 2d ( 1, ) pmf profile displayed high energy barriers , we also
investigated individual rna mononucleosides of a , g , u , and c , to
see if there are intrinsic differences between purines and pyrimidines .
umbrella sampling calculations were utilized to create the 1d pmf
profiles for each rna residue along the torsional axis ( figure s10 ) .
the results indicate that pyrimidines
mostly prefer anti , while purines can have significant
populations in syn ( figure s10 ) . in a and g , gsynanti ( ganti gsyn )
differences are approximately 1.40 and
1.21 kcal / mol , respectively , while in u and c they are 0.39
and 0.21 kcal / mol , respectively ( figure s10 ) .
the percentage of anti conformations
extracted from gsynanti for a , g , u , and c at 300 k are 9% , 12% , 66% , and 58% , respectively ,
in line with previous results .
furthermore ,
the energy barriers seen in purines are lower than the ones seen in
pyrimidines ( figure s10 ) . in 1d pmf profiles ,
there are two barriers for the syn anti transformation : one around 120
( pb ) and the other around 360 ( pa ) ( figure s10 ) .
while the energy
barrier around 120 is only slightly larger
in pyrimidines , the barrier around 360 is over
2 kcal / mol higher than for purines ( figure s10 ) .
the results indicate that purines in free mononucleoside forms
would prefer the syn orientation over anti and will readily sample the syn anti transformation via pa and pb due
to the low energy barriers , while pyrimidines would prefer anti over syn in free mononucleoside forms
and will follow pb to perform the syn anti transformation ( figure s10 ) . even though
the umbrella sampling calculations predicted three transformation
pathways for syn
anti anti anti , we did not observe any
such transformation in the 600 ns md simulation of 3cuginf / syn anti ( except
when na concentration was low ) . an intermediate state
represented in orange ( figure 3 g ) , corresponding to the potential minimum state b shown in figure 10 , was observed
in the md trajectory of 3cuginf / syn anti ( figure 8) where u6 ( in syn conformation )
unstacked from the helical axis .
however , the b e transformation
through p1 was not observed ( figure 10 ) even though this pathway was followed
by 11 aa base pairs in the syn anti anti anti transformation .
one reason for not
seeing the full transformation is due to the high energy barriers
observed in the free energy profile of the 11 uu base pair ( figure 10 ) , which were increased
by the na binding pocket near uu stabilizing the syn anti uu conformation ( figures 8 and 9 ) .
we therefore utilized 1cug ( figure 1a ) and increased the temperature of the system
slowly from 300 to 400 k to study the syn
ten independent md simulations
starting with syn anti and anti anti 11 uu base pair
conformations were run .
anti systems ended up with anti anti uu conformations , while no anti anti syn anti was observed .
anti anti anti transformations
observed in the temperature jump md simulations occurred via p1 and p3 , which were followed 1 and 5 times , respectively
( for definitions of pathways see figure 10 ) .
conformational states observed in the
temperature jump md simulations and the pathways followed during the syn
pathways p1 and p3 include unstacking via minor and major grooves , respectively .
in the temperature jump md simulations , even though numerous i
b transformations were observed , only one of them overcame the energy
barrier and followed the b e transformation ( figure 10 ) .
these results are different
from the corresponding rna cag results , where
the favorable syn
anti anti anti pathway is via p1 in 11 aa base pairs ( figure s7 ) .
indeed , the relative energy barriers of b
e and j g transformations are 2.4 and 6.0 kcal / mol in the
2d ( 1, ) pmf surface for 11 aa base
pairs , while the same barriers for 11 uu base pairs are 4.4
and 3.8 kcal / mol , respectively ( figure s7 ) . as a result ,
anti anti anti transformation pathways for 11
aa and uu base pairs , respectively , due to the associated energy barriers .
the potential and free energy disconnectivity graphs
for the rna system containing one cug repeat
are shown in figures 12 and s12 , respectively .
the free energy
disconnectivity graph was computed at 300 k using a regrouping threshold
of 2 kcal / mol .
the red and blue branches
lead to minima with the uu base
pair in syn anti and anti anti conformations , respectively .
the green and pink branches lead to minima , in which the uridine is
unstacked via minor and major grooves , respectively .
some representative
structures corresponding to different conformational states are also
shown . to make a direct comparison with
the 2d pmf obtained from umbrella
sampling calculations ,
the disconnectivity graph in figure 12 clearly illustrates
the double - funnel character of the underlying potential energy landscape .
the anti anti and the syn
anti states of the uu base pair
corresponding to the two major funnels are colored blue and red , respectively .
this observation is in agreement with the 2d pmf obtained from umbrella
sampling calculations , where the two major free energy basins correspond
to the anti anti and syn anti conformational states .
the two funnels are separated by high energy barriers , leading to
two competing morphologies . to quantify the barriers separating the
two conformational states at 300 k
anti anti anti transformations using
the graph transformation employing a
regrouping threshold of 2 kcal / mol .
this
choice is appropriate , as similar values were obtained in terms of
rate constants and disconnectivity graphs for a range of values around
this selection . the rate constant for the conformational transition
from syn anti to anti
anti is estimated as 17240
s. the reverse transformation
( i.e. , anti
anti syn anti ) is at least 2 orders of
magnitude slower , with an estimated rate constant of 174 s. these rate constants approximately correspond
to time scales of 58 s and 6 ms , respectively .
the presence
of such competing morphologies separated by high barriers is normally
associated with multiple relaxation time scales and features in the
heat capacity profile .
the minima
corresponding to the flipped - out conformations of the
uu base pair are colored green and purple for unstacking through the
minor and major grooves , respectively .
these conformations do not
constitute any major funnel on the energy landscape and are distributed
over a wide energy range in the disconnectivity graph .
the free energy
disconnectivity graph at 300 k ( figure s12 ) displays essentially the same features as the potential energy
landscape , with two major funnels corresponding to the syn anti and anti anti states . in general
, we find that the selected
order parameters distinguish
the two major funnels quite well .
nonetheless , the intermixing of
colors in certain regions of the graph suggests that structural order
parameters alone are not sufficient to correctly represent the complexities
of the underlying landscape .
hence , we use the recursive
regrouping scheme instead , which is based
on kinetic criteria , to estimate the rate constants . the kinetically relevant pathways
between the syn anti and anti anti conformational states
of the uridine base pairs were extracted from the stationary point
databases using the recursive enumeration algorithm , which is based on kinetic criteria to estimate the rate
constants
. the diverse range of pathways
that exist between the two conformational states can be classified
in terms of three distinct mechanisms : ( i ) pathway p1 ( figure 10 ) , in which the uridine flips
out via minor groove ( figure s13a ) prior
to the rotation of the uracil base around its glycosidic bond ; ( ii )
pathway p2 ( figure 10 ) , in which the uridine transforms from syn to anti without unstacking significantly from the helical axis
( figure s13b ) ; and ( iii ) pathway p3 ( figure 10 ) , in which the
uridine flips out via the major groove ( figure s13c ) followed by rotation of the uracil base around its glycosidic
bond resulting a transformation from syn to anti . for pathways
p1 and p3 , unstacking of uridine
outside the helical axis ( via minor and major grooves , respectively )
precedes the rotation of the uracil base around its glycosidic bond
that causes the syn anti transformation .
these transitions are effectively the rate - determining
steps in the two mechanisms . for pathway p2 ,
the rotation around the
glycosidic bond resulting in the flip of the torsion from syn to anti is associated with the surmounting
of a transition state and corresponds to the rate - determining step .
although pathways p1 and p3 have similar path lengths , p3 is associated
with relatively lower barriers and emerges as the fastest
pathway in our kinetic transition network .
pathway p2 is longer
than paths p1 and p3 and makes a smaller contribution .
thus , the properties
of our kinetic transition network , in particular the existence of
three different pathways from syn to anti conformational states as well as the mechanistic details of the
transformation , are consistent with the predictions of the 2d ( 1, ) pmf profile obtained from umbrella sampling . in dm1 ,
inhibition of rna - mbnl1 binding through
small molecules , which will target 11 uu base pairs , could ameliorate
the disease .
therefore , understanding the structural and thermodynamic
properties of rna 11 uu internal loops could help us discover
the binding mechanism of small molecules to rna internal loops and
thus the design rules for drugs , which will effectively target these
rna structures .
previously , we studied the binding mechanism of a
substituted naphthyridine ( c-2 ) that targets rna cug repeats .
the results indicated complex
structural transformations of the rna internal loop in the small molecule
binding process .
the lowest two binding modes displayed 11
uu base pair in conformations near ( 1 = 55 ,
= 200 ) and ( 1 = 55 , 2 = 55 ) .
indeed , ( 1 = 55 ,
= 200 ) represents one of the local minima ,
furthermore , ( 1 = 55 , 2 = 55 ) is one of
the local minima in figure 11 . in other words , upon c-2 binding to rna cug , 11 uu base pair was transformed from global minimum g ( anti anti ) to local minimum e ( anti anti ) ( figure 10 ) .
our previous results combined with the
current work suggest that small molecules can exploit the stable local
minima states of 11 uu base pairs if the final bound state is
thermodynamically favorable .
it is known that mbnl1
binds to rna cug repeats , but the details are
uncertain .
patel and co - workers solved the crystal
structure of the mbnl1 tandem zinc finger 3 and 4 domains ( zn3/4 )
interacting with a single - stranded rna , r(cgcugu ) , which shows guanosine
residues interacting with zn3/4 .
studies
have suggested that the binding to cug hairpins
occurs upon a conformational change in the structure that melts the
hairpin .
based on
the results of 3cug3syw , we discovered that tandem
gc / cg base pairs flanked by 11 uu internal loops are less stable
than when they are located in rna stem regions .
this result might
give insight into how mbnl1 binds to rna cug repeat expansions .
the distortions seen in tandem gc / cg regions
flanked by 11 uu base pairs might enhance the binding of mbnl1
to rna cug repeat expansions .
these studies
also suggest that small molecules that stabilize rna repeats could
be effective modulators of cellular function . using the cossmos database developed
by znosko and co - workers we found 73 rna structures that have cug motifs with 11 uu loops ( table s2 ) .
the biological systems that have the rna cug motifs include rna , ribosomes , zinc finger / rna , transcription / rna ,
and ribosome / antibiotic complexes ( table s2 ) .
importantly , there are many rnas that have single copies of the
cug motif , which might be targeted through
binding to multiple motifs in a cug hairpin
simultaneously or using small molecules that
cooperatively bind to repeats .
the rna
cug motifs in these structures either interact
with mg ions or have tertiary interactions .
note that
all the 11 uu base pairs in these cug
motifs have anti anti conformations . using an in - house code , we extracted all the rna cug motifs from the structures and calculated the ( 1, ) and ( 1,2 ) values for
each 11 uu base pair .
the results were then plotted on top of
the md results , which showed that the regions sampled by md simulations
were in line with the conformations seen in the literature ( figure s14 ) .
basically , the 11 uu base
pairs in these structures have 2 , 1 , or 0 hydrogen - bonds and prefer anti anti .
this observation suggests
that the interaction of ions or tertiary interactions does not disturb
the base orientations of uridines with respect to sugar , so the 11
uu base pairs prefer to stay in anti anti .
furthermore , our binding studies of compound c-2 to
rna cug repeats included over 25 s md
simulations where 11 uu base pair stayed in anti
these results are in line with the umbrella sampling calculations ,
where the free energy difference of syn anti to anti anti ( gsyn anti ganti anti ) is over 5 kcal / mol
for 11 uu base pairs ( figure 10 ) , while no significant difference was seen in the
umbrella sampling calculations of rna cag repeats
( figure s7 ) .
trinucleotide and tetranucleotide
repeat expansions caused by mutations
in certain genes lead to neuromuscular disorders .
these
rna transcripts are known to form stable hairpin structures with 11
or 22 internal loops regularly placed in the stem regions . however ,
a thorough understanding of the atomistic details of rna hairpins
formed by expanded repeats is a must for designing rules and , therefore ,
better compounds , which will target rna repeat expansions at nanomolar
levels . in the present contribution we utilized regular and
umbrella sampling
md simulations of model rna cug systems and
explained the structural and thermodynamic properties of 11
uu internal loops .
the results indicate that rna 11 uu internal
loops are dynamic and can form more than one stable conformation where
the global minimum conformation of the 11 uu base pair is anti anti .
our md results indicate
that the 11 uu base pairs have 2 , 1 , and 0 hydrogen - bond states ,
which are in line with the 73 nmr / x - ray structures we analyzed , as
well as with previous studies . moreover ,
the global picture of the 2d ( 1, ) pmf surface
for 11 uu base pairs has the same topology as one we previously
determined for 11 aa base pairs , but with different energy barriers
and free energy differences . while the syn anti aa conformation is a possible
state for rna cag repeats upon small molecule
binding it is not as stable as anti
this conclusion
follows from umbrella sampling studies where the anti anti uu conformation is over 5 kcal / mol
more favorable than syn anti . the result is also supported by experimental studies where no syn
anti uu conformations were seen
in the reported structures with rna cug motifs .
additionally , the lowest free energy binding state of a compound to
a model rna cug system exhibited a conformation
in line with the present results described .
thus , the local minima conformations discovered for 11 uu
base pairs by the umbrella sampling calculations could be important
targets for small molecule binding .
our studies also showed that a
na binding pocket similar to the one detected in rna cag repeats exists for rna cug
repeats , and it stabilizes the syn anti uu conformation .
this pocket includes three attractive
electrostatic interactions between na ions and rna backbone / bases ,
so it could be used in drug design where electropositive groups such
as nh2 and nh are incorporated in small
molecules to utilize this binding pocket for a higher binding affinity .
hence
, our results should help explain the mechanism behind small
molecule driven structural change in rna cug repeat expansions .
our results also indicate that there is
an intrinsic difference
between rna cag and cug repeats , where purines prefer both syn and anti , while pyrimidines predominantly prefer anti . furthermore
, the differences we see in the
2d pmf surfaces and md calculations for rna cag and cug repeats can be traced to intrinsic
properties in the torsion dependence of the force field .
these results
are , therefore , dependent on improvements implemented recently in
the rna force field .
it was shown that the torsional parameters
for the amber force field needed revision to make physically meaningful
computational predictions including structural and thermodynamic properties
of rna mononucleosides , single - stranded rna , rna structures with modified
residues , and rna hairpins . using these revised rna force
fields , other rna repeat expansions such as ccug , ccg , and cgg
these studies should produce insight that
can be used in understanding the mechanisms of different rna repeat
expansions and designing drugs that will target them .
Output:
| myotonic dystrophy 1 ( dm1 ) is a genetic
disease caused by expansion
of ctg repeats in dna . once transcribed , these repeats form rna hairpins
with repeating 11 nucleotide uu internal loop motifs , r(cug)n , which attract muscleblind - like 1 ( mbnl1 )
protein leading to the disease . in dm1 cug
can be repeated thousands of times , so these structures are intractable
to characterization using structural biology
. however , inhibition
of mbnl1-r(cug)n binding requires
a detailed analysis of the 11 uu internal loops . in this contribution
we employ regular and umbrella sampling molecular dynamics ( md ) simulations
to describe the structural and thermodynamic properties of 11
uu internal loops .
calculations were run on a reported crystal structure
and a designed system , which mimics an infinitely long rna molecule
with continuous cug repeats .
two - dimensional
( 2d ) potential of mean force ( pmf ) surfaces were created by umbrella
sampling , and the discrete path sampling ( dps ) method was utilized
to investigate the energy landscape of 11 uu rna internal loops ,
revealing that 11 uu base pairs are dynamic and strongly prefer
the anti anti conformation .
two 2d pmf surfaces were calculated for the 11 uu base pairs ,
revealing several local minima and three syn
anti anti anti transformation pathways .
although at room temperature the syn anti anti anti transformation is not observed on the
md time scale , one of these pathways dominates the dynamics of the
11 uu base pairs in temperature jump md simulations .
this mechanism
has now been treated successfully using the dps approach .
our results
suggest that local minima predicted by umbrella sampling calculations
could be stabilized by small molecules , which is of great interest
for future drug design .
furthermore , distorted gc / cg conformations
may be important in understanding how mbnl1 binds to rna cug repeats . hence we provide new insight into the dynamic
roles of rna loops and their contributions to presently incurable
diseases . |
PubmedSumm4844 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the systematic review was carried out according to the preferred reporting items for systematic reviews and meta - analyses ( prisma ) guidelines5 .
three databases , namely , medline / pubmed , google scholar and science direct were searched and all studies on pioglitazone carried out in india published in english language between 1999 and 2014 were included .
study characteristics : the search terms used were pioglitazone and india and human and pioglitazone and india and human and patient ( figure ) .
efficacy , bladder cancer , drug utilization and thiazolidinedione. the create alert facility in pubmed was subscribed to keep a track of any latest article .
letters / emails were written to authors and journal indices of articles included in sr were hand searched to identify any publication missed in the search .
the full text of all articles were obtained and read independently by both the authors , and the data were extracted in a pilot form and the final spreadsheet was prepared .
inclusion & exclusion criteria : as per the pico ( population , intervention , control and outcome ) criteria5 , studies included in the sr were those : ( i ) that were carried out in indian t2 dm patients ( and carried out in india ) ( population ) ; ( ii ) with pioglitazone either alone or in combination with other antidiabetic drugs ( intervention ) ; ( iii ) comparing it with baseline or other antidiabetic drugs ( comparison ) ; and ( iv ) efficacy parameters such as percentage decrease in glycosylated haemoglobin ( hba1c ) , changes in lipid profile ; safety parameters such as cases of bladder cancer and utilization pattern such as prescribed dose and combination of pioglitazone ( outcomes ) .
studies were excluded if related to pioglitazone use in other conditions such as ( i ) polycystic ovary syndrome ; ( ii ) psoriasis ; ( iii ) type 1 diabetes mellitus ; ( iv ) in vitro studies ; and ( v ) reviews , commentaries and editorials .
drug utilization studies : the data extracted included ( i ) region in which the study was carried out ( north , south , east , west and central india ) ; ( ii ) the setting in which the study was carried out ( in- or out - patient ) ; ( iii ) type of health care setting ( community / government hospital / private hospital ) ; ( iv ) number of prescriptions studied ; ( v ) patient 's age , body mass index , gender , duration of diabetes , co - morbidities ; and ( vi ) the use of pioglitazone ( dose , whether as monotherapy or in combination with other drugs ) . the overall use of pioglitazone ( percentage ) in each region was calculated from the data provided in individual studies ( usage and number of prescriptions ) .
efficacy studies : the data extracted in the spreadsheet included changes in glucose and lipid profile with respect to baseline namely , fasting plasma glucose , postprandial plasma glucose , hba1c , triglycerides ( tgs ) , total cholesterol ( tc ) , high - density lipoprotein cholesterol ( hdl - c ) , and low - density lipoprotein cholesterol ( ldl - c ) . the dose and duration of pioglitazone and also its effects on requirement of other antidiabetic drugs such as insulin and sulphonylureas , were noted .
safety studies : the data extracted included the following details about patients ( case history ) : ( i ) age ; ( ii ) gender ; ( iii ) duration of t2 dm ; ( iv ) dose of pioglitazone ; ( v ) duration of pioglitazone use ; ( vi ) investigations ; and ( vii ) outcomes .
data from india were compared with the data and publications with similar methodology / data sets analyzed in references from the ema - ar .
ema assessment report was chosen for comparison as it is freely available in the public domain and gives comprehensive information on benefit - risk evaluation of pioglitazone4 .
the drug utilization data from india were compared with that of the general practice research database ( gprd ) , united kingdom4 .
results from clinical trials ( cts ) conducted in india were compared with that of proactive study carried out in europe67 .
epidemiological studies on bladder cancer associated with pioglitazone from india were compared with kaiser permanente northern california ( kpnc ) ( usa)8 , french cohort study9 and gprd study ( uk)10 .
spontaneous reports from who - umc : ema - ar did not have information on data from vigibase . however , to get an estimate of spontaneous reports for pioglitazone , a summary of adverse drug reactions ( adrs ) associated with pioglitazone was obtained from the who - umc vigibase , global individual case safety report ( icsr ) database through personal communication .
the reporting period in this database was from 2000 to november 18 , 2014 for countries such as usa , uk , japan and france while for india it was from 2011 onwards .
the vigibase data were provided as a spreadsheet which included summary of all adrs , country - wise and year - wise adrs .
we extracted adrs related to urinary bladder for india , usa , france , uk and japan from this spreadsheet as the latter three represented regulated markets .
the bladder - related abnormalities in the spreadsheet included bladder calculus , bladder carcinoma , bladder discomfort , bladder fibrosis and bladder neoplasm benign .
sixty six articles fulfilled the inclusion and exclusion criteria and were taken up for the sr .
of these , 13 each were randomized controlled trials and prospective cohort studies , 34 were cross - sectional studies , three case reports , two case series and one was a retrospective cohort study .
thirty two articles were on drug utilization , 26 on efficacy and eight were on safety .
real life , prescription monitoring , drug utilization studies , of which 15 were prospective cohort studies , five were retrospective cohort studies and 12 were cross - sectional studies .
these studies were carried out in tertiary care ( 5 public and 27 private ) hospitals . the study duration varied from two months to two years .
the number of prescriptions studied ranged from 64 to 1185 , and duration of t2 dm was from 0 to 1 year ( newly diagnosed ) to about 10 yr , but duration of pioglitazone use was not specified .
pioglitazone was used mostly in combination with metformin and sulphonylurea , and the prescribed dose was 15 - 30 mg . in one study , it was used in combination with metformin , sulphonylurea and dipeptidyl peptidase - iv inhibitor at 15 mg / day dose11 . in five studies patients from only inpatient departments were included1213141516 , one study included patients from both inpatient and outpatient departments17 while 25 studies included patients from outpatient departments only18192021222324252627282930313233343536373839404142 .
pioglitazone was prescribed to 6.5 - 11 per cent of t2 dm patients in inpatient departments1213141516 .
the extent of the use of pioglitazone in outpatient departments ( 26 studies ) was described as percentage of t2 dm patients in 16 studies ( table i ) and as percentage of antidiabetic drug prescriptions in 10 studies ( table ii ) .
there was regional variation in pioglitazone use across india , being more in the north compared to the south ( table ii ) .
pioglitazone utilization in different regions of india expressed as percentage of prescriptions of type 2 diabetic mellitus patients in outpatient departments pioglitazone utilization in different regions of india expressed as percentage of antidiabetic drug prescriptions in outpatient departments glycaemic control : there were 26 studies ( 13 randomized and 13 non - randomized , controlled , comparative cts ) with primary objective to determine efficacy of pioglitazone in t2 dm patients .
eight were monotherapy4344454647484950 , one add - on to metformin51 , four add - on to sulfonylurea52535455 , and eight were add - on to sulphonylurea and metformin combination5657585960616263 .
two studies evaluated add - on to metformin , sulphonylurea and insulin6465 ; three evaluated and noted decrease in -amylase , glucokinase and gamma - glutamyl transferase activities666768 . the results from 13 studies from india and from proactive studies carried out in europe are summarized in ( table iii ) .
studies in india have been done in younger patients , with shorter duration of t2 dm , shorter trial duration , and lower dose of pioglitazone ; however , the decrease in hba1c ( efficacy ) was found to be comparable to proactive studies . in one study , 7.5 mg of pioglitazone given with insulin , sulphonylurea , metformin and -glucosidase inhibitor was found to be effective in achieving good glycaemic control59 .
comparison of efficacy of pioglitazone in studies from india with proactive studies other effects : pioglitazone did not have any detrimental effect on lipid profile in indian patients , which is comparable to that in proactive study .
it was shown to decrease serum tg ( 10 - 35% ) , tc ( 5 - 30% ) and ldl - c ( 1.4 - 31.5%)454647485052 and increase hdl - c ( 2.5 - 14.4%)4547 .
it also demonstrated an increase in apolipoprotein - a1 and a decrease in apolipoprotein - b which corresponded with increase in hdl - c and decrease in ldl - c , respectively4446 .
it decreased significantly homeostasis model of assessment of insulin resistance , plasma fasting insulin and increased adiponectin ( 2.7 fold ) compared to baseline43454656 .
it was observed to produce a significant decrease in c - reactive protein , tumour necrosis factor - alpha and serum malondialdehyde and increase in serum magnesium , angiotensin , interleukin-8 and serum glutathione5368 . in one study , a significant decrease in systolic ( 11.8% ) and diastolic ( 11.6% ) blood pressure was noted when compared to sulphonylureas or other insulin secretagogues47 .
bladder cancer : there were two case reports and one case series of eight patients697071 . of these 10 patients , nine were males , age being 65 yr and 64 yr in the case reports and 43 - 76 yr in the case series , dose used was 15 - 30 mg / day , duration of use was 1 - 9 years , eight had developed transitional cell carcinoma , one had bladder dysplasia while the nature of malignancy of one patient was not reported .
one patient died of metastasis to lung and liver , another had recurrence of haematuria on rechallenge with pioglitazone while one was in remission for 11 months after receiving six cycles of mitomycin chemotherapy .
the outcome of the remaining patients was not reported . in a retrospective cohort study carried out in india on 1077 diabetics with cancer ,
20 were bladder cancer cases , of whom one was in the pioglitazone exposed group which consisted of 31 patients with exposure for more than two years and dose 7.5 - 15 mg / day .
kpnc study ( usa ) which included 193,099 diabetic patients found significant risk of bladder cancer in pioglitazone exposed patients with cumulative dose more than 28,000 mg and cumulative duration more than two years8 . the french cohort study with 1,491,060 diabetic patients found significant association with exposure more than one year and two years9 while gprd study of the uk in 207,714 diabetics found no significant association10 ( table iv ) .
comparison of bladder cancer cases in pioglitazone - exposed and non - exposed patients in studies from india , united states of america , france and united kingdom in the who - umc , vigibase , there were 101 spontaneous reports on pioglitazone from india , most common ones being hypoglycaemia ( 19.8% ) and oedema ( 19.8% ) but none on bladder abnormalities while globally there were 1862 reported cases of bladder carcinoma associated with pioglitazone .
other safety issues : in cts , compared to baseline , significant increase in body weight ( 1.61.3 kg ) , increase in body mass index ( 0.70.3 kg / m ) , reduction in haemoglobin and compared to placebo reduction in total , free and bioavailable testosterone with increase in androstenedione were observed4449556573 .
no significant change in liver function tests , urine composition ( ph , proteinuria , pyuria or haematuria ) compared to baseline was observed59 .
hypoglycaemia , haematemesis , myocardial infarction , renal stone and fracture were reported in cts4448 .
incidence of fracture in pioglitazone group ( 1.9% ) was not significantly different compared to placebo group ( 1.9% ) during a three - year study48 . in a case report a patient with grave 's disease and t2 dm developed chemosis , proptosis and lid retraction while on pioglitazone with reversal on its discontinuation and treatment with steroids and surgical decompression74 .
increased micronuclei formation75 and reversible atrial and mitral valve regurgitation with pioglitazone use76 have also been reported .
bladder cancer : there were two case reports and one case series of eight patients697071 . of these 10 patients , nine were males , age being 65 yr and 64 yr in the case reports and 43 - 76 yr in the case series , dose used was 15 - 30 mg / day , duration of use was 1 - 9 years , eight had developed transitional cell carcinoma , one had bladder dysplasia while the nature of malignancy of one patient was not reported .
one patient died of metastasis to lung and liver , another had recurrence of haematuria on rechallenge with pioglitazone while one was in remission for 11 months after receiving six cycles of mitomycin chemotherapy .
the outcome of the remaining patients was not reported . in a retrospective cohort study carried out in india on 1077 diabetics with cancer , 20 were bladder cancer cases , of whom one was in the pioglitazone exposed group which consisted of 31 patients with exposure for more than two years and dose 7.5 - 15 mg / day .
kpnc study ( usa ) which included 193,099 diabetic patients found significant risk of bladder cancer in pioglitazone exposed patients with cumulative dose more than 28,000 mg and cumulative duration more than two years8 . the french cohort study with 1,491,060 diabetic patients found significant association with exposure more than one year and two years9 while gprd study of the uk in 207,714 diabetics found no significant association10 ( table iv ) .
comparison of bladder cancer cases in pioglitazone - exposed and non - exposed patients in studies from india , united states of america , france and united kingdom in the who - umc , vigibase , there were 101 spontaneous reports on pioglitazone from india , most common ones being hypoglycaemia ( 19.8% ) and oedema ( 19.8% ) but none on bladder abnormalities while globally there were 1862 reported cases of bladder carcinoma associated with pioglitazone .
other safety issues : in cts , compared to baseline , significant increase in body weight ( 1.61.3 kg ) , increase in body mass index ( 0.70.3 kg / m ) , reduction in haemoglobin and compared to placebo reduction in total , free and bioavailable testosterone with increase in androstenedione were observed4449556573 .
no significant change in liver function tests , urine composition ( ph , proteinuria , pyuria or haematuria ) compared to baseline was observed59 .
hypoglycaemia , haematemesis , myocardial infarction , renal stone and fracture were reported in cts4448 .
incidence of fracture in pioglitazone group ( 1.9% ) was not significantly different compared to placebo group ( 1.9% ) during a three - year study48 . in a case report a patient with grave 's disease and t2 dm developed chemosis , proptosis and lid retraction while on pioglitazone with reversal on its discontinuation and treatment with steroids and surgical decompression74 .
increased micronuclei formation75 and reversible atrial and mitral valve regurgitation with pioglitazone use76 have also been reported .
bladder cancer : there were two case reports and one case series of eight patients697071 . of these 10 patients , nine were males , age being 65 yr and 64 yr in the case reports and 43 - 76 yr in the case series , dose used was 15 - 30 mg / day , duration of use was 1 - 9 years , eight had developed transitional cell carcinoma , one had bladder dysplasia while the nature of malignancy of one patient was not reported .
one patient died of metastasis to lung and liver , another had recurrence of haematuria on rechallenge with pioglitazone while one was in remission for 11 months after receiving six cycles of mitomycin chemotherapy .
the outcome of the remaining patients was not reported . in a retrospective cohort study carried out in india on 1077 diabetics with cancer , 20 were bladder cancer cases , of whom one was in the pioglitazone exposed group which consisted of 31 patients with exposure for more than two years and dose 7.5 - 15 mg / day .
kpnc study ( usa ) which included 193,099 diabetic patients found significant risk of bladder cancer in pioglitazone exposed patients with cumulative dose more than 28,000 mg and cumulative duration more than two years8 . the french cohort study with 1,491,060 diabetic patients found significant association with exposure more than one year and two years9 while gprd study of the uk in 207,714 diabetics found no significant association10 ( table iv ) .
comparison of bladder cancer cases in pioglitazone - exposed and non - exposed patients in studies from india , united states of america , france and united kingdom in the who - umc , vigibase , there were 101 spontaneous reports on pioglitazone from india , most common ones being hypoglycaemia ( 19.8% ) and oedema ( 19.8% ) but none on bladder abnormalities while globally there were 1862 reported cases of bladder carcinoma associated with pioglitazone .
other safety issues : in cts , compared to baseline , significant increase in body weight ( 1.61.3 kg ) , increase in body mass index ( 0.70.3 kg / m ) , reduction in haemoglobin and compared to placebo reduction in total , free and bioavailable testosterone with increase in androstenedione were observed4449556573 .
no significant change in liver function tests , urine composition ( ph , proteinuria , pyuria or haematuria ) compared to baseline was observed59 .
hypoglycaemia , haematemesis , myocardial infarction , renal stone and fracture were reported in cts4448 .
incidence of fracture in pioglitazone group ( 1.9% ) was not significantly different compared to placebo group ( 1.9% ) during a three - year study48 . in a case report a patient with grave 's disease and t2 dm developed chemosis , proptosis and lid retraction while on pioglitazone with reversal on its discontinuation and treatment with steroids and surgical decompression74 .
increased micronuclei formation75 and reversible atrial and mitral valve regurgitation with pioglitazone use76 have also been reported .
with pioglitazone being initially banned by the indian drug regulatory authority and later the ban being revoked , along with varying regulatory decisions in european countries , the need was felt to analyze its utilization , efficacy , safety in indian t2 dm patients and compare it with ema - ar .
the data available in ema - ar were comprehensive , however , data available from india were limited with respect to prescription monitoring studies , controlled cts for efficacy , case reports on adrs , and epidemiological study on adrs . compared to the data from ema - ar , in india , information on drug utilization in terms of patient years of use is not available .
however , analysis of studies from india has brought out important differences in drug utilization . in the gprd ( uk ) database ,
the defined daily dose of pioglitazone is 30 mg77 . in india , it is mostly used in combination with metformin and sulphonylurea at a dose of 15 - 30 mg / day2628 .
there is also regional variation in pioglitazone prescription with greater use in northern and western india compared to central and southern india with no studies from east india . whether the lower body weight of indians78 makes up for the lower dose used and gives similar exposure as in european population with higher
efficacy of pioglitazone has been studied in randomized and non - randomized comparative studies in india .
there is a lack of adequate epidemiological data and spontaneous reporting of adrs from india .
sample size , dose and duration of use are important variables , in the epidemiological studies . in the french cohort study with large sample size ,
significant association between pioglitazone use and bladder cancer was noted even with more than one year of use9 . in the kpnc study with smaller sample size
compared to french cohort , risk for bladder cancer was noted with cumulative exposure greater than two years and cumulative dose greater than 28,000 mg , while in gprd study , which was a propensity score matched study , no association between pioglitazone and bladder cancer was noted810 .
pioglitazone is metabolized mainly by cyp2c879 , and any variation of this enzyme affecting exposure predisposing to development of bladder cancer through formation of carcinogenic metabolites has not been reported .
factors predisposing to the development of bladder cancer are male sex , increasing age , cigarette smoking , exposure to chemicals such as aromatic amines , acrolein , arsenic , aniline dye , schistosoma haematobium infection , pelvic irradiation , chronic irritation and indwelling catheter80 .
the incidence of bladder cancer per 100,000 population in india has been reported to be three , while in the usa and uk , it is 29.7 and 14.01 - 20.01 , respectively81 .
whether and how this background rate will affect the pioglitazone potential for carcenogenicity needs to be studied .
subsequent to the ema assessment in 2011 , 10 yr follow up of proactive study patients and kpnc cohort study final analysis with 10 yr follow up did not find significant association between pioglitazone and bladder cancer8283 .
though details are not yet published , there may be variables such as discontinuation of pioglitazone to be considered . in cts , case reports and spontaneous reports in the pharmacovigilance programme of india ( pvpi ) ,
most common adrs reported were weight gain , oedema and hypoglycaemia4873 , all of which are listed in summary of product characteristics ( smpc ) and ema - ar for pioglitazone .
average weight gain in indian trials ( 1.68 kg ) had been lesser than in proactive study ( 3.8 kg ) which may be because in indian cts636473 dose of pioglitazone was 7.5 - 30 mg / day while in proactive it was 45 mg / day and duration of treatment was also longer84 .
bone fractures were reported but incidence was similar to that with placebo which could be because of smaller number of patients / women ( n=204/26 ) in the study48 which is contradictory to a meta - analysis ( n=24,544 ) in which a significant increase in incidence of bone fracture in women was noted , with 896 cases of fracture being reported in 22 randomised cts85 .
decrease in serum testosterone observed in one study from india was not reported in smpc or ema - ar , and its clinical significance has also not been established49 .
a case report of worsening of thyroid ophthalmopathy with pioglitazone use has been reported from india and this warrants caution in using pioglitazone in patients with thyroid abnormalities74 .
there are no published case reports and icsrs in vigibase of macular oedema , a listed adr for pioglitazone from india . as per the recommendation by dtab in july - august 2013 ,
indian package inserts of pioglitazone containing products carry boxed warning contraindicating its use as a first - line therapy in diabetes mellitus , use in patients with active bladder cancer and uninvestigated haematuria as well as discontinuation if adequate effect is not observed in 3 - 6 months3 .
elderly patients should be started on lowest possible dose and regularly monitored because of risk of bladder cancer and heart failure .
however , the boxed warning does not provide any guidance on cumulative dose or duration of use .
we were not able to identify any reporting or publication bias in the publications included in this sr .
further as studies of different levels of evidence ( case reports to randomized controlled trials ) were included , the strength of evidence for the various outcomes could not be sufficiently estimated . in conclusion , regional variation in pioglitazone use was observed in india , with higher use in north and west compared to south and central regions . in india ,
pioglitazone is used more often as triple drug combination instead of dual drug therapy with metformin and at lower doses compared to uk .
compared to kpnc or french studies which found significant association between incidence of bladder cancer and pioglitazone cumulative dose > 28,000 mg and duration of use more than one year , in retrospective cohort study from india with 15 - 30 mg pioglitazone taken for more than two years , association between incidence of bladder cancer and pioglitazone use was not seen .
smaller sample size , lower dose of pioglitazone and lower background incidence of bladder cancer might be some of the possible reasons for not finding an association . in controlled cts , though on fewer patients , at shorter duration of treatment and with lower dose , efficacy of pioglitazone on hba1c and lipids was similar to that in proactive studies .
adrs have not been reported to pvpi and it is required that spontaneous reporting must be encouraged .
studies on compliance to warnings given in the package insert for pioglitazone and epidemiological studies with larger sample size and regional representation are needed .
Output:
| background & objectives : with pioglitazone ban and subsequent revoking in india along with varying regulatory decisions in other countries , it was decided to carry out a systematic review on its safety , efficacy and drug utilization in patients with type 2 diabetes mellitus ( t2 dm ) in india and compare with the data from the european medicines agency assessment report ( ema - ar).methods : systematic review was performed as per the preferred reporting items for systematic reviews and meta - analyses ( prisma ) guidelines , searching medline / pubmed , google scholar and science direct databases using pioglitazone and india and human and pioglitazone and india and human and patient and compared with ema - ar .
spontaneous reports in world health organization vigibase from india were compared with vigibase data from other countries.results:sixty six publications , 26 ( efficacy ) , 32 ( drug utilization ) and eight ( safety ) , were retrieved . in india , pioglitazone was used at 15 - 30 mg / day mostly with metformin and sulphonylurea , being prescribed to 26.7 and 8.4 per cent patients in north and south , respectively .
the efficacy in clinical trials ( cts ) was similar to those in ema - ar .
incidence of bladder cancer in pioglitazone exposed and non - exposed patients was not significantly different in an indian retrospective cohort study .
there were two cases and a series of eight cases of bladder cancer published but none reported in vigibase.interpretation & conclusions : in india , probably due to lower dose , lower background incidence of bladder cancer and smaller sample size in epidemiological studies , association of bladder cancer with pioglitazone was not found to be significant .
reporting of cts and adverse drug reactions to clinical trials registry of india and pharmacovigilance programme of india , respectively , along with compliance studies with warning given in package insert and epidemiological studies with larger sample size are needed . |
PubmedSumm4845 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: canagliflozin ( invokana ) is a novel therapy for type 2 diabetes mellitus ( dm ) approved in a new class acknowledged as sodium - glucose co - transporter 2 ( sglt2 ) inhibitors .
canagliflozin inhibits the glucose reabsorption by the kidney , increasing glucose elimination and reducing blood glucose levels in diabetic patients .
acute pancreatitis is a very rare but severe side effect with an incidence < 1% .
we report a case of a 50-year - old man who received a few doses of canaglifozin and developed pancreatitis - induced diabetic ketoacidosis requiring hospitalization in the intensive care unit .
a 50-year - old white man presented to the emergency department with malaise , weakness , abdominal pain , and loss of vision that progressively worsened over 3 days .
he has a history of a long - standing well - controlled type 2 dm treated with insulin , glyburide , and metformin .
4 days before admission his endocrinologist stopped his lantus ( insulin glargine ) and prescribed him on canagliflozin 100 mg oral daily along with glyburide and metformin .
after 10 days of treatment , he developed malaise , weakness , abdominal pain that progressively worsened . on the day of the presentation , he developed blurry vision .
blood test showed blood glucose of 506 mg / dl ; sodium of 125 , potassium 6.8 , chloride of 94 , total carbon dioxide < 5 and anion gap of 26 meq / l ; creatinine 2.0 mg / dl , trop i was negative ; amylase 643 , lipase 982 u / l , aspartate aminotransferase 18 u / l ; total bilirubin 0.9 mg / dl ; atrial blood gas ph 6.85 , partial pressure of carbon dioxide 11 mmhg , partial pressure of oxygen 149 mmhg , bicarbonate 1.9 mmol / l , and electrocardiogram showed normal sinus rhythm but no st - t change .
he was diagnosed diabetic ketoacidosis induced by acute pancreatitis along with acute kidney injury from dehydration . computed tomography of abdomen demonstrated the evidence of acute inflammation of pancreas .
the patient denied any history of recent alcohol use and his serum triglyceride level was normal at 95 mg / dl ( normal range , < 150 mg / dl ) .
his serum creatinine , sodium , potassium , lipase , and amylase level returned to normal after 3 days , and we could stop insulin infusion after the anion gap returned to the normal range .
the patient continues to do well at 2-month follow - up visit without any recurrent symptoms .
canagliflozin is one of sglt2 inhibitors and has been approved by the food and drug administration for type 2 dm by inhibiting sglt2 in the proximal renal tubules .
canagliflozin reduces the reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose ( rtg ) .
sglt2 is the main site of filtered glucose reabsorption ; reduction of filtered glucose reabsorption and lowering of rtg result in increased urinary excretion of glucose , thereby reducing plasma glucose concentrations .
its safety and effectiveness were assessed in nine clinical trials involving over 10,285 patients with type 2 dm .
the most common adverse effects described in the clinical trials were genital yeast infections , urinary tract infections , and increased urination .
anaphylaxis , acute respiratory distress syndrome , or significant electrolyte abnormalities have not been demonstrated in the literature review .
an ongoing trial , canagliflozin cardiovascular assessment study , will provide us more information on risks of malignancies , serious cases of pancreatitis , and other adverse events . in summary , our case demonstrates very rare but serious side - effect , acute pancreatitis in the use of canagliflozin . as the utility of canagliflozin expands
Output:
| canagliflozin ( invokana ) is an innovative treatment for type 2 diabetes mellitus ( dm ) approved in a new class acknowledged as sodium - glucose co - transporter 2 inhibitors .
acute pancreatitis is a very rare side effect with an incidence < 1% . a 50-year - old white male with dm type 2 presented to the emergency department with acute onset of abdominal pain after 4 days treatment with canagliflozin .
he was successfully diagnosed with diabetic ketoacidosis induced by acute pancreatitis .
canagliflozin was discontinued .
his diabetic ketoacidosis was improved after aggressive intravenous fluid along with intravenous insulin infusion .
our case demonstrates very rare but serious side effect , acute pancreatitis in the use of canagliflozin . as the utility of canagliflozin expands
, physicians must be aware of this potentially fatal adverse effect .
more specific details on potential candidates for this novel therapy are urgently needed . |
PubmedSumm4846 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: with the widespread use of highly active antiretroviral therapy ( haart ) , the life expectancy of hiv - infected persons in the united states has increased markedly .
hiv - infected persons are at higher risk for cancer compared with the general population [ 2 , 3 ] .
utilization of highly active antiretroviral therapy ( haart ) has been associated with decreased incidence rates for aids - defining cancers ( adcs ) among hiv - infected persons [ 4 , 5 ] , but its impact on non - aids - defining cancers ( nadcs ) has been mixed [ 68 ] .
an elevated risk of anal cancer [ 9 , 10 ] and hodgkin lymphoma ( hl ) has been observed among haart users [ 11 , 12 ] . after adjusting for cd4 + cell count and hiv viral load , a relationship between duration of antiretroviral therapy and incidence of nadcs
was not observed in a cohort study of hiv - infected adults . in the general population , health insurance coverage has been associated with lower mortality rates and higher utilization of cancer prevention measures such as screening procedures and hpv vaccine uptake . among adults between 18 and 65 years of age in 2007 , 67% had private insurance , mostly through their employers , 14% were covered by medicaid , and 17% were uninsured . insurance coverage varied by educational level and geographic region . among adults ,
28.0% of those who had not completed high school had private insurance compared with 53.9% with a high school degree or equivalent and 75.2% of those who pursued postsecondary education .
private health coverage was reported by 6062% of those in the west and south and 6668% of those in the midwest and east .
reports vary on the health insurance coverage among hiv - infected persons . in the medical monitoring project of hiv - infected persons who sought medical care in 2009 , 81.1% had some insurance coverage and 30.6% were covered by private insurance over the preceding 12 months . in a study of men who have sex with men ( msm ) conducted in 21 metropolitan areas by the national hiv behavioral surveillance system ,
75% of participants had current health insurance and 39% were solely covered by private insurance . among hiv - infected persons , factors associated with private insurance were white race , female gender , men who have sex with men , and having less than two cd4 + counts measures of 200 cells / mm in the preceding year .
risk factors and receipt of health care are related to health insurance coverage among hiv - infected persons .
commercially insured patients initiated antiretroviral therapy at an earlier stage of their disease defined by cd4 + cell counts than those on medicaid .
inpatient hospitalizations occurred less frequently among hiv - infected patients with private insurance compared to those who were uninsured or who had other insurance .
hiv - infected msm with private insurance were less likely to miss primary hiv care appointments than those without insurance . while use of antiretroviral therapy and health care coverage are beneficial for the management of hiv , the implications are unclear with respect to development of cancer .
the objective of this study was to explore the incidence of cancer among commercially insured hiv - infected individuals receiving antiretroviral therapy .
the source of the data for this study was the lifelink health plan claims database of paid insurance claims data from managed care plans and other sources in the united states .
the full database includes information on over 73 million persons from over 80 commercial health care plans in the us .
the database includes duration of participation on a health care plan from enrollment date or first claim date to termination date or last claim date , gender , age at enrollment , geographic region of residence , and insurance claims information .
, we obtained the paid health insurance claims for 65,341 individuals who had at least one claim with an icd-9-cm diagnostic code for hiv ( 042 , v08 , or 079.53 ) and at least one filled prescription for an antiretroviral medication between january 1 , 2006 , and september 30 , 2012 .
we excluded persons under 18 years of age , those for whom gender information was missing , and those for whom the initial claim date for hiv was after plan termination .
cancer cases were identified based on claims in which at least one diagnostic code indicated cancer and the procedure performed was for cancer treatment with surgery , radiation therapy , or chemotherapy .
incident cases were defined as cancer cases diagnosed at least 60 days after the claim for antiretroviral treatment .
if more than one cancer diagnosis was detected for an individual , this report includes the cancer diagnosis from the first claim date .
each individual 's duration of risk from cancer was from the date of the initial antiretroviral claim until the termination of participation in the health plan .
duration of risk from cancer was further divided by attained age : < 30 , 3039 , 4049 , 5059 , or 60 years of age .
for example , an individual who was 35 years of age at the initial hiv claim and terminated the health plan at 42 years of age would contribute 5 years to the cumulative duration of risk of those 3039 years of age and 2 years to the cumulative duration of risk of those 4049 years of age . for aids - defining cancers ( adcs ) and non - aids - defining cancers ( nadcs ) that occurred in at least 5% of the cancer cases , incidence rates per 100,000 person - years and their 95% poisson confidence intervals
poisson regression analyses were used to evaluate the association of age group and gender on incidence rates . to determine whether cancer incidence rates among hiv - infected individuals differed from those for the general population , the expected number of cases for each gender - age group ( < 30 , 3039 , 4049 , 5059 , and 60 ) were estimated using incidence rates from the surveillance epidemiology and end results ( seer ) program ( http://seer.cancer.gov/ ) .
the cochran - armitage test was used to evaluate the trends for the proportion of cancers that were adcs with age for each gender .
the study was reviewed by the institutional review board ( irb ) at the university of arkansas for medical sciences .
the mean ( sd ) ages at initial claim for antiretroviral therapy for men and women were 44.6 ( 9.6 ) years and 43.0 ( 9.8 ) years and their mean durations of participation in a health care plan following initial antiretroviral claim were 3.7 ( 3.2 ) years and 3.9 ( 3.5 ) years , respectively . the number of person - years at risk by gender and age group is summarized in table 1 .
a total of 1,130 persons had at least one treatment claim with a diagnosis of cancer : 978 men and 152 women .
the most frequently reported cancers were non - hodgkin lymphoma ( nhl ) , kaposi sarcoma ( ks ) , anal cancer , and prostate cancer ( table 2 ) .
the proportion of cancers that were aids - defining decreased with age for both men ( p < 0.001 ) and women ( p < 0.001 ) ( figure 1 ) . among persons under 40 years of age , the majority of cancers were adcs .
the incidence of non - hodgkin lymphoma did not vary by age or gender ( table 3 ) .
the incidence rates for kaposi sarcoma decreased with age with lower rates for those 60 years and older compared to those 3059 years of age ( p = 0.038 ) which , in turn , were significantly lower than the incidence rates for persons under 30 years of age ( p = 0.045 ) .
ks occurred more frequently among men ( ir = 103.5 ) compared to women ( ir = 12.9 ) ( p < 0.001 ) .
anal cancer and hodgkin lymphoma incidence rates varied by gender , but not by age ( table 4 ) .
( p = 0.011 ) , and for hodgkin lymphoma were 40.6 and 12.9 , respectively ( p = 0.025 ) .
hiv - infected persons 60 years or older had higher incidence rates than those 3059 years of age for colorectal ( p = 0.003 ) , lung ( p < 0.001 ) , and prostate ( p < 0.001 ) cancer .
as expected , incidence rates for ks and nhl were elevated compared to those in the general population and their sirs declined with age .
sirs for women and men were 15.66 ( 95% ci : 8.55 to 19.49 ) and 34.3 ( 95% ci : 28.46 to 36.56 ) for anal cancer , respectively , and 4.8 ( 95% ci : 1.28 to 7.56 ) and 10.7 ( 95% ci : 8.01 to 11.84 ) for hodgkin lymphoma , respectively . for colorectal , lung , and prostate cancer , incidence rates for hiv - infected persons
were lower than those for the general population . for lung and colorectal cancer , the sirs for persons 60 years and older were lower than those for individuals who were 3059 years of age
from our examination of the incidence of cancer among privately insured hiv - infected adults in the us who were receiving antiretroviral therapy , we made several observations .
we confirmed that infection - related cancers , including nhl , ks , and anal cancer , were the most commonly reported cancers in this population .
consistent with previous reports , we found that the incidence rates of noninfection related nadcs such as colorectal and prostate cancer were lower than those for the general population .
our finding that the incidence rate of lung cancer was lower than in the general population varies from previous reports .
the proportion of cancer cases in this study that was adcs was lower than previously reported [ 2224 ] . among hiv - infected cancer cases , about half were adcs in an italian study , one - third were adcs in a single institution study in the us , and 60% were adcs in an australian observational database .
our finding of the decline with age in the proportion of cancers that are adcs is consistent with reports on the age - related decline in cancers attributable to infectious agents [ 25 , 26 ] .
incidence rates for ks in this study were similar to those reported in other studies during the haart era [ 4 , 8 ] .
decreases in the incidence rate of ks have been observed with the increasing use of haart [ 6 , 27 , 28 ] and increases in cd4 + cell counts [ 29 , 30 ] .
the increased risk of ks among men was related to the higher prevalence of human herpesvirus 8 infection , the etiologic agent of ks , among msm compared to other risk groups [ 30 , 31 ] .
the declining incidence of ks associated with age observed in this study has been described previously .
the incidence of nhl observed in this study was similar to or lower than reported previously [ 4 , 8 ] .
although a gender disparity in nhl incidence was not observed in this study , other reports showed that hiv - infected msm have the highest risk of nhl , followed by other men and women .
the risk of nhl was inversely correlated with cd4 + cell count [ 29 , 30 ] . like ks ,
the incidence of nhl has decreased with time [ 6 , 27 , 28 ] . although the incidence rates of both nhl and ks have decreased with time .
hiv - infected persons remain at elevated risk for both of these aids - defining cancers .
our hl incidence was similar to previous reports [ 8 , 33 , 34 ] .
the gender difference in hl incidence is similar to that reported in the general population .
there are mixed reports on the association between cd4 + cell counts and risk of hl among hiv - infected persons .
the incidence of hl was positively correlated with cd4 + cell counts which suggests that improvements in cd4 + lymphocyte counts related to haart use lead to an increasing risk of hl [ 33 , 36 ] .
lower cd4 + lymphocyte counts in the 1 - 2 years preceding hl diagnosis were significantly associated with an elevated hl risk in the swiss hiv cohort study .
it has been reported that hl incidence is highest in the 13 months following haart initiation and decreases but remains elevated 46 months following haart initiation .
our finding that hl incidence among hiv - infected persons was elevated compared to the general population corroborates previous reports [ 2 , 6 , 33 , 38 ] .
our anal cancer incidence rate for men was between the rates for msm and other men reported in the north american ( na ) accord study but lower than those from other reports [ 4042 ] .
anal cancer incidence in women was similar to that in the na - accord study .
anal cancer incidence rates among hiv - infected persons have increased with time [ 27 , 28 ] .
the sir in this study was similar to that reported previously [ 2 , 6 , 8 ] .
human papillomavirus ( hpv ) infection is causally related to anal cancer . among hiv - infected msm ,
detection of anal hpv was associated with receptive anal intercourse and number of male sexual partners in the preceding 6 months . among hiv - infected men , the prevalence of anal hpv-16 , one of the high risk hpv types , decreases with educational level . in a study of msm ,
those with health insurance were less likely to engage in unprotected anal intercourse with male partners and had higher educational attainment than their uninsured counterparts .
since our participant population was insured , the rate of anal cancer in men may reflect a lower prevalence of anal hpv due to less risky sexual behavior and higher educational attainment . in our study ,
risks for cancers that are not infection - related were not elevated compared to the general population .
the observed incidence of colorectal cancer does not differ significantly from previous reports [ 29 , 41 ] .
the lung cancer incidence rate among those 3059 years old was lower compared to their older counterparts , consistent with the increasing risk of lung cancer with age in the general population . compared to the general population ,
the incidence rate in the younger age group did not differ significantly , but older hiv - infected persons had a lower lung cancer incidence rate .
our findings vary from reports of an elevated risk of lung cancer associated with hiv [ 2 , 5 , 6 , 8 , 40 , 41 ] .
it has been reported that hiv patients are not at elevated risk after adjusting for smoking and other risk factors , but other reports show that hiv is an independent risk factor for lung cancer [ 5 , 49 ] .
hiv - infected persons are diagnosed with lung cancer at earlier ages and at lower cumulative smoking exposures than the general population [ 48 , 50 ] .
the decreased incidence of lung cancer in this study may reflect a lower prevalence of smoking in our population . in a study of msm that measured health access using three indicators based on primary care clinic visits in the preceding 2 years , current health insurance , and perceived barriers to health care , smoking prevalence decreased with the increase in positive health access indices . among adults in the us ,
the proportion with private health insurance coverage increases with educational level and smoking prevalence declines with educational level .
a report from the french hiv database study reported an inverse relationship between lung cancer risk and cd4 counts and an elevated risk of lung cancer was observed among hiv - infected individuals with cd4 + cells counts below 200 l in an integrated health care system in the us .
other studies did not show a correlation between cd4 count and lung cancer risk [ 53 , 54 ] .
our finding that prostate cancer incidence was reduced in hiv - infected men confirms previous reports [ 55 , 56 ] . although it was suggested that the decreased incidence rate was associated with a lowered use of the prostate - specific antigen ( psa ) test to screen for prostate cancer , a comparison of hiv - infected and hiv - uninfected men in california found no difference with respect to psa screening utilization . as our case definition required an insurance claim for cancer treatment , cancer cases that were not treated
it has been widely reported that hiv - infected persons are less likely to receive treatment for cancer than their immunocompetent counterparts [ 5759 ] .
the disparity in receipt of treatment persists even among privately insured cancer patients . among lung cancer patients with private insurance ,
23% of those infected with hiv and only 10% of those who were uninfected with hiv were untreated .
since the database is one of administrative claims , the actual date of diagnosis was unknown .
our use of the 60-day window between initiation of antiretroviral use and cancer diagnosis may have led to an undercounting of cancer cases .
individual level information was not available for race / ethnicity , socioeconomic status , education level , level of immune suppression , or measures of sexual activity .
the database did not allow evaluation of the relationship between haart , markers of hiv disease , and cancer incidence .
this study in a population of commercially insured hiv - infected persons treated with antiretroviral therapy found elevated incidence rates for ks and nhl and infection - related nadcs , anal cancer , and hodgkin lymphoma .
incidence rates for lung and colorectal cancer were not elevated in this hiv - infected population .
similar to other studies , prostate cancer incidence was lower among hiv - infected men compared to the general population .
although privately insured hiv - infected persons have greater access to health care services and earlier exposure to antiretroviral therapy ( schneider ) and engage in fewer risky behaviors ( mckirnan ) than those with public insurance or who lack insurance , this did not appear to reduce the cancer incidence rates in this population .
commercially insured hiv - infected adults treated with antiretroviral therapy were at greater risk of infection - related cancers compared to the general population
. their risk for common non - aids defining cancers of the lung , colon / rectum , and prostate was not elevated .
Output:
| the objective of this study was to explore the cancer incidence rates among hiv - infected persons with commercial insurance who were on antiretroviral therapy and compare them with those rates in the general population .
paid health insurance claims for 63,221 individuals 18 years or older , with at least one claim with a diagnostic code for hiv and at least one filled prescription for an antiretroviral medication between january 1 , 2006 , and september 30 , 2012 , were obtained from the lifelink health plan claims database .
the expected number of cancer cases in the general population for each gender - age group ( < 30 , 3039 , 4049 , 5059 , and > 60 years ) was estimated using incidence rates from the surveillance epidemiology and end results ( seer ) program .
standardized incidence ratios ( sirs ) were estimated using their 95% confidence intervals ( cis ) . compared to the general population ,
incidence rates for hiv - infected adults were elevated ( sir , 95% ci ) for kaposi sarcoma ( 46.08 ; 38.7448.94 ) , non - hodgkin lymphoma ( 4.22 ; 3.634.45 ) , hodgkin lymphoma ( 9.83 ; 7.4510.84 ) , and anal cancer ( 30.54 ; 25.6232.46 ) and lower for colorectal cancer ( 0.69 ; 0.520.76 ) , lung cancer ( 0.70 ; 0.54 , 0.77 ) , and prostate cancer ( 0.54 ; 0.450.58 ) . commercially insured , treated hiv - infected adults had elevated rates for infection - related cancers , but not for common non - aids defining cancers . |
PubmedSumm4847 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: according to analyses of the world health organization ( who ) , more than 800 000 people died from suicide in 2012 , and the number of attempted suicides is estimated to be about 20 times higher .
however , the lethality of suicidal behavior is clearly higher in males , resulting in higher rates of completed suicides than in females .
the male - female rate of age - adjusted suicide rates is especially high in europe ( about 4:1 ) and high - income countries , but is lower in low- and middle - income countries ( 1.6:1 ) .
a recent study with data from assessment regions of four different european countries confirmed the higher lethality of suicidal behavior in men ( lethality of 13.9% vs 4.1% , figure 1 ) .
the main reason for this gender difference in lethality was the choice of more lethal methods by males .
in addition , even within the same method , the outcome of suicidal acts was more lethal in males than in females , suggesting that there are gender differences for other aspects , such as intention to die or the social context in which the suicidal behavior is performed figure 2 .
as can be seen in figure 1 , intoxication is by far the most often chosen suicidal method , and this is even more the case for females . in the aforementioned study , for females ,
71% of all registered suicidal acts are due to intoxication , whereas in males , this is the case in only 50% .
because intoxication is so often used as a suicidal method , suicide rates depend on how lethal these intoxications are . in europe
however , in most low- and middle - income countries , pesticides and other toxic substances that are banned in europe are available in many households .
consequently , many of the suicidal intoxications by females have a lethal outcome , explaining the more equal male - female rate of suicides . in china ,
suicide rates are even higher for females than for males due to a high frequency in young women in rural areas of suicide bypesticides or lethal poisons .
with regard to completed suicides , hanging is overall the method used most frequently in europe . in countries such as switzerland or
the united states where firearms are broadly available , they are the most often used method for completed suicides . in the united states , every day more than 100 people commit suicide , about 50% using firearms . compared with other high - income countries ,
the rate of firearm suicides in the united states is 8 times higher , whereas the overall suicide rate is average .
there is also evidence that the availability of firearms at home increases suicide risk . in most countries ,
suicide rates are low below the age of 15 and increase with age , especially in older age .
knowledge about the causes and determinants of suicidal behavior ( defined here as attempted and completed suicides ) is important in order to develop efficient suicide - prevention programs . when discussing the causes for suicidal behavior in the context of depression or other psychiatric disorders
, the patient 's perspective has to be kept separate from the more objective medical perspective . from the patient 's perspective ,
most suicidal patients feel they are in a life situation with unbearable suffering and without hope for relief . however , their perceptions of their life situations are often strongly distorted by psychiatric disorders . in the context of depression ,
existing private , professional , or health problems are magnified and become the main focus .
the tinnitus or the lower back pain , for example , that has been tolerated well by the patient outside of the depressive episode becomes unbearable and will probably be reported as the reason for their hopelessness and suicidal thoughts . in schizophrenia , acoustic hallucinations or paranoid delusions
it is therefore important to interpret the reasons for suicidal intentions provided by the patient in the context of possible distortions caused by psychiatric disorders . from an outside perspective , the reasons for suicidality provided by the patient are interpreted as a result of the psychiatric eg , depressive or delusional symptomatology . if depression is treated , then hope , energy , and the ability to experience pleasure will be regained , and all these problems , although objectively unchanged and possibly serious , will become manageable again , and part of the negative aspects of life . in order to put the patient 's perspective in a more objective context , it is important that psychiatric disorders such as depression are carefully diagnosed .
disorders such as depression have to be taken as independent disorders and not as a mere consequence of difficult life circumstances .
two models concerning the causal links between depression and other mental disorders , psychosocial factors , and suicides are presented .
it considers psychosocial circumstances such as unemployment rate , social coherence at the societal level , or stressful life circumstances at the individual level to be dominant causal factors leading both to mental disorders , such as depression , and to suicides . however , there are good arguments to assume that model b might be closer to the truth , as suggested , for example , by the following findings : suicidal acts are rarely an act of free will , but are , in most cases , the tragic result of untreated psychiatric disorders .
psychological autopsy studies showed that around 90% of suicide victims in high - income countries had been suffering from psychiatric disorders .
most important in this context are affective disorders , which have been present in more than 50% of suicide victims .
alcohol and drug dependence , schizophrenia , and personality disorders are further mental illnesses that are often identified in suicide victims by psychological autopsy studies
.
there have been several publications claiming that the economic crisis has induced an increase in suicide rates ( for example , see refs 11 and 12 ) .
furthermore , it has to be discussed by which mechanisms the economic crisis could influence suicide rates . according to model b
, a plausible hypothesis would be that in some countries the economic crisis would cause deterioration in care for people with mental disorders . in countries in which patients have to pay for antidepressants or psychotherapy and where mental health services are shut down because of the economic crisis , care for patients with mental disorders would deteriorate and more patients would remain untreated .
this interpretation is supported by a recent publication by ricardo gusmao and the european alliance against depression ( eaad ) : data from 29 european countries showed that changes in suicide rates were not related to gross domestic product ( gdp ) , unemployment rate , or alcohol consumption , but to the prescription of antidepressants .
an increase in the rate of prescription of antidepressants was associated with a decrease in suicide rates .
the suffering associated with severe somatic disorders is often seen as a factor possibly leading to suicidal behavior .
there are several studies suggesting that this is the case ( see ref 15 , for example ) .
for example , the increase in somatic complaints often observed within depressive episodes could lead to a better recognition rate of somatic disorders , as they are then more likely reported , or depression could increase the incidence of some somatic disorders .
of special interest for this discussion is a large study from great britain , in which over a period of 8 years and in cooperation with nearly 600 primary care providers , the patient charts of over 4 million patients were collected .
they contained 873 suicide cases , enabling the analysis of how many of these suicide victims had at least one out of a list of 11 severe somatic disorders ( stroke , cancer , asthma , cardiovascular disease , diabetes mellitus , hypertonus , chronic obstructive pulmonary disease , epilepsy , chronic lower back pain , osteoporosis , osteoarthritis ) .
this was found to be the case for 38.7% of suicide victims . however , this was also the case for 37% of the 17 000 controls who were of comparable age and gender .
the diagnosis of cancer was present in 3.4% of the suicide victims ; however , this was also true for 3.2% of the controls .
these disorders apparently have not increased the suicide risk , although it can be assumed that many of the patients had named the suffering and fears associated with these somatic diagnoses as reasons for their suicidal intentions .
the objective perspective , however , shows that severe somatic disorders do not strongly increase the suicide risk .
the presence or absence of depression or other mental disorders is more likely to be the crucial determinant .
after the reunification of germany in the year 1990 , a period of elevated social stress and societal change was experienced in the eastern part of germany . the unemployment rate
increased from zero to 20% , societal values were changed , and many professional careers came to a sudden end . according to the sociologist emile durkheim , this would be a classic scenario leading to increases in suicide rates .
however , the opposite , namely a sharp decrease in suicide rates , was found in the eastern part of germany . this can be considered as a nearly perfect disproving of durkheim 's theory .
according to this model , targeting undertreatment of depression and other psychiatric disorders plays a central role in the prevention of suicidal behavior .
the amount of resources most countries invest in research and prevention of suicidal behavior is out of balance considering the size of the problem and the room for improvement in this field .
it appears that decision makers are prone to invest more resources elsewhere , such as in preventing deaths by traffic accidents instead of deaths by suicide .
what are the reasons for this ? sometimes there might simply be a lack of knowledge about the high numbers of suicidal acts and the possibilities to prevent them .
however , more deeply rooted personal and societal beliefs , as well as myths about suicidal behavior , also play a role .
an implicit concept often found is that suicides are acts of free will and that there might be understandable and real reasons for some people to commit suicide in difficult life circumstances . to prevent such acts
is then considered to have a lower priority than to prevent deaths by traffic accidents or other causes . however , as argued above , suicides are rarely acts of free will , but are in most cases a consequence of mental disorders .
it is therefore an important signal that the action plan for mental health developed by the who in 2012 calls all member states to increase efforts to improve mental health and to reduce suicide rates by 10% by the year 2020 .
national suicide prevention programs have to address all levels of society , including , among others , legislation , public opinions and attitudes , the health care system , or the people affected by mental disorders .
the interventions can aim to positively influence the reasons that cause people to engage in suicidal behavior ( eg , reducing hopelessness and despair within a depressive episode ) , but can also target other factors influencing the number and lethality of suicidal behaviors , such as reducing access to lethal methods or unfavorable media reporting inducing the werther effect ( imitation suicide ) .
an impressive recent example of the werther effect arose with the railway suicide by the german national goalkeeper robert enke , who suffered from depression .
this suicide was followed by intense media reporting , including the broadcast of the funeral in a soccer stadium .
this reporting induced not only a sharp increase in railway suicides in the days following this intense reporting , but had long - term effects . in the 2 years after the suicide of robert enke ,
the mean daily number of railway suicides was 2.7 compared with 2.3 in the 2 years before this event .
furthermore , it could be shown that this effect was also spreading to some neighboring countries . to avoid or reduce
, the focus will be on the community based four - level intervention model promoted by the eaad ( www.eaad.net ) .
this is , worldwide , the most often implemented and best evaluated intervention concept simultaneously targeting depression and suicidal behavior .
it was first evaluated within the model project nuremberg alliance against depression and has since been implemented in more than 100 regions in europe . during the 2-year intervention period in nuremberg ( 500 000 inhabitants ) ,
intense activities were started simultaneously on the following four levels : ( i ) cooperation with general practitioners ( gps ) .
training was offered , as well as informational material that could be handed out to patients with depression .
this intervention level is justified in that most suicidal patients are seen by primary health care providers and that more expertise in providing care for suicidal and/or depressed patients according to treatment guidelines is required .
( ii ) a professional public relation campaign with the key messages depression can hit everybody , depression has many faces , and depression can be treated .
the information campaign comprised an opening ceremony in the city hall , a series of public events , posters , leaflets , and a cinema spot .
( iii ) training of community facilitators and gatekeepers , including teachers , priests , geriatric caregivers , journalists , pharmacists , and other professional groups that are potentially in contact with depressed individuals in their working routine .
with regard to the journalists , the focus was on increasing knowledge and sensibility concerning the risks of reporting about suicidal behavior in the media . therefore , a media guide , together with background information , was given to journalists , providing recommendations for beneficial reporting in order to reduce the werther effect .
( iv ) support of self - help by founding self - help groups and providing patients and relatives with information .
this 2-year - intervention was evaluated by investigating changes in the number of suicidal acts ( completed + attempted suicides ; primary outcome ) .
this was done for the intervention region and 2-year intervention period compared with a 1-year baseline and corresponding changes in the control region ( the city of wuerzburg ; 286 885 inhabitants ) . a 24% reduction in suicidal acts compared with the baseline
was observed in nuremberg , whereas no major changes were found in the control region .
further analysis showed that the effect was especially pronounced for serious suicide attempts conducted with more lethal methods .
this finding was not unexpected , because the training of gps , policemen , and other community facilitators probably increased their recognition rate for suicidal behavior .
for example , it depends on the awareness of the family doctor who visits an older patient with an intoxication at home whether this is classified as a suicide attempt or not .
such a bias is less likely for more severe suicide attempts , which are more reliably detected .
meanwhile , under the auspices of the german depression foundation , more than 75 regions and cities have started their own alliances against depression in germany , building on the available intervention and evaluation materials and supported by a coordinating center .
because of the interest of regions from other european countries , the eaad was founded .
it was first started as a european union ( eu)-funded research project and is now continued as a nonprofit association that promotes implementation of this four - level intervention concept in and outside of europe .
this has led to a further improvement in and enrichment of the intervention materials , as best practice materials from different countries have been integrated into the intervention concept .
furthermore , with regard to completed suicides , the evaluation of the activities in hungary supports the effectiveness of this intervention concept . in the intervention region szolnok , a significant reduction in completed suicides
was observed both compared with a control region and with changes in national suicide rates . in the meantime , the european commission 's green paper on mental health ( http://ec.europa.eu/health/mental_health/policy/eu/green_paper/index_en.html ) and the who 's recent suicide prevention report have listed the four - level intervention concept of the eaad as a best practice example for suicide prevention and optimization of care for people with depression .
recently , the intervention materials have been further complemented . in order to support self - help and to reduce the treatment gap in psychotherapy , the ifightdepression tool has been integrated .
this internet - based , guided self - management tool has been developed and consented to within the eu - funded project predi - nu ( preventing depression and improving awareness through networking in the eu ; http://www.eaad.net/mainmenu/research/predi-nu/ ) and is based on the principles of cognitive behavioral therapy .
several such programs have become available in recent years and have been found to be equivalent to face - toface cognitive behavioral therapy .
many lessons have been learned by the eaad consortium from the many regional alliances against depression that have become active in the last 15 years : implementation research performed within the european project
( optimizing suicide prevention programs and their implementation in europe ) , aiming at a further implementation and evaluation of the four - level intervention concept ( http://www.eaad.net/mainmenu/research/ospi/ ) , revealed that being active simultaneously at four different levels develops strong synergistic and also catalytic effects .
for example , the public relations campaign motivates people with depression to seek help from their gp ; one 's gp might then be motivated to improve his expertise in treating depression and thus participate in the training sessions . furthermore , this public relations campaign might lower the threshold for gps to confront patients who often have a somatic disease concept and present somatic complaints with a possible psychiatric diagnosis .
a few examples for catalytic effects were identified by the process analysis performed within the ospi - europe project .
another is the offering of new mental health services because mental health and suicide prevention got on the radar of health politicians and the general public .
depression and suicidal behavior are only partly overlapping phenomena , because there are other disorders and causes for suicidal behavior and because not all patients with depression have suicidal tendencies .
however , it turned out to be a special strength of this four - level intervention concept that both depression and suicidal behavior are intervention targets .
this offers the possibility to shift the focus between these two aims depending on the target group of specific interventions .
when addressing the general public , the topic of depression is on center stage , with the topic of suicide being more in the background .
the reason for that lies in the unknown risks inherent in public relations campaigns that mainly target suicide prevention . reducing the stigma and the social threshold associated with suicidal behavior or increasing the cognitive availability of suicide and suicidal methods might have unwanted effects on suicide rates .
the long - term increase in railway suicides after the intense media reporting about the suicide of the german national goal keeper robert enke in 2009 calls for caution .
in addition , a public relation , campaign that primarily targets depression is likely to have a broader impact on the attention of the general public and the community facilitators , because of the high number of people directly or indirectly affected by depression .
focusing the intervention on depression without broadening it to other mental disorders that are known to be related to suicidal behavior proved to be a favorable strategy .
mental disorders comprise a large number of completely different disorders with different epidemiology , causes , treatments , and prevention strategies .
furthermore , experience from many alliances against depression showed that positive effects of the depression campaign for example , effects on stigma or help - seeking behavior
people with anxiety disorders , schizophrenia , obsessive - compulsive disorder , or other mental disorders also feel addressed and supported by the depression campaign .
in summary , evidence - based intervention concepts that simultaneously target suicidal behavior and depression are available . the eaad offers regions and countries that are interested in starting similar regional campaigns an extensive catalog of intervention and evaluation materials , continuous support in the implementation process , and training involving a train - the - trainer concept .
in addition , broad experience has been gained on how to extend the four - level intervention concept from a model region to a nationwide campaign . in countries with a well - established civil society ,
the regions starting regional alliances against depression have to identify themselves with their local alliance and gain support from volunteers and local sponsors .
Output:
| more than 800 000 people die every year from suicide , and about 20 times more attempt suicide . in most countries
, suicide risk is highest in older males , and risk of attempted suicide is highest in younger females .
the higher lethal level of suicidal acts in males is explained by the preference for more lethal methods , as well as other factors . in the vast majority of cases ,
suicidal behavior occurs in the context of psychiatric disorders , depression being the most important one .
improving the treatment of depression , restricting access to lethal means , and avoiding the werther effect ( imitation suicide ) are central aspects of suicide prevention programs . in several european regions ,
the four - level intervention concept of the european alliance against depression ( www.eaad.net ) , simultaneously targeting depression and suicidal behavior , has been found to have preventive effects on suicidal behavior .
it has already been implemented in more than 100 regions in europe . |
PubmedSumm4848 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: multiple myeloma ( mm ) is a neoplasm of plasma cells accounting for 1015% of hematopoietic neoplasms .
it is more common in people of african descent , occurring twice as frequently compared to caucasians .
plasma cell leukemia ( pcl ) is a very rare type of mm characterized by high numbers ( > 20% ) of circulating plasma cells in the peripheral blood .
it comprises of an estimated 24% of cases of mm and is an aggressive disease with poor prognosis .
the majority of cases occur de novo as primary pcl but it may also occur as leukemic transformation of underlying mm . because of the rarity of this disease , knowledge of its presentation and clinical course has been largely dependent on small studies and case reports .
the clinical presentation typically involves symptoms attributed to end organ damage seen in mm ( hypercalcemia , renal failure , anemia , and lytic bone lesions ) or to leukemia ( leukocytosis , thrombocytopenia and organomegaly ) .
we report a case of pcl with atypical presentation as a chest wall mass and discuss the diagnostic approach as well as treatment options .
a 65-year - old african - american male with a history of type 2 diabetes mellitus and inguinal and abdominal wall hernia presented with complaints of abdominal pain located in the left inguinal region , brought on by heavy lifting .
examination was significant for pallor , hepatomegaly and mild abdominal tenderness at the site of the inguinal hernia .
1a ) and a left chest wall mass with destruction of the underlying rib ( fig .
an ultrasound - guided core needle biopsy of the chest mass , showed a diffuse monotonous population of small to medium - sized lymphocytes with plasmacytoid features ( fig . 2 ) .
the tumor cells were positive for cd138 and cd56 with monoclonal lambda restriction by in situ hybridization and showed a high proliferation index with ki67 ( 60% ) .
laboratory investigation was significant for elevated serum calcium of 12.2 g / dl ( reference 8.510.6 ) with normal parathyroid hormone level and evidence of acute renal failure [ creatinine 1.9 mg / dl ( reference 0.61.2 ) ] .
a complete blood count revealed mild leukocytosis [ 11.2 10/l ( reference 3.210.6 10 ) ] , macrocytic anemia with a hemoglobin of 8.0 g / dl ( reference 14.617.8 ) and mean corpuscular volume 101.9 fl ( reference 7794 ) .
serum protein electrophoresis and immunofixation showed a monoclonal spike with igg lambda , and quantitative igg levels were markedly elevated at 3,139 mg / dl ( reference 7911,643 ) .
a review of his peripheral blood smear showed 2535% circulating atypical lymphocytes with plasmacytoid features ( fig .
3 ) , confirmed to be neoplastic plasma cells by flow cytometry and consistent with pcl . a bone marrow biopsy revealed marked infiltration with monoclonal plasma cells comprising > 50% of total bone marrow cellularity .
prior to the initiation of chemotherapy , the patient spontaneously developed hyperkalemia , worsening renal failure ; creatinine 3.2 mg / dl and elevated uric acid to 8.9 mg / dl ( reference 48.5 ) , suggestive of tumor lysis syndrome . he was managed with i.v .
the patient was referred for clinical trial where he was given induction chemotherapy with cybord ( cyclophosphamide , bortezomib , and dexamethasone ) on days 1 , 8 , 15 , and 22 of each 28-day cycle for a total of 4 cycles .
pcl was first reported in 1906 in a patient who presented with bone pain , a palpable rib mass , rib fractures , anemia , and splenomegaly [ 5 , 6 ] .
interestingly , this parallels our patient , in whom pcl was only diagnosed incidentally after presenting with abdominal pain , and then found to have hepatosplenomegaly and a neoplastic chest wall mass . although pcl lies in the spectrum of plasma cell dyscrasias ( of which mm is most common ) , there are some distinguishing features of the disease .
a review of the literature revealed cases manifesting as lymphadenopathy , hepatomegaly , splenomegaly , leptomeningeal myelomatosis , and soft tissue tumors [ 6 , 7 ] . in contrast ,
bone involvement with resultant lytic lesions , bone pain and pathological fractures is the predominant feature in mm .
patients with pcl are usually younger with a median age of 55 , whereas that for mm patients is 65 . the diagnosis of pcl is based on laboratory parameters . according to the consensus statement by the international myeloma working group
, pcl is defined by the presence of > 20% circulating plasma cells and/or an absolute plasma cell count > 2 10/l . as the diagnosis hinges on establishing an increased number of plasma cells in the peripheral blood , it is important to note that circulating plasma cells in pcl are often small with scant cytoplasm resembling plasmacytoid lymphocytes , and can easily be missed on automated differentials , especially when the white blood cell count is only minimally elevated . in the setting of organomegaly , soft tissue mass and hypercalcemia , serum and urine protein electrophoresis with immunofixation should be obtained to identify a monoclonal immunoglobulin . a careful review of the peripheral smear
should then be performed with peripheral blood flow cytometry to confirm the diagnosis of pcl .
a bone marrow biopsy with cytogenetics should be done in all patients diagnosed with pcl .
pcl is a highly aggressive tumor , with a high disease burden and proliferation index . as a result ,
this has been reported after commencing chemotherapy , but it may occur , as with our patient , even prior to chemotherapy .
it is important to identify patients who are at risk and closely monitor for markers of cell lysis : elevated serum potassium , lactate dehydrogenase and phosphorus , and a fall in serum calcium .
elevated uric acid levels can cause uric acid nephropathy , a predominant cause of acute renal failure in tumor lysis syndrome . due to the rare nature of pcl
, there is no standard treatment as randomized studies are not available and treatment data are extrapolated from mm studies .
the clinical outcome following chemotherapy with conventional agents has been shown to be much worse in pcl compared to mm .
new therapeutic strategies utilizing agents such as lenalidomide , bortezomib , and dexamethasone ( rvd ) , melphalan , prednisone , bortezomib , and thalidomide ( vmpt ) and bortezomib , thalidomide , and dexamethasone ( vtd ) have shown encouraging outcomes .
the overall prognosis is poor with a median survival of 611 months [ 8 , 10 ] , but some improvements in outcomes have been shown with newer therapies and stem cell transplantation . in a study of 445 patients with primary pcl , using the seer database and comparing overall survival in patients diagnosed between 1973 and 2005 to those diagnosed between 2006 and 2009 , there was an increase in overall survival from 5 to 12 months . .
since virtually all patients with pcl who attain a complete remission develop relapse , maintenance chemotherapy should be considered [ 12 , 13 ] .
agents such as lenalidomide , bortezomib , and thalidomide have been used for maintenance therapy . moreover , because of the high rate of recurrence and poor outcome with chemotherapy alone , consolidation with hematopoietic stem cell transplant provides the best hope for remaining in complete remission .
finally , patients with pcl , whenever possible , should be offered the opportunity to participate in clinical trials .
prompt diagnostic evaluation of a chest wall mass followed by peripheral smear evaluation led to timely diagnosis of pcl and early initiation of therapy .
pcl has varied clinical presentation ; as such , increased awareness and thorough evaluation with particular attention to the peripheral smear is paramount to establishing the diagnosis .
tumor lysis syndrome can complicate this aggressive disease ; therefore , there should be close monitoring of renal function .
due to the low prevalence of pcl , the chemotherapy regimens used are largely based on those used for mm .
it is important to report outcomes of therapies / regimens used to help establish guidelines for the management of pcl , pending a randomized clinical trial .
patients should also get early referral to a bone marrow transplant center , as there is a higher likelihood of achieving and maintaining complete remission with combined chemotherapy followed by hematopoietic stem cell transplantation .
the authors state no conflict of interests and have received no payment in the preparation of this paper .
Output:
| plasma cell leukemia ( pcl ) is an uncommon neoplasm of plasma cells , with an aggressive clinical course and poor outcome , even with current standard of care .
it can occur either de novo ( primary pcl ) or as a progression of multiple myeloma ( mm ) .
this disease has unique diagnostic criteria but certain genetic markers and clinical features may overlap with mm .
due to the low prevalence of pcl , guidelines on its management are extrapolated from the management of mm and based on small retrospective studies and cases reports / series .
we present an interesting case of pcl in a middle - aged african - american male , who was diagnosed incidentally after chest wall imaging for an unrelated complaint .
the diagnostic approach , management and outcomes of pcl are discussed . |
PubmedSumm4849 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the entry of contaminants into the environment due to human and natural activities is one of the most important issues facing today 's communities . due to the industrial and economic growth and
the production of a variety of compounds and chemicals followed by increased consumption man makes some unwanted pollutants , many of which cause serious problems and risks for the environment and for man himself .
the most important natural resources of environmental pollution are soil and rock weathering and natural events such as earthquakes and floods .
the entry of municipal , industrial , and agricultural waste into the environment is another way of the environment pollution by human .
the importance of water resources , particularly surface waters ( rivers ) , in meeting the water needs of humans , animals and industries indicates the essential need to protect them against contamination . as municipal , industrial , and agricultural waste enters the water , biological and chemical contaminants including heavy metals also enter water resources .
although some of these metals are essential as micronutrients , their high concentration in the food chain can cause toxicity and environmental impacts and endanger aquatic ecosystems and their users [ 2 , 3 ] .
rivers as water resources , not only in terms of drinking water supply but also in terms of their function in recreational and sport activities such as water sports and fishing , are very important to man 's health .
the investigation of the entry sources , effects , and control of pollutants in rivers has , therefore , always been one of the research topics of environmental scientists .
tembi river , located in the outskirts of masjed soleyman , iran , is open to untreated municipal sewage , runoff , abattoir wastewater , and leachate of solid wastes around it .
regarding the above - mentioned issues and due to the fact that it is a place for the migration of birds in cold seasons as well as for public promenade , swimming , and fishing the present study was thus carried out to investigate the concentration of heavy metals such as copper , zinc , lead , chromium , cadmium , nickel , and manganese due to the discharge of sewage of masjed soleyman into this river .
after determining the location of the sampling points before and after the entry of the sewage , 96 samples ( 48 water samples and 48 sediment samples ) were collected by grab method for 1-year period ; four samples of water and four samples of sediment were collected in each month ee and 3 liters of water was collected in each of sampling from below the water surface and 30 g of sediment samples from a depth of 20 cm under the bed river were collected .
samples of water acidified with nitric acid ( ph = 2 ) along with other samples were transferred to the laboratory .
one gram of each sample was weighed carefully and 5 ml of concentrated nitric acid ( merck , 99.99% ) was added to each sample . the sample , then , was heated up to 80c until near dryness .
the suspension was filtered ( whatman filter merck , 0.45 m ) and the filtrate was diluted by deionized water to a final volume of 50 ml .
three liters of each collected water sample was first concentrated on a sandy oven at 80c until the volume reached 50 ml . then 4 ml concentrated sulfuric acid ( merck , 98% ) was added to each sample and digested by digesdahl apparatus for 3 minutes .
the 10 ml hydrogen peroxide ( merck , 30% ) was then added and heated until oxidation was completed . after cooling , each sample filtered by filter ( whatman filter merck , 0.45 m ) .
the filtrate was diluted by deionized water to a final volume of 50 ml .
the prepared samples were analyzed by a graphite furnace atomic absorption spectrometry ( gfaas , model aanalyst300 ) to determine the metals .
it was conducted to determine the difference of metal ion concentrations among the water and sediment in upstream and downstream of tembi river in different seasons .
the correlation analysis was also carried out to determine the relationship between the concentration of metal ions in water and sediment .
the mean concentration of cd , cr , cu , fe , pb , nis and zn in water and sediment samples before and after the sewage entry into the tembi river is presented with their standard deviations in tables 1 and 2 .
the results of the analysis of water and sediment samples in upstream and downstream of the river revealed that the mean concentration of cd , cr , cu , fe mn , pb , and zn in the downstream water was higher than that in the upstream water in different seasons ( p < 0.001 ) .
table 1 indicates the effect of the entry of sewage ( including untreated municipal sewage , runoff , abattoir wastewater , and leachate of solid wastes around the river ) on tembi river . in a similar research wogu and
okaka investigated 9 similar metals in the warri river in nigeria , which receives the industrial , agricultural , and urban sewage , and showed that the concentration of cd , cr , mn , and ni in this river is higher than the stated standard level for it , and that its water is harmful to the public health and hygiene .
it is to be noted that the mean concentration of metals in water in downstream and upstream has increased from summer 2011 to spring 2012 .
pb has had the highest mean concentration of 1.95 0.09 mg / l in downstream and cd has had the lowest concentration of 0.07 0.001
the seasonal distribution of the mean concentrations of metal of cd , cr , cu , fe , mn , ni , pb , and zn in tembi river water have been shown to be as follows ( the maximum amounts are related to hot seasons ) :
( 1)(0.070.35,0.130.58,0.260.71,0.241.87 , 0.070.91,0.160.8,0.591.91,0.120.4)mg / l .
these results show the effect of dry seasons and water evaporation on concentration increase of heavy metals in water .
obasohan and eguavoen have stated in their research that dry seasons affect the accumulation of heavy metals in water and its reared fish . in a similar study , ahmed et al .
investigated the distribution of heavy metals concentration in the buriganga river in nigeria and found out that the seasonal distribution of cd , cr , cu , ni , and pb varies seasonally as follows :
( 2)(7.0812.33,489.27645,107.38201.29 , 7.510.32,58.772.45)mg / l .
they have also stated that the maximum and minimum concentrations are those of ni and cd , respectively .
the comparison of the mean concentrations of heavy metals in the tembi river water with the standard value in drinking water and those in the water used for agriculture for aquatic life and surface water standards suggests that the mean concentration of cu lies within the standard range for drinking water and the mean concentrations of mn and cd lie within the standard range of agricultural water .
only do the mean concentrations of zn lie within the standard range for all three kinds of water . in general ,
mean concentrations of cd , cr , mn , and pb were higher than surface water standards ( table 3 ) .
the mean concentrations of metals in the sediments of the tembi river downstream have increased in comparison with those in its upstream .
the maximum and minimum levels of concentration are related to mn in downstream and cd in upstream areas , respectively ( table 2 ) . regarding the rise in the concentrations of these metals in downstream water ,
in fact ; increased heavy metals concentration in water in downstream lead to increasing of their concentration in sediment in downstream . in a similar study kowsari and
naei stated that physicochemical characteristics of water affect the precipitation of these elements in sediment .
the mean concentration of metals in the sediments of the river upstream , where the sewage enters tembi river , changes similarly in four seasons .
in other words , the average concentration of metals in sediments in autumn and winter is lower than that in summer .
the amounts of heavy metals in sediment varied seasonally as follows : summer > autumn > winter > spring .
the cause of these changes was high rain in autumn and winter which gives rise to flow of the water in the river . due to the turbulence created by increase of flow
, some sediments and heavy metals inside them are displaced and carried away from the river bed . as
summer starts , the rise in temperature and evaporation and the end of the rain period cause the rise in heavy metals concentration in water and finally in sediments because metal ions transfer from water to sediment .
the seasonal variation of distribution of cd , cr , cu , fe , mn , ni , pb , and zn in the sediments is as follows :
( 3)(1040,1174,37100,210280,278820,52150,641270,2174)mg / kg . in this regard mor et al . , in a survey of pollution that resulted from oil wells and heavy metals in the tembi river sediments , announced the amounts of variation in the concentrations of cd , cr , cu , ni , pb , and zn as follows :
( 4)(2.396.5,70130,1674,1133,56120,50236)mg / kg . also , ahmed et al
. announced the seasonal distribution of the concentrations of cd , cr , cu , ni , and pb in the sediments of the buriganga river as follows :
( 5)(2.364.25,118.63218.19,21.7532.54,147.06258.17,64.7177.13)mg / kg .
the comparison of mean concentrations of the these metals with the standards for fresh water sediments indicates that , except zn , the mean concentrations of cd , cr , cu , ni , and pb were higher than the standards for fresh water sediments [ 15 , 16 ] while only the mean concentrations of cd in marine sediments were higher than the standards ( table 4 ) .
however , due to increased metals concentration in the sediments of tembi river , the rise of concentrations of heavy metals , in comparison with guideline in sediments , is expected in future .
based on the above - mentioned points , it is clear that the water and sediments of the tembi river were contaminated by heavy metals and , therefore , using this water for recreational purposes , washing , and fishing is detrimental to human health and the environment .
it is , thus , necessary to take serious and essential measures to control the entry of the sewage , treat it before entering the river , manage the quality of water and the sediments of the river , and utilize water for various purposes .
Output:
| this study was carried out to examine heavy metals concentration in water and sediment of upstream and downstream of the entry of the sewage to the tembi river , iran .
samples were collected from upstream and downstream and were analyzed for cd , cr , cu , fe , pb , ni , and zn by atomic absorption spectrophotometer . the results indicated that the average concentration of the metals in water and sediment on downstream was more than that of upstream .
the comparison of the mean concentrations of heavy metals in water of the tembi river with drinking water standards and those in the water used for agriculture suggests that the mean concentration of cu and zn lies within the standard range for drinking water and the mean concentration of mn , zn , and pb lies within the standard range of agricultural water .
the highest average concentration on downstream for pb in water and for mn in sediment was 1.95 and 820.5 ppm , respectively .
also , the lowest average concentration on upstream was identified for cd in water and sediment 0.07 and 10 ppm , respectively . with regard to the results
, it gets clear that using the water for recreational purposes , washing , and fishing is detrimental to human health and the environment . |
PubmedSumm4850 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: chemotherapy remains the
main treatment option for most cancers
despite of its limitations , such as systemic toxicity , severe side
effects , and limited efficacy .
the major reason for chemotherapy failure
is poor delivery of drug to cancer cells and/or intracellular targets .
there are a number of barriers that have to be overcome for successful
treatment , and multidrug resistance ( mdr ) is one of them .
tumors of
different origin have different susceptibility to chemotherapy , and
frequently cancers are intrinsically resistant . on the other hand ,
even though many primary tumors and metastatic lesions , for example
breast , ovarian , and small cell lung carcinomas initially respond
well to the chemotherapeutic treatment , cancers often relapse and
develop drug resistance .
moreover , cancer cells simultaneously acquire
resistance not only to the drug the patient was treated with but also
to the broad spectrum of drugs that are structurally and functionally
unrelated to each other .
initially mdr was attributed to the expression
of drug efflux transporters on the cell membrane that actively pump
the drugs out of the cells .
now it is
generally recognized that mdr is a complex phenomenon and usually
is governed by one or more of the following mechanisms : ( 1 ) active
drug removal by drug efflux transporters of the atp - binding cassette
( abc ) superfamily , such as p - glycoprotein ( pgp , abcb1 ) , multidrug
resistance - associated protein 1 ( mrp1 , abcc1 ) , and breast cancer resistance
protein ( bcrp , abcg2 ) ; ( 2 ) loss of cell surface receptors or drug
transporters or alterations in membrane lipid composition that limit
diffusion of the drug into the cells ; ( 3 ) compartmentalization of
the drug in cellular vesicles ; ( 4 ) altered / increased drug targets ;
( 5 ) increased drug metabolism ; ( 6 ) alterations in cell cycle ; ( 7 )
active damage repair ; and ( 8) inhibition of apoptosis ( figure 1 ) . mechanisms of mdr in cancer cells : ( 1 ) active drug efflux
by drug
transporters , such as pgp , mrp , and bcrp ; ( 2 ) loss of cell surface
receptors and/or drug transporters or alterations in membrane lipid
composition ; ( 3 ) compartmentalization of the drug in cellular vesicles ;
( 4 ) altered / increased drug targets ; ( 5 ) alterations in cell cycle ;
( 6 ) increased drug metabolism / enzymatic inactivation ; ( 7 ) active damage
repair ; and ( 8) inhibition of apoptosis . despite much effort contributed to overcoming mdr , the success
is still very limited in clinical settings .
first , the modification of treatment regimens by increasing the
dose of the administered drug(s ) or using non - cross - resistant drugs .
second , use of small molecule inhibitors of drug efflux transporters
to increase the drug uptake in mdr tumors .
third , use of
antibodies and antibody fragments to target and inhibit drug efflux
transporters .
fourth , silencing of the gene expression of the drug
efflux transporters or antiapoptotic proteins , such as bcl2 using antisense oligonucleotides , sirna , or micro rna .
fifth , use
of small molecules to suppress non - abc transporter - mediated resistance . finally , use of nanotechnology - based carriers to bypass drug efflux
transporters in mdr cancer cells . of
unfortunately ,
a simple dose increase has been associated with increased risks of
systemic toxicity and severe side effects , while finding a proper
combination of non - cross - resistant drugs in many cases is complicated .
as far as the use of the pgp inhibitors is concerned , the outcomes
were often poor , and many such inhibitors failed due to toxicity or
drug metabolism associated issues .
moreover , most
of the approaches under development face traditional drug delivery
issues , which are especially severe in the cases of nucleic acid or
protein therapeutics .
nanotechnology offers several advantages
both for the delivery
of the chemotherapeutic agents , allowing them to bypass drug efflux
transporters , and for the delivery of agents that could inhibit drug
resistance mechanisms to increase efficacy of the chemotherapy .
nanomedicines have longer circulation times and can passively accumulate
in the tumors with leaky vasculature and poor lymphatic drainage by
the enhanced permeability and retention ( epr ) effect . attaching specific tumor - targeting antibodies , antibody fragments ,
or other targeting moieties ( receptor ligands , peptides , etc . )
can
result in active targeting of the nanomedicines to the tumor cells ,
which can further improve drug delivery .
second , two or more active
compounds can be incorporated into a single carrier allowing simultaneous
delivery of several cytotoxic drugs for combination therapy and/or
a cytotoxic drug with a mdr modulator , such as small molecule inhibitor ,
antibody , or nucleic acid .
third , a nanocarrier can be designed in
such a way that it will release its cargo at the tumor site in response
to specific tumor conditions , such as ph or presence of particular
enzymes , therefore limiting other organs and tissues to the exposure
to free drug and reducing systemic toxicity . finally ,
in contrast
to small molecules that mainly utilize diffusion to penetrate the
cells , nanocarriers are taken up by either passive
endocytosis or receptor - mediated endocytosis and , therefore , can bypass
drug efflux transporters on the plasma membrane . in the latter case
the endocytosis is triggered by interaction of targeting ligand with
its receptor on plasma membrane , which accelerates the uptake compared
to passive endocytosis .
if the receptor is predominantly
expressed on cancer cells , in addition to faster uptake this allows
selective targeting of the nanocarrier to cancer cells .
one such example is represented by a class of copolymers ,
called pluronic block copolymers or poloxamers , that are widely used
in various drug delivery systems and in tissue engineering .
pluronics are triblock copolymers of poly(ethylene
oxide ) ( peo ) and poly(propylene oxide ) ( ppo ) , arranged in peo - ppo - peo
structure . depending on the length of the blocks the hydrophilic
lipophilic
balance ( hlb ) of the copolymers changes . in the solution pluronics
the core of the micelles contains ppo blocks and allows incorporation
of hydrophobic drugs .
previously thought to be inert ,
pluronics display a unique set of biological activities and have been
shown to be potent sensitizers of mdr cancer cells in vitro and in vivo .
moreover , pluronics were shown to prevent the development of mdr
upon selection with an anthracycline antibiotic , doxorubicin ( dox ) ,
both in vitro and in vivo .
we have also recently demonstrated that pluronics in combination
with dox can deplete tumorigenic cell subpopulations and decrease
cancer cells tumorigenicity and tumor aggressiveness upon
treatment in vivo . in
this review
the first drug efflux transporter in cancer cells was described
by juliano and ling in 1976 .
they have
shown that drug - resistant chinese hamster ovary cells express a 170
kda membrane glycoprotein , now known as p - glycoprotein ( pgp , abcb1 ) ,
that was unique to the drug - resistant cells .
the cells were selected for resistance to colchicine and showed
cross - resistance to a wide range of different compounds . the degree
of drug resistance correlated with the amount of pgp on the cell surface .
later , in early 1990s a second drug efflux transporter , called multidrug
resistance - associated protein ( mrp1 or abcc1 ) , was discovered in a
drug - resistant lung cancer cell line .
normally
mrp1 plays a major role in cell detoxifying mechanism by transport
of exogenous and endogenous compounds conjugated to glutathione ( gsh ) ,
which for some substrates is required as a cofactor for mrp1 activity .
in contrast , pgp does not require a cofactor and can efflux a wide
variety of functionally and structurally diverse but commonly hydrophobic
drugs .
another important drug efflux
transporter , named breast cancer resistance protein ( bcrp , abcg2 ) ,
was identified in 1998 by doyle et al . in human breast cancer cell
line selected for dox resistance .
its
expression is associated with resistance to number of drugs , such
as mitoxantrone , camptothecins , anthracyclines , etc .
pgp , mrp1 , and bcrp belong to the large superfamily of
atp - binding cassette ( abc ) membrane transporters with 48 members of
the superfamily that are divided into 7 subgroups ( a g ) .
they
have conserved structures and ubiquitously expressed in all forms
of living organisms , from bacteria to humans .
it is a product
of mdr1 gene and can be found in many normal tissues ,
like epithelial cells of gastrointestinal tract , liver , the luminal membrane of proximal tubular epithelial
cells in kidney , cornea , and the luminal membrane of the endothelial cells in the blood
overall , pgp is mostly expressed
in tissues with barrier functions and its main role is to protect
the organism from toxic compounds .
it has a typical structure for
abc transporters and comprises two trans - membrane domains ( tmds ) ,
each of which has 6 membrane - spanning helixes , and two intracellular
nucleotide - binding domains ( nbds ) , which bind and hydrolyze atp providing
energy for transmembrane movement of the drugs ( figure 2 ) .
pgp substrates are mostly hydrophobic ( but structurally
unrelated ) and partition into a lipid bilayer . among these substrates
are important anticancer drugs including
several anthracyclines ( dox , daunorubicin , mitoxantrone ) , vincristine ,
taxanes , etoposide , teniposide , actinomycin d , and others .
understanding
the mechanism of pgp function is critical for the design of novel
effective mdr modulators .
recently the crystal structure of mouse pgp , which has 87% sequence
identity to human pgp , was described ( figure 2 ) . by analyzing the costructures of pgp complexes
with two cyclopeptide inhibitors
the authors elucidated the mechanism
of drug efflux by pgp and provided insight into the transporter s
broad substrate specificity .
the drug - binding pocket of pgp is localized
in the tm domain of the protein .
the inward - open conformation of pgp
allows the substrate access both from cytoplasm and from the inner
leaflet of the membrane but not from the upper leaflet or extracellular
space .
the upper part of the drug - binding pocket contains predominantly
hydrophobic and aromatic amino acid residues , and the lower half of
the chamber has more polar and charged residues .
the drug - binding
pocket in pgp is very large and in inward - facing conformation is accessible
through two portals that are wide enough to fit hydrophobic drugs
and phospholipids and allow pgp to scan the inner
leaflet to select and bind specific lipids and hydrophobic drugs before
transport .
overall , the authors proposed ,
that pgp has broad flexibility and can sample widely open conformations
to accommodate large substrates , explaining the broad substrate specificity
of the transporter .
usually the drug enters pgp s binding site
from the inner leaflet of the membrane , which stimulates the binding
of two molecules of atp by nbds followed by their dimerization .
the
dimerization of nbds causes the major conformational change in the
protein and formation of the outward - facing structure , open to the
extracellular space .
the drug is released due to the change of the
affinity of the protein to it or is facilitated by atp hydrolysis ,
which brings the protein back to the initial state .
( a ) pgp is
a transmembrane protein with drug - binding pocket localized in the
inner leaflet of the plasma membrane , and two nbd localized in cytoplasm .
functional pgp is localized in cholesterol , sphingomyelin , and gm1
ganglioside - rich membrane microdomains , called lipid rafts , where
it is surrounded by fluid phase of the membrane , containing unsaturated
fatty acids like dppc .
pgp is pictured in inward - open ( outward closed )
conformation ready to bind substrate .
the model is based on x - ray
analysis and nmr data from protein data
bank ( http://www.rcsb.org/ ) .
( b ) incorporation of pluronic
into lipid bilayer disrupts lipid rafts , possibly causing conformational
changes in pgp , which results in inhibition of pgp atpase and transport
activities .
as was mentioned
above , pluronic block copolymers are potent sensitizers of mdr cells .
the sensitization mechanism is complex and involves multiple events
happening at different levels in the cell .
cell
interaction starts in the cell membrane , where drug efflux transporters
are localized .
pluronics were shown to be strong inhibitors of abc
transporters , specifically pgp , mrp , and bcrp .
the inhibition might be in part
due to the alterations of lipid microenvironment of the transporters
by pluronic . due to their amphiphilic structure
, pluronic block copolymers
can interact with cell membrane and change its properties , which are critical for proper function of abc
transporters .
membrane structure and composition play a crucial role in cell
physiology , function , and signaling .
plasma membrane is a heterogeneous
structure composed of various domains with different lipid composition
and packing . in particular , so - called
lipid rafts are compact membrane microdomains containing
predominantly cholesterol and sphingolipids ( mainly sphingomyelin )
with long and saturated fatty acids , that are floating
in more fluid membrane phase that contains glycerophospholipids with
shorter and unsaturated acyl chains ( figure 2 ) .
these domains are resistant to low
temperature solubilization by some detergents , like triton x100 or
brij 96 , and this is used for their isolation . depending on the cell
line and the method used for membrane fractionation pgp can be found
either mostly in detergent - resistant membrane fractions or distributed
between the detergent - resistant and detergent - soluble fractions .
furthermore , it was found that pgp distribution between different
membrane fractions depends on the transporter s expression
level : the lower the expression of pgp is , the greater portion of
pgp is localized in detergent - resistant cholesterol - rich membrane
domains .
it is well - known that the function
of most membrane proteins is directly linked to the composition and
viscosity of their lipid microenvironment .
pgp is a lipid flippase and requires interaction with phospholipids
for continuous display drug - mediated atpase activity and interaction with the substrate .
moreover , an increasing number of studies report that pgp
localization in lipid rafts and precise properties of rafts are essential
for the transporter s proper function . for example
depletion of cholesterol with methyl--cyclodextrin
in drug - resistant vlb human t - cell lymphoblastic leukemia cells led
to disassembly of the lipid rafts , redistribution of pgp from lipid
rafts to other microdomains of plasma membrane , and inhibition of
pgp transporter activity .
on the other hand , enrichment of membranes
with cholesterol also resulted in inhibition of pgp function , although
the localization of pgp did not change compared to control .
however ,
the increase in cholesterol content changed the lipid raft distribution
and composition , which most likely accounts for the impairment of
the pgp function .
it was also shown recently
that caveolin-1 overexpression decreases plasma membrane cholesterol
levels ( similar to the effect of methyl--cyclodextrin that
depletes cholesterol from the membrane ) and results in the increase
of membrane fluidity and inhibition of pgp function in drug - resistant
hs578t / dox cells .
another study by barakat
et al . demonstrated that there are two functionally different populations
of pgp in drug - resistant human cem lymphoblastic leukemia cells .
the first population localized in detergent - resistant
membrane fraction has higher atpase activity , which is completely
inhibited by orthovanadate and activated by verapamil .
the second
population localized in soluble membrane fractions has lower atpase
activity and is less sensitive to orthovanadate .
moreover , verapamil ,
a well - known pgp activator , inhibits pgp atpase activity in this second
population .
the authors conclude that
interaction of pgp with its substrates could be affected by different
lipid microenvironment in soluble membrane fractions , specifically
by lower content of cholesterol compared to the detergent - resistant
membrane fraction .
pluronic
binding to the cell membrane depends on pluronic hydrophobicity
and the temperature .
the binding is driven
by hydrophobic interactions of ppo chain blocks with the fatty acid
residues in the lipid bilayer and by hydrophilic interactions of peo
chain blocks with the polar groups of the lipids at the membrane surface .
this binding may lead to either membrane destabilization or healing of injured membranes .
pluronics also exhibit ionophoric activity and can facilitate transmembrane
transport of low molecular drugs , accelerate phospholipid s
flip - flop rate , and decrease membrane microviscosity .
pluronic effects on the membrane
transport depend on the copolymer hlb , concentration , and the exposure
time .
for example , hydrophobic pluronic l61 ( ( eo)4-(po)30-(eo)4 , hlb 3 , mw 2000 g / mol , eo = ethylene oxide ;
po = propylene oxide ) depending on the level of its aggregation can
act either as a transmembrane carrier of drug molecules or as an ion
channel .
specifically , it was proposed
that l61 monomers and dimers can act as the carriers while l61 oligomers
are likely to form the channels . on the
other hand hydrophilic pluronic f68 ( poloxamer 188 , ( eo)76-(po)39-(eo)76 , hlb 29 , mw 8400 g / mol ) with
80% peo content effectively restores damaged cell membranes after
electroporation , heat shock , or intense radiation . using x - ray
reflection ( xr ) and grazing - incidence x - ray diffraction ( gixd ) methods
in a model langmuir lipid monolayer of 1,2-dipalmitoyl - sn - glycero-3-phosphocholine ( dppc ) and 1,2-dipalmitoyl - sn - glycero-3-[phospho - rac-(1-glycerol ) ] ( dppg ) , wu
et al .
have shown that f68 interacts with the damaged membrane areas ,
but does not affect the ordered membrane phase , and gets excluded
when lipid packing density is restored .
recently it was demonstrated that f68 molecules do not insert into
lipid bilayer nor affect the overall lipid packaging , however , they
facilitate the membrane sealing activity by diminishing the fluctuation
of membrane surface and hydration of the inner part of the bilayer .
however , in another study using giant unilamellar
vesicles ( guv ) as model membrane system wang et al . demonstrated that
f68 can incorporate in the membranes , disrupt their integrity , and
act as a permeabilizer if it is exposed to the membranes for sufficient
time .
overall , the interaction
of pluronics with lipid membranes proceeds in two steps : ( 1 ) the absorption
at the membrane and ( 2 ) the insertion in the membrane ( figure 3 ) .
the first step is common to all pluronics and
does not depend much on the copolymer structure .
the second step depends
strongly on the hydrophobicity of the copolymer with the more hydrophobic
copolymers being morel likely to insert .
pluronics with longer ppo blocks insert into
the membrane below the polar head groups , loosen the lipid packaging ,
and , therefore , act as permeabilizers , they can translocate through the membrane ( depending on their hlb ) .
furthermore , using molecular dynamics simulations nawaz and coauthors
observed that membrane bends upon insertion of pluronics .
they have shown that membrane - disruptive activity
of pluronics is due to interaction of hydrophilic blocks with the
polar head groups of the lipid molecules and depends on the length
of the peo block .
short peo blocks drag the polar groups toward the
inner part of the membrane , which results in membrane bending and
permeabilization .
pluronics with longer peo blocks can temporarily
stabilize the local structure of the membrane .
schematic presentation
of interaction of pluronics with different
hydrophobicity with lipid membranes : ( 1 ) absorption of pluronic molecules
on the surface of the membrane , ( 2 ) insertion into the lipid bilayer ,
and ( 3 ) translocation through the membrane .
pluronic copolymers can significantly increase the antitumor
activity
of pegylated liposomal drugs in vivo , specifically
doxil by stimulating the drug release from liposomes at the tumor
site .
one of the main problems of long
circulating liposomal drugs is insufficient release of the active
compound at the tumor site .
post - administration
of pluronic p85 ( ( eo)26-(po)40-(eo)26 , hlb 16 , mw 4600 g / mol ) 48 h after doxil results in dox release
and redistribution toward tumor bulk along with a marked improvement
of antitumor activity .
this effect is time - dependent as it is essential
to allow sufficient time for the liposomes to accumulate at the tumor
site before administering pluronic .
it is likely that that the enhanced
antitumor effect at least in part is due to facilitated release of
dox from the liposomes in the tumors induced by pluronic .
furthermore ,
in addition to permeabilization effect on liposomal membranes the
copolymer could also sensitize the mdr cells and deplete the cancer
stem cells ( cscs ) ( as discussed below ) .
another
important aspect in pluronic interactions with lipid membranes
is the dependence of these interactions on the cell type and the membrane
composition .
for example , the membrane microviscosity of murine myeloma
sp2/0 cells significantly decreased after treatment with l61 , while
the membrane viscosity in normal mouse splenocytes was less affected . moreover , pluronic p105 ( ( eo)37-(po)56-(eo)37 , hlb 15 , mw 6500 g / mol ) was demonstrated
to permeabilize the acidic endosomal vesicles in drug - resistant a2780/adr
cells , while the vesicles in sensitive cells were less affected .
several studies have reported lower
fluidity and higher heterogeneity of plasma membrane in mdr cells
compared to sensitive cells .
drug - resistant cells
also contain smaller amounts of unsaturated fatty acids and have higher
content of esterified cholesterol and triglycerides . using liposomes of different lipid composition and viscosity
it
was demonstrated that the l61 effects on lipid flip - flop and membrane
permeability toward dox increase as the membrane viscosity increases .
pluronics inhibit pgp and mrp atpase activities
by decreasing maximum
reaction rate ( vmax ) and the affinity
of the enzyme to atp as well as to the substrates such as vinblastine
( expressed as increase in michaelis constant , km ) .
some neutral detergents , such
as tween-20 , nonidet p-40 , and triton x-100 , were also shown to inhibit
pgp atpase activity at concentrations that are required for membrane
fluidization .
overall , alterations in
membrane structure and fluidity induced by various compounds strongly
affect pgp function .
therefore , it was suggested that inhibition of
the transporter s activity by pluronic is at least partly due
to the pluronic - induced changes in the local membrane environment
( figure 2 ) .
to further
understand the mechanism of pluronic sensitization of
mdr cancer cells one needs to focus on the events at the subcellular
level , which were characterized in great detail using p85 as an example .
this copolymer exhibits evident and profound
selectivity with respect to energy metabolism in mdr cancer cells .
it is rapidly taken up by the cells via a caveolae - mediated endocytosis
pathway and colocalizes with mitochondria
already 15 min after exposure to the cells .
this results in a drastic depletion of intracellular atp levels
in mdr cancer cells , while non - mdr cells require significantly higher
doses of pluronic to achieve similar depletion .
noteworthy , the ability
to deplete cellular atp levels strongly correlates with the chemosensitization
properties of the copolymers in mdr cells .
the selectivity of pluronic copolymers toward mdr phenotype is probably
attributable to innate metabolic and physiological differences between
mdr and non - mdr cells .
in contrast to normal cells , that use oxidative
phosphorylation for atp production , cancer cells mostly rely on glycolysis
as an adaptation to hypoxic conditions in the early stages of tumor
development .
drug - resistant cells require
more atp to support the drug efflux transporter activity and drug
metabolism .
adaptations leading to mdr therefore in part are associated
with changes in energy metabolism to meet new energy requirements .
it was shown that human breast cancer cells with acquired resistance
to dox exhibit 3-fold higher glycolysis rate than their sensitive
counterparts .
another study by miccadei
et al . found that both respiration and glycolysis rates are increased
in drug - resistant ehrlich cells , resulting in almost 50% higher atp
production compared to the drug sensitive cells .
it was also shown that mdr cells have significantly higher
activity of the respiratory chain complexes in mitochondria where
nearly 50% of atp was produced , compared to only 35% of atp produced
in mitochondria of sensitive cells .
moreover , it was later demonstrated
that mdr cancer cells have lower mitochondrial membrane potential ,
use fatty acids for mitochondrial oxidation when glucose becomes limited ,
and have high levels of expression of uncoupling protein 2 ( ucp2 ) ,
which results in less efficient atp synthesis .
overall , the compromised mitochondrial function in mdr
cells may be the achilles heel of mdr cells that allows effective
and selective inhibition of atp production in drug - resistant cells .
when pluronic reaches mitochondria of mdr cells , it inhibits complexes
i and iv of the respiratory chain and depletes mitochondrial membrane
potential .
the mechanism of pluronic
inhibition of respiratory chain complexes activities is not
fully understood . in mitochondria
in other words pluronic
may act as a prooxidant , which were shown to induce apoptosis in cancer
cells .
noteworthy , the effects of pluronic
on pgp activity , atp levels , and cytotoxicity are reversible .
pgp
function is restored 1 h after the removal of pluronic . at the same
time
the sensitization
effect of pluronic is abolished in the same time frame , while it takes
about 10 h to restore atp levels .
interestingly ,
pgp expression seems to be essential for pluronic effects on respiration
and atp levels .
inhibition of oxygen consumption as well as atp depletion
by pluronic was observed not only in drug - selected resistant cells
but also in cells stably transfected with mdr1 gene , encoding pgp .
inhibition of pgp with highly specific inhibitor gf120918 abolished
the pluronic - induced atp depletion , while the inhibitor itself did
not affect atp levels in mdr cells .
pluronic effects in mdr cancer cells exhibit remarkably simple
and clear structure functional relationships .
the studies of the concentration dependence of the pluronic
in mdr cells effect suggested that these effects are produced mainly
by the copolymer single chains as they leveled up or decreased above
the cmc .
hydrophilic pluronics with hlb 20 and above have little if
any sensitization effect in mdr cells . using pgp expressing brain
microvessel endothelial cells ( bmecs )
it was demonstrated that such
pluronics do not decrease membrane microviscosity , do not inhibit
pgp atpase activity , practically do not internalize in the cells ,
and do not induce atp depletion . of all
other pluronics with hlb fewer than 20
the most active in mdr cells
are the copolymers with intermediate lengths of the hydrophobic ppo
block from about 30 to about 60 po units .
these
copolymers bind with the cell membranes , decrease membrane microviscosity ,
and inhibit pgp atpase activity .
moreover ,
they internalize into cells and produce atp depleting effects . the
copolymers with shorter ppo blocks , fewer than 30 po units , also internalize
in cells . however , they do not decrease membrane microviscosity , do
not inhibit pgp atpase , and do not deplete atp .
presumably , they are
not sufficiently disruptive to the membrane structures
to produce all these effects . the copolymers with longer ppo blocks
but they do not penetrate inside the cells and do not
reach mitochondria remaining stuck in the cell membranes , presumably
due to their extreme hydrophobicity . accordingly
notably , it was demonstrated that both atp depletion and inhibition
of pgp atpase activity are essential for the sensitization of pgp
overexpressing cells .
when one of these factors was
excluded , the drug efflux pump remained functional in both mdr cancer
and pgp - expressing bmecs .
oxidative stress is
a condition in which the balance between the
production of reactive oxygen species ( ros ) by cells and the ability
to detoxify them is impaired .
if oxidative stress persists , the formed
peroxides and free radicals will damage all components of the cell ,
including membranes , proteins , and dna .
accumulation of significant
damage , which a cell fails to repair , will lead to apoptosis .
generally ,
oxidative stress is associated with increased production of ros and/or
decreased ability of the cell to eliminate these species .
glutathione
is a major cellular antioxidant that protects the cells against ros ,
toxins , and drugs .
it is a tripeptide that exists in reduced ( gsh )
and oxidized ( gssg ) states , and normally more than 90% of cellular
glutathione is in a reduced state .
an accurate ratio between gsh and
gssg is important to maintain the intracellular redox state , with
a decrease in gsh / gssg ratio indicative of oxidative stress .
gsh is
also a cofactor of glutathione s - transferase ( gst ) ,
the major cellular detoxifying enzyme .
furthermore , several members
of the mrp family of abc transporters require gsh for transport activity .
pluronic was shown to deplete the gsh levels and inhibit the gst activity
in several mdr cell lines .
inhibition
of the gsh / gst detoxifying system in turn decreases the mrp - mediated
efflux .
the decrease of cellular gsh is also an early sign of apoptosis
induced by oxidative stress , death receptor activation , or mitochondrial
apoptotic signaling .
one of the
major sources of ros in the cells is electron transport
chain in mitochondria . in normal conditions oxygen
is reduced in mitochondria
by cytochrome c oxidase ( complex iv ) to produce water .
however , a small amount of electrons passing through the electron
transfer chain reduce oxygen to produce superoxide radical .
the main
superoxide radical producing complexes in mitochondria are nadh dehydrogenase
( complex i ) and cytochrome bc1 complex ( complex iii ) .
it is well - known that inhibition of complex i by certain inhibitors
like rotenone , piericidin a , and rolliniastatin increases the ros
production . as was mentioned above , pluronic quickly reaches mitochondria
and inhibits complexes i and iv in mdr cells ( figure 4 ) .
moreover , it stimulates the production of ros and release
of cytochrome c , which are the early signs of mitochondrial
apoptotic pathway . if ros are not neutralized ,
they induce damage of mitochondrial membrane , proteins , and dna .
this
leads to permeabilization of outer mitochondrial membrane , swelling
of mitochondria , and release of proapoptotic proteins , like cytochrome c , apoptosis inducing factor ( aif ) , and endonuclease g. in cytoplasm
cytochrome c binds to apoptosis protease activating
factor ( apaf-1 ) and forms apoptosome .
the activated caspase 9 in turn
activates the effector caspases , which all together contribute to
the completion of apoptosis .
similar to atp depletion and inhibition
of respiration , pluronic induced the ros formation and cytochrome c release selectively in mdr cells , while non - mdr cells
did not respond in that manner .
pluronic quickly enters the cells , reaches mitochondria ,
and induces mitochondrial membrane depolarization ( 1 ) , inhibition
of complexes i ( 2 ) and iv ( 3 ) , release of cytochrome c ( 4 ) , and atp depletion ( 5 ) .
in addition to induction of ros production and cytochrome c release in mdr cells , pluronic promotes drug - induced apoptosis .
treatment of mdr cells with dox / pluronic p85 formulation significantly
enhanced the proapoptotic signaling compared to the drug alone and
inhibited the antiapoptotic defense mechanisms in vitro .
it was demonstrated that dox / pluronic treatment
of tumor - bearing mice significantly increased levels of caspases 8
and 9 compared to dox alone .
overall ,
pluronic induces early as well as late stages of proapoptotic
signaling in mdr cells in vitro and in vivo .
inhibition of mitochondria respiratory chain complexes is most
likely the main reason for increased ros production in mdr cells after
treatment with pluronic .
additionally , depletion of major intrinsic
cellular antioxidant gsh would increase cell sensitivity to the ros .
it has been shown that drug - induced ros production may be directly
linked to their cytotoxic activity and that
detoxification of free radicals by gsh / gst is very important in mdr
cells to facilitate drug resistance .
therefore , when combined with dox , pluronic not only drastically
increases the drug accumulation in the cells but also promotes the
apoptosis in the mdr cells .
the mechanism of development of mdr in cancer remains
a highly
debated subject , and most likely there is no uniform theory that will
apply to all cancers .
it is now widely accepted that cscs play an important role in cancer
development , metastasis , and development of drug resistance .
cscs
comprise a small cell subpopulation within the tumor with distinct
functional and phenotypical characteristics .
first , cscs overexpress
specific markers . however , these markers differ from cancer to cancer
and to date there is no uniform marker that can be used to isolate
cscs from every tumor .
second , cscs
have unlimited ability to divide and produce cells of all other phenotypes
in the tumor .
third , cscs are able to form tumors when transplanted
into mice and to form so - called tumorspheres when grown in anchorage
independent conditions .
finally , cscs are intrinsically drug resistant :
they overexpress drug efflux transporters , such as pgp and bcrp , have
active antiapoptotic pathways , and spend most of their time in the
g0 nondividing cell cycle state , which makes them insensitive
to cytostatic drugs often used in chemotherapy .
therefore , cscs can avoid classical chemotherapy and repopulate
the tumor , possibly leading to mdr development
. moreover , there are
reports suggesting that cscs phenotype is dynamic and can
be acquired by non - cscs under certain conditions .
overall , successful therapy needs to be equally efficient in eliminating
both bulk tumor cells and cscs .
in addition to mdr chemosensitization
properties , pluronics also
prevent the development of mdr upon selection with cytotoxic drugs in vitro and in vivo .
specifically , in one study human breast carcinoma mfc7 cells were
selected with dox for drug resistance in the presence or absence of
p85 at concentration below cmc ( 0.001 wt % ) .
the cells cultured with dox / p85 were not able to grow at concentrations
of the drug exceeding just 10 ng / ml . in contrast , cells cultured with
dox alone eventually developed mdr and could tolerate up to 10,000
ng / ml dox in the culture media .
further analysis has shown that cells
treated with dox / p85 did not overexpress pgp and , therefore , remained
sensitive to the drug .
in contrast , cells exposed to dox alone exhibited
significant overexpression of pgp . this developed drug resistance
can be resensitized by pluronic to the initial level of the drug sensitive
cells .
interestingly , when the cells were selected with lower concentration
of dox , they were not sensitized by pluronic , even though they displayed
low levels of pgp expression and detectable levels of mdr1 mrna .
functional
analysis of pgp activity using accumulation of pgp substrate ( rhodamine
123 ) showed that pgp in those cells was not or nearly not functional
compared to more resistant cells . even though
cells selected with lower concentrations of dox were not sensitized
with pluronic , they showed strong atp depletion in response to pluronic
treatment .
moreover , it was demonstrated
that selection of cells with dox and dox / p85 resulted in very different
changes in the gene expression patterns in these cells .
p85 alone ,
however , had little if any effect on the gene expression .
similar results were observed in p388 murine
leukemia tumor cells selected for dox resistance with or without p85
both in vitro and in vivo .
overall , this suggests that simple addition
of inert polymer excipient to the drug drastically
changes pharmacogenomic responses of cancer cells to this drug .
however , our understanding of the mechanism behind the prevention
of mdr development by pluronic and alterations in gene expression
profiles is very limited . in view of csc theory
a small population
of tumor cells is guiding tumor progression , metastasis , and mdr development .
since cscs share certain characteristics of mdr cells , such as overexpression
of drug efflux transporters ( pgp , bcrp ) and altered metabolic pathways , we proposed that pluronics can sensitize cscs to chemotherapeutic
drugs similar to mdr cells . in a recent study using the same p388
leukemia ascitic tumor model as before
, we demonstrated that dox / pluronic combination , sp1049c , comprising
mixed micelles of pluronic f127 ( ( eo)100-(po)65-(eo)100 , hlb 22 , mw 12 600 g / mol ) and l61 , effectively
decreases frequency of tumor initiating cells and , as a result , suppresses
tumorigenicity and tumor aggressiveness in vivo . in agreement with previous findings
, sp1049c
also prevented the development of mdr by inhibition of bcrp overexpression .
in contrast to dox alone , sp1049c depleted the tumorigenic cd133 +
and aldh+ cell subpopulations .
furthermore , in vitro pretreatment of ascitic cells with sp1049c significantly reduced
the in vitro colony forming potential of the cells
already at 10 ng / ml dox , while dox alone had the same effect at 10
times higher concentration .
as mentioned above , dox / pluronic combination
drastically changes the gene expression profiles in cancer cells compared
to dox or pluronic alone upon continuous exposure . in this work we
have shown that dna methylation patterns also change drastically upon in vivo treatment of cancer cells with sp1049c compared
to saline control , polymers , or dox alone .
it is well - known that misregulation
of dna methylation / demethylation plays an important role in cancer
origin , progression , angiogenesis , metastasis , and mdr development .
sp1049c not only induced the strongest epigenetic changes but also
showed very small overlap of affected genes with other treatment groups .
functional analysis of affected genes done using ingenuity pathway
analysis ( ipa ) has shown that the top affected biological functions
and canonical pathways affected by sp1049c treatment relate to cellular
function , growth , and maintenance , as well as regulation of stem cell
differentiation and pluripotency .
altogether , on top of mdr sensitization ,
the prevention of mdr development by pluronics , depletion of tumorigenic
cell subpopulations , and decrease of tumorigenicity and tumor aggressiveness
offer significant advantages for the development of new formulations
of approved and/or experimental therapeutics .
pluronic copolymers attracted a lot
of attention in drug delivery
and tissue engineering applications .
pluronic - based micellar formulation
of dox , sp1049c , was the first in class polymeric micelle drug to
advance to clinical stage and has successfully
completed phase ii clinical trial in advanced esophageal cancer patients . in studies in rodent and nonrodent animal models
it has been demonstrated , as well as in patients , that mtd and pharmacokinetic
profiles of dox alone and sp1049c are very similar .
moreover , animal studies using mdr overexpressing
tumors have shown that pluronic formulations in vivo exhibit key effects
observed in mechanistic studies in vitro .
first , noninvasive single photon emission computed tomography ( spect )
and tumor tissue radioactivity sampling demonstrated that intravenous
coadministration of pluronic p85 with a pgp substrate , tc - sestamibi , greatly increases the tumor uptake of this substrate
in the mdr tumors .
second , p magnetic resonance spectroscopy
( p - mrs ) in live animals and tumor tissue sampling for
atp suggest that p85 and dox formulations induce pronounced atp depletion
in mdr tumors .
finally , these formulations were also shown to increase
tumor apoptosis in vivo by terminal deoxynucleotidyl transferase dutp
nick end labeling ( tunel ) assay and reverse transcription polymerase
chain reaction ( rt - pcr ) for caspases 8 and 9 . in phase
i clinical
study of sp1049c in 26 patients , maximum tolerated
dose ( mtd ) and dose - limiting toxicity ( dlt ) were determined as 70
and 90 mg / m respectively .
ii study 21 patients ( 19 evaluable
for response ) with metastatic or locally advanced unresectable adenocarcinoma
of the esophagus and gastroesophageal junction ( gej ) were treated
with 75 mg / m sp1049c every 3 weeks until disease progression
or unacceptable toxicity . in this study
sp1049c demonstrated prominent
single agent antitumor activity ( 47% objective response rate in the
evaluable population , 9 partial responders , 10 month median overall
survival , and 6.6 month progression free survival ) with toxicity profile
similar to that of dox at equivalent dose and administration schedule .
unique biological activities of pluronics in addition to their
drug solubilization properties make pluronics a very attractive platform
for drug delivery . for example
, in recent work chen and coauthors
used mixed micelles of p105 and f127 to overcome pgp - mediated mdr
to methotrexate ( mtx ) in vitro and in vivo .
this system has shown relatively
high drug loading and ph - dependent drug release , improved pharmacokinetics ,
biodistribution and antitumor activity in human lung ( a549 ) and oral
epidermoid carcinoma ( kbv ) mdr xenograft tumor models , and reduced
systemic toxicity ( table 1 ) . the same group
has also used pluronic p105/f127 mixed micelles to deliver docetaxel
( dtx ) to taxol - resistant non - small cell lung cancer . while in drug sensitive cells the micelles had similar
ic50 to taxotere , in drug - resistant a549/taxol cells they demonstrated
10-fold lower ic50 compared to taxotere control ( 0.059 g / ml
vs to 0.593 g / ml ) . in in vivo a549/taxol drug - resistant tumor
model dtx loaded mixed pluronic micelles showed 69.05% tumor inhibition ,
versus 34.43% for taxotere control ( table 1 ) . in another work shen et al .
developed novel pluronic - polyethylene
imine ( pei)/d--tocopheryl polyethylene glycol 1000
succinate ( tpgs ) nanoparticles to overcome paclitaxel ( ptx ) drug resistance
and codeliver survivin shrna .
tpgs was
used to improve micelle stability and drug loading , p85 was used to
form micelles and inhibit gst activity , and pei was used to bind shrna .
these complex nanoparticles have shown a synergistic effect in cytotoxicity
experiments in a549/t ptx resistant cells , but not in parental a549
drug sensitive cells , and displayed effective antitumor activity in vivo in mdr tumor model .
furthermore , the authors have
shown that gst isolated from mdr cells was 3.8 times more active than
extracted from sensitive cells and that both p85 and p85pei
conjugate effectively inhibited only gst of mdr cells but not of non - mdr
cells .
this is an important observation , since gst plays an important
role in ptx metabolism and its inhibition would increase accumulation
of ptx in the cells .
other examples that use pluronic mdr reversal
properties for overcoming mdr include poly(caprolactone)-modified
pluronic p105 ( p105-cl ) ptx loaded micelles developed by wang et al .
these polymers displayed atp depletion , inhibition of mitochondrial
function , and membrane fluidization activities , similar to what was
reported before for other pluronics .
a few years
earlier the same group developed folate - targeted pluronic micelles
for delivery of ptx and circumvention of mdr .
the authors have shown that folate conjugated pluronic
p105 or l101 ptx loaded micelles better accumulate in mcf7/adr cells
and have significantly higher efficiency compared to nontargeted micelles
of ptx alone ( table 1 ) .
the biological response - modifying properties
are , however , not
unique to pluronics .
a number of other natural and synthetic polymers
have been reported to inhibit drug efflux transporters .
for example , polymers developed by cambon and colleagues with similar
architecture to pluronics , but with poly(styrene oxide ) ( pso ) instead
of ppo , also form micelles which have shown efficient drug loading
and ph - dependent release , as well as pgp inhibition activity .
furthermore , in another study from the same
group the authors evaluated the structure activity relationships
of nearly 30 copolymers with structures similar to pluronics , but
containing different hydrophobic blocks , including propylene oxide ,
lactide , methylene , butylene oxide , valerolactone , caprolactone , styrene
oxide , and glycidyl .
many of the screened
copolymers induced increase of dox accumulation in the pgp overexpressing
mdr cells , as well as inhibition of pgp atpase activity .
notably ,
the most active copolymers had longer hydrophobic chains compared
to what is considered optimal for pluronics , that is , pluronics with intermediate length of hydrophobic block
and relatively low hlb . furthermore , tpgs was also reported
to inhibit pgp .
tpgs is a common form
of vitamin e , and it
has been recognized as a potent enhancer of oral absorption of drugs
due to inhibition of drug efflux transporters .
compared
tpgs with different peg lengths ( 2006000 ) and have found that
commercial tpgs-1000 is one the most potent analogues in the series
of polymers .
other pharmaceutical excipients , including some tweens
( pegylated sorbitanes ) , brij ( alkyl - peo surfactants ) , and myrj ( peo - stearates ) ,
also demonstrated pgp inhibition , that strongly depends on hlb of
the polymer , albeit they generally remain
less potent than pluronics . altogether ,
there are number of
polymers that possess the advantageous
properties of inhibition of drug efflux transporters and can be used
to overcome cancer mdr or to improve oral drug bioavailability .
pluronics ,
however , represent the most studied group of potent polymers with
respect to molecular mechanism of pgp inhibition and mdr sensitization .
considering similar activities observed in other groups of polymers ,
it is likely that some general patterns of structure activity
relationships of pluronics ( hlb , architecture , etc . ) and spectrum
of biological effects can be extrapolated to other amphiphilic polymers .
intrinsic
and acquired drug resistance represents the great obstacle
for successful treatment of cancer .
numerous approaches have been
utilized in attempts to overcome drug resistance with limited success .
in this review
we have discussed the biological properties of pluronic
block copolymers and other polymers with similar biological activities ,
which , in addition to carrier function , make them an attractive platform
for drug delivery .
the mdr chemosensitization activity of pluronics
( and other surfactants ) has been known for a while now , and the mechanisms
have been extensively studied ( figure 5 ) . however ,
we are still far from complete understanding of how exactly pluronics
interact with mdr cells and why these effects are specific to mdr
phenotype .
recent studies have shown that combination of chemotherapeutic
drug ( dox ) with pluronic effectively depletes tumorigenic cell subpopulation
and decreases tumorigenicity and tumor aggressiveness .
this finding being so simple by nature drastically
changes the whole concept from pluronics being just another mdr modulator
to a class of agents that might help to combat cancer at its root
by killing cscs . on the other hand
, we now have even more questions
regarding the mechanism of action of pluronic than we had before .
we believe that thorough understanding of these mechanisms will allow
better design of pluronic ( and similar polymers)-based drug delivery
systems for effective cancer therapy .
( a ) pluronic binding
with plasma membrane of mdr cancer cells ( 1 ) induces membrane fluidization ,
disruption of membrane microdomains , and inhibition of drug efflux
transporters activity ( pgp shown as an example ) .
pluronic
also reaches mitochondria where it ( 2 , 3 ) inhibits complexes i and
iv of mitochondria respiratory chain and ( 3 ) induces inner mitochondrial
membrane depolarization .
this ( 4 ) results in atp depletion and ( 5 )
promotes cytochrome c release and ros generation
in mdr cells .
altogether , the mdr cells respond to a dox / pluronic
combination by ( 6 ) an increased proapoptotic signaling and decreased
antiapoptotic defense .
( b ) moreover , dox / pluronic combination effectively
depletes tumorigenic subpopulation of cscs , prevents development of
mdr , and significantly alters dna methylation and gene expression
profiles .
Output:
| multidrug
resistance ( mdr ) remains one of the biggest obstacles
for effective cancer therapy .
currently there are only few methods
that are available clinically that are used to bypass mdr with very
limited success . in this review
we describe how mdr can be overcome
by a simple yet effective approach of using amphiphilic block copolymers .
triblock copolymers of poly(ethylene oxide ) ( peo ) and poly(propylene
oxide ) ( ppo ) , arranged in a triblock structure peo - ppo - peo , pluronics
or poloxamers , raised a considerable interest in the
drug delivery field .
previous studies demonstrated that pluronics
sensitize mdr cancer cells resulting in increased cytotoxic activity
of dox , paclitaxel , and other drugs by 23 orders of magnitude .
pluronics can also prevent the development of mdr in vitro and in vivo .
additionally , promising results of
clinical studies of dox / pluronic formulation reinforced the need to
ascertain a thorough understanding of pluronic effects in tumors .
these effects are extremely comprehensive and appear on the level
of plasma membranes , mitochondria , and regulation of gene expression
selectively in mdr cancer cells .
moreover , it has been demonstrated
recently that pluronics can effectively deplete tumorigenic intrinsically
drug - resistant cancer stem cells ( csc ) .
interestingly , sensitization
of mdr and inhibition of drug efflux transporters is not specific
or selective to pluronics .
other amphiphilic polymers have shown similar
activities in various experimental models .
this review summarizes
recent advances of understanding the pluronic effects in sensitization
and prevention of mdr . |
PubmedSumm4851 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: palatal myoclonus is a movement disorder in which there are rhythmic jerky movements of the soft palate .
it is generally classified as somatosound or objective tinnitus and is rare compared to sensorineural tinnitus or subjective tinnitus .
according to etiologic factors , platal myoclonus has been classified as two distinct forms : 1 ) symptomatic palatal myoclonus , which a condition that is secondary to identifiable brainstem or cerebellar disease , and 2 ) essential palatal myoclonus , which presents clicking tinnitus in the absence of a brain lesion ( 1 ) .
patients with symptomatic palatal myoclonus show pathologic hypertrophic degeneration of the inferior olive and dentate nucleus , which initiates rhythmic , spontaneous , synchronized discharges within the inferior olive that results in a brainstem " oscillator . "
in contrast to the known pathologic mechanism of symptomatic palatal myoclonus , there are no reports of the neurophysiology of essential palatal myoclonus .
the pathophysiologic hypothesis of this condition is a spontaneous oscillator in other parts of the brainstem , which is related with the palate motor function ( nucleus ambiguous - the levator palatini , facial nucleus - the median and paramedian muscles , and the hypoglossal nucleus - the palatopharyngeus and palatoglossus ) ( 1 ) .
orofacial buccal dystonia is a focal dystonia with sustained spasms of the masticatory , facial or lingual muscles ( 2 ) .
a well - known condition for orofacial buccal dystonia is meige 's syndrome , which is a form of cranial dystonia that 's characterized by bilateral dystonic spasms of the facial muscles and frequently by bilateral dystonic spasms of other cranial muscles ( 2 ) . in this condition , blepharospasm is a most common and disabling manifestation , and it is typically associated with lower facial or oromandibular dystonia .
spasms of the neck and limb muscles may accompany the cranial dystonia and in most cases the cause of spasm is unknown ( idiopathic or primary ) .
secondary meige 's syndrome is encountered in patients with focal brain or brainstem lesions ( 3 ) .
we recently experienced a rare case of orofacial buccal dystonia in a patient who presented to our hospital 's otolaryngology department due to an annoying clicking tinnitus of the ear , and this patient was finally diagnosed as essential palatal myoclonus . to the best of our knowledge ,
this is the first case report of orofacial buccal dystonia , which predominantly presents as palatal myoclonus .
botulinum toxin a injection and counseling with psychiatric consultation relieved the disabling symptoms of the ear and the orofacial area .
a 22-year - old female presented to the ear , nose and throat ( ent ) department with an 18-month history of persistent clicking tinnitus and left facial pain .
the patient 's tinnitus and sensation of involuntary palatal movement developed about one or two months after starting the use of a wire type orthodontic appliance .
there was accompanying involuntary tremor - like dystonia on the left side of her face and buccal area , which was unnoticeable to other people . clicking tinnitus and
involuntary muscle contraction of the face and buccal area prompted the patient to visit several dental , ent and neurologic clinics ; a diagnosis had still not been made after more than a year , and this caused the patient stress .
the tinnitus and dystonic spasm with painful sensation on the left facial area were aggravated over time .
the patient felt being rejected , sad , frustrated , depressed and even anxious because the painful symptoms remained undiagnosed for a long time .
the patient 's attempts at relief included herbal medicine , acupuncture and massage , but none of these treatments were successful .
the patient also experienced symptom - related depression , anxiety and insomnia , which also created much anxiety among her family members .
the patient visited a local neurological clinic where she received brain magnetic resonance imaging ( mri ) and an electromygraphic study of her face .
clonazapam was prescribed without a proper diagnosis by one neurologist , but the symptoms were not relieved .
the patient identified that the tinnitus was exacerbated by touching the tongue to the palate .
more than 18 months had passed without any definitive diagnosis when the patient first presented to our department .
after a careful and long history taking under the suspicion of palatal myoclonus with orofacial buccal dystonia , we thoroughly examined her palate and face .
when the patient touched the palate with the tongue , clicking tinnitus was clearly audible and this could be heard by people next to her as one or two rapid clicks per second .
symmetric bilateral contraction of the anterior margin of the soft palate that was synchronous with the patient 's clicking tinnitus was observed on both the oral and nasopharyngosocopic examinations .
however , we could not detect any noticeable contractions on the buccal area , which is where the patient felt the most severe dystonic movement and pain .
we again used a fiberoptic laryngoscope to detect the movement of the buccal muscle and finally found the subtle contraction of the muscles in the left upper lip and buccal mucosal area .
the patient also felt an involuntary movement of the muscles around the left nose and chin and even in the deep part of the left anterior neck , but there were no definite tremor - like motions evident on physical examination .
the pure - tone , speech and impedance audiometry , including assessment of the static compliance , were normal .
consultation with the neurologic department ruled out other neurologic disorders and this was confirmed by the absence of any other accompanying neurologic deficits .
all of this led us to diagnose the symptoms as essential palatal myoclonus associated with orofacial buccal dystonia and this was possibly triggered by the orthodontic appliance .
the patient refused medication for a long time as she had already unsuccessfully tried different types of muscle relaxants , 5-ht1 agonist , a levo - dopa agent and anticonvulsants , which were all prescribed by another neurologist . following an ineffective 1-month course of medical therapy with a combination of muscle relaxant ( baclofen , pacific pharma , seoul , korea ) , anticonvulsant ( rivotril , rhoche korea , seoul , korea ) and anxiolytic agent ( xanapam , myung in pharm , hwasung , korea ) , the patient was treated with an injection of botulinum toxin a ( dysport , ipsen korea , seoul , korea ) under the guidance of electromyography ( emg ) .
emg of the tensor veli palatine , orbicularis oris and orbicularis oculi muscles showed bursts of abnormal electrical activity ( fig .
botulinum toxin a was injected into both sides of the tensor veli palatini muscles bilaterally via the mouth ( 15 u each ) and by a nasal route ( 10 u each ) ( fig .
the two most painful and dystonic movement sites on the patient 's face ( the orbicularis oculi and oris ) were selected first and emg - guided botulinum toxin injections were performed ( 10 - 15 u ) .
two days later , she felt decreased clicking tinnitus and a decreased painful sensation with dystonia on her left face .
therefore , botulinum toxin a was injected into every point of the abnormal muscle contraction on the face where the patient pointed and this was confirmed by emg to have been done .
the injected muscle area and the dose of botulinum toxin a are demonstrated in table 1 . on the review at week after injection of botulinum toxin a , her tinnitus and muscle dystonia were markedly decreased .
she developed a hypernasal voice and mild facial weakness , but she was satisfied with the treatment .
indeed , the patient wanted to be treated again to have complete cession of her tinnitus and palatal muscle contraction .
so , two more consecutive injections into the palatal muscles ( 30 u in total to each side of the tensor veli palatine muscle ) and one more injection into the left buccal area ( 15 u ) were done .
at the same time , the patient received counseling , which included general information about brain reorganization and behavioral modification designed to avoid triggering tinnitus and to reduce focusing on the tinnitus and facial muscle dystonia as well .
psychiatric consultation proved beneficial in easing the patient 's feelings of depression and anxiety . at the 2-month follow - up , the palatal myoclonus tinnitus had completely stopped and this was confirmed by nasopharyngoscopic examination .
palatal myoclonus is known to be a cause of objective tinnitus and is classified as symptomatic if the dysfunction or symptoms are caused by a lesion of the connections between the dentate nucleus , red nucleus and inferior olivary nuclei ( guillain - mollaret triangle ) and as essential if there is no identifiable brain lesion .
. contractions of the palatal muscles , including the levator veli palatini muscle and tensor veli palatini muscle cause rapid opening and closing of the eustachian tube , which produces an objective clicking tinnitus that is clearly audible by the examiner .
palatal myoclonus should be distinguished from middle ear myoclonus , which is another form of objective tinnitus . in middle ear myoclonus ,
the sound of the tinnitus is a buzzing instead of clicking , and movement of the tympanic membrane rather than palatal tremor is evident .
treatment for middle ear myoclonus involves sectioning of the stapedial and tensor tympani muscles ( 4 ) .
orofacial dystonia , which is a part of oromandibular dystonia , has been reported by both neurologists and dentists . making the diagnosis of dystonia and the distinction between the different focal types such as jaw dystonia , orofacial mandibular dystonia ,
tongue dystonia and cranial dystonia are purely clinical ( 2 , 3 , 5 ) .
making the diagnosis is elusive in patients with unrecognized triggers and who present during periods of quiescence .
further , there is no gold standard diagnostic test or biomarker for testing the validity of the diagnosis .
the key to establishing the correct diagnosis includes early detection of the presenting complaint , as well as having an understanding of the functional orofacial anatomy that is responsible for the unique clinical signs and symptoms . in our case ,
more than 18 months passed before establishing the correct diagnosis and this was followed by proper treatment .
only the suspicion of the possible diagnosis along with thorough knowledge about the disease will prevent a delayed diagnosis .
orofacial dystonia affects more women than men with a mean age of symptom onset between 31 and 58 years ( 6 , 7 ) .
other possible etiologies are that the orofacial dystonia is drug - induced or peripheral disease - induced , or it is associated with postanoxia , neurodegenerative disorder or head injury ( 8 , 9 ) . for our case ,
the use of an orthodontic appliance might have been a possible etiologic factor that triggered the orofacial dystonia and palatal myoclonus because the patient had a clear memory of her symptom onset as related to wearing the orthodontic appliance .
considering the previous reports about " edentoulous dyskinesia " ( 10 , 11 ) , we can suggest that a possible mechanism in our case is that the malaligned teeth and the orthodontic appliance may have caused an impairment of proprioception in the oral cavity leading to brain reorganization and subsequent development of dystonia .
we believe that the temporal and anatomical association between these two events might be considered as the cause since our patient showed orofacial dystonia and palatal myoclonus immediately after using the fixed orthodontic appliance . stress and emotional factors could be other contributing factors that reinforced the dystonia and palatal myoclonus .
the current lack of knowledge of the exact pathophysiology of dystonia and palatal myoclonus has made it difficult to prescribe specific pharmacologic therapy .
systemic pharmacologic therapy consists of a wide variety of medications , including cholinergics , benzodiazepam , antiparkinsonism drugs , anticonvulsants , muscle relaxants , 5-hydroxytryptopha , levedopa and lithium ( 1 , 2 , 8 , 9 ) . surgical therapy
is another option , which includes eustachian tube obliteration and ventilation tube placement ( 12 ) , dissection of the palatal muscles ( 13 ) for the palatal myoclonus and detachment of the involved muscles for the orofacial dystonia ( 5 ) .
another more widely accepted therapeutic strategy for palatal myoclonus and orofacial dystonia is aimed to control parts of the brain using botulinum toxin , which blocks somatic input and output through peripheral blockage of involuntary muscle movement ( 6 , 14 , 15 ) .
this toxin is a potent neurotoxin that inhibits the calcium - mediated release of acetylcholine into the synaptic junction , resulting in local chemical denervation and loss of neuronal activity in the targeted organ .
it has been used for treating many different types of disorders that showed abnormal movement .
blepharospam , oromandiblar dystonia and hemifacial spasm are representative well known indications for botolum toxin injection therapy .
botolum toxin injection became recognized as a potential treatment for palatal myoclonus in the 1990s ( 6 , 15 ) .
the main possible side effects of botulinum toxin treatment are related to a neuromuscular inhibition that exceeds the therapeutic goal or it spreads to the muscle groups adjacent to the muscle that is targeted for treatment . for palatal
myoclonus , botulium toxin injection into the palatal muscle can lead to symptoms like velopharyngeal insufficiency , a hypernasal voice or dysphagia . to avoid or minimize side effects
, the toxin dosage should be as high as necessary , but as low as possible .
however , botulinum toxin injection is considered to be a safe and effective first line therapy .
since there is the lack of experience concerning the optimal dosage of botulinum toxin for special cases like ours , we tried to inject less than 30 u of toxin into each of the problematic sites of the orofacial buccal dystonia and palatal muscles at a single trial . to get the proper therapeutic response
the dosage guideline for botulinum toxin injection for treating orofacial dytonia and palatal myoclonus should be established in the future .
we present here a case of palatal myoclonus associated with orofacial buccal dystonia , and this is the first such report in the medical literature .
to establish the correct diagnosis for such a case , early detection of the presenting complaint , as well as a thorough understanding of the functional orofacial anatomy that 's responsible for the unique clinical signs and symptoms , is necessary . in our case ,
we believe that counseling and psychiatric care also played a role in the therapeutic success .
since botulinum toxin has been proven to be safe and effective for many neuromuscular disorders , and this was also seen in our case , it can be considered to be proper treatment for orofacial buccal dystonia and palatal myoclonus .
Output:
| palatal myoclonus is a rare condition in which there are rhythmic jerky movements of the soft palate and sometimes of the other muscles innervated by the brainstem a particularly annoying symptom is a rhythmic clicking sound in the ear due to the opening and closing of the eustachian tube .
orofacial buccal dystonia is a focal dystonia with sustained spasms of the masticatory , facial or lingual muscles .
the frequent symptoms of this disease have mainly been reported to be involuntary and possibly painful jaw opening , closing , deflecting and retruding , or a combination of the above .
however , the subtle and unnoticeable involuntary movement of multiple facial muscles , which might be an infrequent symptom of orofacial buccal dystonia , makes this disease hard to diagnose . understanding the functional orofacial anatomy that is responsible for the clinical signs and symptoms is necessary for making a proper diagnosis . here
we report on a rare case of palatal myoclonus that was associated with orofacial buccal dystonia , and such a case has not been previously reported .
we describe the diagnostic approach and excellent treatment results after botulinum toxin a ( dysport ) injection and proper counseling . |
PubmedSumm4852 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: urinary tract infections ( utis ) account for 8.3 million doctor visits yearly in the united states and are the second most common type of infection in the body .
it is one of the most serious health problems affecting millions of people each year .
utis include acute as well as chronic cystitis , prostatitis , pyelonephritis , and urethritis .
lower urinary tract infection is more common among women with an incidence of one in five women at any point throughout their life .
men are usually devoid of utis , but sometimes due to an obstruction such as a stone or enlarged prostate they experience this .
prevalence of utis in men under 50 years is uncommon . although most of the cases of uti are asymptomatic or with a few distressing complaints like frequency , urgency of urination , pain during urination , difficulty in passing urine , and feeling of heaviness or pain in the pubic region even at rest , different anatomic ( obstructing lesions ) and physiologic ( estrogen deficiency , genetic factors , and regular antibiotic coverage ) factors are predisposing factors for utis .
anal intercourse and hiv infection also contribute to infection of urinary tract [ 3 , 4 ] .
the majority of causative organisms of uti are gram - negative bacteria in which escherichia coli alone contribute to 80 percent of cases .
proteus mirabilis , klebsiella pneumonia , and enterobacter aerogenes are also involve in the pathogenesis of the disease .
gram - positive bacteria include staphylococcus saprophyticus ( 1015% ) , enterococci , and staphylococcus aureus ( associated with calculi and catheterization ) .
microbiologically , uti is defined as presence of at least 10 organisms / ml of urine in an asymptomatic patient or as more than 100 organisms / ml of urine in a symptomatic patient with accompanying pyuria ( > 5 wbcs / ml ) .
conventional antibiotics are the first choice in an acute episode of uti ; therefore resistance of pathogenic bacteria to antibiotics is of high clinical concern .
the concept of the control of drug resistance is rather widely held today [ 6 , 7 ] .
several reports are available about the multidrug resistance of bacteria especially staphylococcus , pseudomonas , and escherichia
. therefore the world looks at some alternative and effective medicine particularly of natural origin .
some of the clinical studies recommend that mannose , cranberry , and probiotics can be natural options for long - term prevention from utis .
ayurveda and some other conventional systems of medicines state that plants are main reservoirs of natural entities which have been used for the treatment of different ailments .
it was reported that over 70% of the indian people believe in nature for their food as well as medicines .
the moringaceae is a single - genus family of oil seed trees with 14 well known species .
moringa oleifera , commonly known as horseradish tree or drumstick tree and saijan in hindi , ranges in height from 5 to 10 m [ 9 , 10 ] .
it is indigenous to sub - himalayan regions of northwest india , africa , arabia , southeast asia , and the pacific and caribbean islands .
the drumstick tree was used as food and medicine for centuries ; it is only recently that scientific basis for these uses has been recognized .
the stem bark has been reported to contain two alkaloids , namely , moringine and moringinine , vanillin , -sitosterol , -sitostenone , 4-hydroxymellin , and octacosanoic acid and phenolics .
its bark possesses antibacterial [ 1521 ] activities against varieties of both gram - positive and gram - negative bacteria , antifungal , anticholesteremic , antilipidemic , antifertility , anti - inflammatory , diuretic , antiurolithiatic , antioxidant , antisickling , cardioprotective , hepatoprotective , and hypoglycaemic effect .
the aim of the present study was to find out the efficacy of m. oleifera stem bark as a potential treatment for urinary tract infection .
a total of 30 patients were registered from the dravyaguna out patient department , ayurveda wing , sir sunderlal hospital , institute of medical sciences , banaras hindu university , varanasi , after proper screening on the predesigned pro forma .
the cases were selected , also , on the basis of the following inclusion ( adult , uncomplicated uti , and patients with bph ) and exclusion ( patients with renal failure , calculus , and stricture or any structural pathology and pregnant women ) criteria . then all the cases are screened for other possible causes of uti before including in the final sample .
the work has been approved by the ethical committee of the institute of medical sciences , banaras hindu university , varanasi ( ref : dean/2010 - 11/92 dated : 5th may 2010 ) .
identification of drug was carried out in the department of dravyaguna , faculty of ayurveda , institute of medical sciences , banaras hindu university , varanasi .
the stem bark is powdered coarsely for decoction in ayurvedic pharmacy , faculty of ayurveda , institute of medical sciences , banaras hindu university , varanasi .
30 patients with uti were randomized and divided into two groups , 15 patients in each .
one group is treated with trial drug shigru bark decoction ; 40 ml ( made by boiling 15 g of coarse powder in 100 ml water ) for 21 days , twice daily , is given to patients for treatment ; another group was named control group in which standard modern medication was administered . to assess the effect ,
but after getting investigations and effect of the drugs on subsequent follow - ups ( responding / not responding ) , these cases were classified also as per the characteristic of urine , sign / symptoms concerned with the specific pathogen grown in the urine .
patients were also advised to drink lukewarm water , avoid sexual intercourse , suppression of natural urge of urination , exercise , excessive speech , uneven sitting and lying postures , exposure to wind , cold , heat , and dust , anger , and grief .
patients of both groups were advised to come for follow - up every 7 days . at every follow - up changes in clinical features were noted and the investigations were repeated .
the patient of test group was advised to continue the oral medication that was continued for the next 7 days . in control group patients
were advised to continue the prescribed antibiotic in the therapeutic doses for the duration of the next 15 days .
all these patients were followed for at least two months . those cases with a minimum of the three follow - ups or who had minimum treatment for duration of one and half months were included for analysis of result .
assessment was made on the following criteria during follow - up : changes in clinical symptomatology ( table 1);finding in the routine and microscopic examination of urine;finding in urine culture .
changes in clinical symptomatology ( table 1 ) ; finding in the routine and microscopic examination of urine ; finding in urine culture .
results on continuous measurements are presented on mean sd and results on categorical measurements are presented in number ( % ) .
the age distribution of the patients in the sample set was 2565 years ( mean age of 36.16 ) .
the prevalence of uti was highest within 2535 years ( 30% ) followed by 3545 years ( 20% ) , 1525 years ( 20% ) , 4555 years ( 16.67% ) , and 5565 years ( 13.33% ) .
the majority of cases were female ( 56.67% ) and 43.33% of cases were male patients which is in agreement with earlier studies [ 3135 ] .
the peculiarities of female anatomy with shorter urethra and closeness of the urethral meatus and anus have been reported as factors which influence the higher prevalence in women .
the age group analysis showed that young patients usually female in the range of 2535 years had high prevalence rate of uti .
this result is in agreement with previous studies [ 37 , 38 ] which shows that among sexually active young women the incidence of symptomatic uti is high and the threat is firmly connected with sexual intercourse , fresh utilization of diaphragm with spermicide , and a positive history of recurrent utis .
the majority of cases were married ( 70% ) , followed by 7 ( 23.33% ) unmarried and 2 ( 6.67% ) widows .
the majority of cases were hindu ( 90% ) ; only 10% of cases were muslim as circumcision seems to reduce the overall incidence of uti in muslims .
prevalence of disease is highest in business and housewife ( both 26.67% ) then followed by student ( 16.67% ) farmers ( 13.33% ) , service class ( 10% ) and unemployed ( 6.66% ) [ 40 , 41 ] .
the majority of cases belonged to rural area ( 53.33% ) followed by urban area ( 46.67% ) .
a maximum number of cases are from the disease that were of middle class ( 73.33% ) followed by lower ( 20% ) and upper ( 6.67% ) .
it was observed that total duration of illness ranged from 6 month-1 year ( 33.33% ) to 5 years ( 13.33% )
. clinical profile of these patients exhibited fever ( 80% ) , oliguria ( 70% ) , burning urination ( 66.67% ) , frequency ( 63.33% ) , pain , and urgency ( 60% ) .
routine and microscopic urine examination of these patients at starting of treatment exhibited sugar ( 53.33% ) , albumin ( 50% ) , rbc ( 33.33% ) , epithelium ( 26.67% ) , pus cell ( 30% ) 10% patients with crystals . in our study gram - negative aerobic rods predominated , among which e. coli was the commonest uropathogen responsible for uti .
it accounted for 60.0% of all positive cultures , while k. pneumoniae and proteus mirabilis were the next most common organisms , accounting for 16.67% and 10% of culture in the present study , respectively .
pseudomonades aeruginosa , streptococcus faecalis , and staphylococcus aureus are also present in some of the patients ( table 2 ) .
the percentage of causative bacterial class was analogous to some other previous studies [ 4347 ] . in our study
we found that fever was absent in only 6.67% of cases at the end of treatment in test group ; however a gradual decrease in the number of patients has been observed ( table 3 ) .
table 4 reveals therapeutic effect within both groups in successive follow - ups , which is highly significant in group a ( p < 0.001 ) and significant in group b ( p < 0.005 ) after treatment ( at ) .
initial mean reduced from 2.88 0.719 to 2.31 0.704 after treatment regimen in group a and from 3.25 0.577 to 2.75 0.683 in group b. intergroup comparison between before treatment ( bt ) and after treatment ( at ) was not found to be significant .
it means that the tested drug is effective in controlling fever but it is not as effective as antibiotics .
successful reduction in burning sensation during urination was observed ( table 3 ) in both groups . only in 26.67% of cases burning urination
was relieved at the end of treatment in group a , while 6.67% of cases were relieved from the complaint at in group b. table 4 showed effect on burning urination in both groups on successive follow - ups which is highly significant in group a ( p < 0.001 ) and significant in group b ( p < 0.005 ) .
it means that the tested drug is effective in controlling the burning sensation during urination but not as effective as antibiotics .
relief from pain during urination is observed in both groups . in 40% of cases pain
was completely relieved at the end of treatment in group a. in group b , 6.67% of cases were relieved from the complaint at ( table 3 ) .
table 4 showed significant changes in relieving pain in both groups in successive follow - ups ( p < 0.01 ) . in 6.67% of cases , frequency of urination was normalized at the end of treatment in group a. in group b , 6.67% of cases were relieved from the complaint at ( table 3 ) .
table 4 showed significant changes in frequency in both groups in successive follow - ups ( p < 0.05 ) .
improvement in amount of urine is also observed in both groups . in 6.67% of cases ,
oliguria was relieved at the end of treatment in group a. in group b , 6.67% of cases were relieved from the complaint at ( table 3 ) .
table 4 showed significant improvement in oliguria disorder in both groups in successive follow - ups ( p < 0.05 ) .
the routine and microscopic urine examination of these patients after treatment showed significant effect of the test drug . pus cell and
the culture reports showed that the herb has prominent effect on e. coli and other bacteria like k. pneumoniae and p. mirabilis .
however , p. aeruginosa , s. faecalis , and s. aureus were not found to be present in any of the patients at the end of the treatment .
as evident from table 5 , the majority of cases were cured ( 56.67% ) after three weeks of treatment , followed by improving ( 20% ) and relapsing ( 13.33% ) .
this study was conducted on volunteer patients in the department of dravyaguna , faculty of ayurveda , institute of medical sciences , banaras hindu university , varanasi , india , spread over a period of one and half years .
the study was carried out according to the institution guidelines for biomedical research involving human subjects .
our data show that decoction of m. oleifera is an effective remedy for symptomatic relief in utis .
this is an encouraging result which clearly favors promotion of m. oleifera as a remedy among rural communities especially belonging to low socioeconomic strata as m. oleifera is easily accessible and is cheap and safe .
the results demonstrated a significant reduction of symptoms in both groups a and b over a period of two months .
levofloxacin has been utilized for several years and it is still considered one of the most effective agents in utis . however , recurrence is quite common ; therefore new drugs from herbal origin with similar or superior efficacy and possibly fewer long - term effects need to be investigated .
m. oleifera is one of the common indian herbs used for different conditions related to urinary system such as urolithiasis and benign prostrate hyperplasia .
this plant has been used in india and other parts of asia for thousands of years for nutritional as well as medical purposes . in traditional literature , preparations of the m. oleifera
stem bark of m. oleifera has been tested against a variety of microorganisms like e. coli , s. aureus , b. cereus , p. aeruginosa , and p. mirabilis .
it shows prominent effect against e. coli ( mic 64 g / ml ) , which is a major causative factor in the utis . in the present study , m. oleifera decoction provides symptomatic relief to the patients during the trial ; possible explanation for this effect might be due to the antibacterial and anti - inflammatory agents present in the plant [ 15 , 1721 , 23 ] .
urinary stone is also one of the conditions which facilitate utis ; therefore antiurolithiatic activity of drumstick might also contribute in its action on urinary system .
urinary tract infection in addition aggravates the oxidative stress in some cases like diabetes and pregnancy .
so antioxidant activity of m. oleifera bark is effective against oxidative stress produced in uti probably because of phenolic component .
painful and inconvenient , a uti results in frequent urges to urinate with little production of urine and is accompanied by a severe burning sensation .
diuretic abilities of moringa also appear to inhibit adheration of infection - causing bacteria to the wall of the bladder , so they are sloughed off in urine as reported in the similar case of cranberry .
however , as this is the first attempt to assess the effect of m. oleifera in utis , clinical trial of longer duration with a larger sample size should play a vital role in commercialization of m. oleifera .
from the clinical study , it has been concluded that stem bark of m. oleifera , at a dose of 40 ml bd , is effective on most of the cardinal symptoms of urinary tract infection .
the drug was well tolerated and does not generate any adverse effect during the entire clinical study .
the drug is also helpful in eradicating urinary pathogens like e. coli that are responsible for uti .
Output:
| objective .
urinary tract infections ( uti ) are the most common problem in clinical practice . usually they are asymptomatic and are commonly present with distressing symptoms like pain and burning sensation on urination .
antibiotics are widely used to treat utis ; however , they have their own limitations like resistance , reinfection , and relapses . the purpose of the current study was to evaluate the value of moringa oleifera lam .
stem bark as a potential medicine for utis
. study design .
30 patients with uti were randomly divided into two groups with 15 patients in each group .
shigru bark was given to patients of the first group ( trial group ) and modern medicines were prescribed to the other group of patients .
at least three follow - ups are taken in both groups at the end of every week of treatment .
results .
after treatment 66.67 % were cured , 13.33 % improved , 13.33% patients have no change , and 6.67% relapsed in trial group and in control group 46.67% were cured , 26.66% improved , 6.67% patients have no change , and 20% relapsed . interpretation and conclusion .
the trial drug is significant in the management of uti .
this study needs to be done on a large scale and for a long time . |
PubmedSumm4853 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: jacob arthurin 1827 first coined the term rodent ulcer to describe what we now know as a basal cell carcinoma ( bcc ) .
it is the most common cutaneous malignancy worldwide , accounting for 6575% of all skin cancers .
gross differences are noted in the percentage of skin cancer in the asians ( 24% ) and blacks ( 1 - 2% ) as compared to the caucasians ( 3540% ) .
although the incidence of skin cancers in india is lower as compared to the western world , absolute number of cases may be significant due to large population .
the existing literature on bcc in india is scant with lack of clinical studies with statistical analysis .
so , this study was undertaken to fill this deficit in literature of bcc with focus on epidemiology , risk factors , and clinical and pathological aspects of the disease .
bcc is a nonmelanocytic skin malignancy arising from basal cells of the epidermis or follicular structures and is seen mostly on sun exposed areas , especially head and neck , occasionally over the trunk and limbs , and rarely on the palms , soles , mucous membranes , and genitals [ 4 , 5 ] .
recently , it has been indicated that bcc occurrence is higher along embryonic fusion planes as compared to other areas of the midface , evidence that supports this hypothesis for bcc pathogenesis .
ninety - five percent of these neoplasms occur in patients aged more than 40 years , although cases in childhood and congenital basal cell epitheliomas have been reported [ 79 ] . in children ,
it is usually associated with a genetic defect , such as basal cell nevus syndrome , xeroderma pigmentosum , nevus sebaceous , epidermodysplasia verruciformis , rombo syndrome , or bazex syndrome .
sunlight is the most frequent association with development of bcc ; risk correlates with the amount and nature of accumulated exposure , especially during childhood .
a latency period of 2050 years is typical between the time of ultraviolet ( uv ) damage and bcc clinical onset .
uvb is believed to play a greater role in the development of bcc than uva . in a 2012 systematic review and meta - analysis of 12 studies with 9328 cases of nonmelanoma skin cancer , wehner et al . found that indoor tanning was associated with a significantly increased risk of both basal and squamous cell skin cancers .
apart from uvr , x - ray and grenz ray exposure is also linked with development of bcc .
arsenic has been used as a medicinal agent , predominantly the fowler solution of potassium arsenite , which was used to treat many disorders , including asthma and psoriasis , and is linked to the risk of development of multiple malignancies after a long latency period spanning many years .
the risk of developing new nonmelanoma skin cancer is reported to be 35% at 3 years and 50% at 5 years after an initial skin cancer diagnosis .
a study among adults in the united states reports a strong association between excessive alcohol drinking and higher incidence of sunburn , suggesting a linkage between alcohol consumption and skin cancer .
a hospital based study was conducted at a tertiary care hospital situated in punjab , north india , from 2011 to 2013 .
patients of all ages attending skin outpatient department with suspected lesions were screened for bcc after taking an informed written consent .
patients with histopathologically confirmed bcc were enrolled in the study . detailed history with recording of various patient variables like age , gender , duration of symptoms , fitzpatrick skin phototype , skin color , average daily sun exposure ( hours / day ) , occupation , residence place ( rural or urban ) , exposure to chemicals including pesticides , radiation exposure history , treatment with psoralen uva ( puva ) or narrow band uvb ( nbuvb ) , smoking , alcohol intake , history of personal or family history of skin cancers , personal or family history of other cancers , history of genetic disorder like xeroderma pigmentosum , albinism , and history of previous treatment .
clinical examination was done with data collection on various tumor variables which included the following : size , location , number , morphological subtype , and pigmentation . for descriptive purposes ,
the lesions were classified based on size into small ( less than 1 cm in diameter ) , medium ( 1 - 2 cm in diameter ) , and large ( > 2 cm in diameter ) .
investigations included complete blood count with differentials , bleeding time , clotting time , renal function tests , liver function tests , and viral markers .
diagnosis was confirmed by histopathological examination of biopsy specimen with documentation of histopathological variant . to analyze the results , descriptive statistics such as mean ,
various analytic tests such as test , p value , and t - test were used .
a total of 36 histopathologically confirmed cases of bcc were enrolled in the study from 2011 to 2013 .
an increase was seen in absolute number of cases diagnosed per year with 9 , 11 , and 16 patients in 2011 , 2012 , and 2013 , respectively ( figure 6 ) . out of these patients ,
males were 36.1% ( 13/36 ) and females were 63.9% ( 23/36 ) with m : f being equal to 0.57 : 1 ( figure 7 ) .
age of the affected cases ranged from 29 to 92 years of age . the mean sd age of the patients was 60.9 14.2 years ( 65.92 14.35 years for males and 57.96 13.54 years in case of females ) .
although the difference in mean age between males and females was not statistically significant ( data was analyzed using unpaired t - test ) , it carries a clinical relevance as females tend to seek medical care earlier than males for suspicious , asymptomatic , and cosmetically disfiguring lesions .
the greatest number of patients was in the age group of 6180 years ( 47.2% ) followed by 4160 years ( 38.95% ) , 2140 years ( 8.3% ) , and 81100 years ( 5.6% ) , respectively ( figure 8) .
the youngest age of presentation in case of females was 29 years , while in males the corresponding age was 45 years .
correlation between gender and age group was not statistically significant ( fisher exact test p value being 0.177 ) , implying that these two variables are independent ( table 1 ) . out of all patients , 69.4% ( 25/36 ) hailed from rural areas .
a statistically significant association was seen between duration of disease and illiteracy ( value = 6.95 and p value = 0.01 ) .
this meant that illiterate patients present at a later stage of disease attributable to lack of awareness about disease entity .
farming was the main occupation among male patients ( 92.3% ) , while housekeeping was the major job among female patients ( 95.7% ) .
the duration of disease before seeking medical care ranged from 5 months to as long as 15 years , with mean duration being 4.7 years .
the average duration of sun exposure was 6 hours / day in case of males and 2.91 hours / day in female patients .
this difference in duration of sun exposure was statistically significant ( t - value being 6.71 and p value = 0.000 ) ( table 3 ) .
however , the females were intermittently exposed to high intensity sunlight due to work in open kitchens and fields during sowing and harvesting seasons .
none of the patients had been taking photoprotective measures such as use of sunscreens and protective clothing .
there was no history of treatment with puva or nbuvb in any of the study cases .
no patient had features suggestive of genodermatoses associated with predilection for cutaneous malignancies like xeroderma pigmentosa , albinism , and so forth .
out of 36 patients , one ( 2.8% ) had been previously treated for breast and endometrial carcinoma .
all the cases belonged to fitzpatrick skin types iii and iv ( calculated via fitzpatrick scoring scale ) .
out of total 36 patients , two ( 5.6% ) had 2 lesions at the time of presentation .
one female ( 2.8% ) patient had multiple lesions over face followed by development of ulcerative growths on ear and mons pubis .
she was later diagnosed with bcc having noncontiguous and distant cutaneous metastasis ( figure 1 ) .
the size of lesions ranged from as small as 0.5 cm to 5 cm in diameter .
the size of lesions was found to have a statistically significant association with duration of disease ( = 11.10 ; p value = 0.004 ) ( table 4 ) .
the distribution of lesions was as follows : nose ( 50% ) , cheeks ( 22.2% ) , ear and preauricular area ( 13.9% ) , lower eyelid ( 13.9% ) , temporal area ( 5.6% ) , upper lip ( 2.8% ) , forehead ( 2.8% ) , scalp ( 2.8% ) , and mons pubis ( 2.8% ) ( table 5 ) .
nose was the most significant site of involvement in our study ( = 14.43 ; p value = 0.01 , while corresponding values without involving nose as site of bcc were 1.00 and 0.80 ) .
the most common morphological subtype of bcc was nodular / noduloulcerative growth ( 77.8% ) ( figures 1 and 2 ) .
a significant percentage of bcc was clinically pigmented ( 22.2% ) ( table 6 ) .
the most common histopathological variant was nodular subtype ( 77.8% ) with a significant proportion of tumors being pigmented ( 16.7% ) ( table 7 ) .
other subtypes included basosquamous ( 8.3% ) , micronodular ( 2.8% ) , morpheaform ( 2.8% ) , keratotic ( 2.8% ) , and adenoid ( 2.8% ) bcc and bcc with adnexal differentiation ( 2.8% ) .
consequently , most of the studies have focused on white populations in europe , usa , and australia with scarcity of data from developing countries ( table 9 ) .
estimates of the incidence of bcc are imprecise since there is no cancer registry that collects data on bcc .
although incidence rates of bcc vary significantly according to the ethnicity and geographic location , most studies show a rising trend in its incidence worldwide . this has been largely attributed to fair complexion and ozone layer depletion resulting in increased uv radiation reaching earth 's surface .
factors other than the mentioned above need to be searched and verified as darker skin complexion in indians should otherwise be protective against bcc .
moreover , ozone layer destruction is most evident over the temperate and polar regions , while india is a tropical country [ 15 , 16 ] .
this finding highlights the need for early institution of uv protection and skin cancer screening in the pediatric and young adult population . however , there was no case below the age of 20 years in our study .
relative risk of bcc is more for children who have undergone radiation therapy for enlarged thymus or neoplasms such as medulloblastoma .
bccs are more common in males as reported in most studies worldwide , presumably due to greater occupational and recreational exposure to ultraviolet radiation ( uvr ) .
however , an unusual female preponderance was noticed in our study which is consistent with findings of another indian series .
indian housewives especially rural women work in open kitchen ( figure 4 ) during their household chores and work in the fields during sowing and harvesting seasons exposing them to intermittent , high intensity uvr .
it might explain higher frequency of bcc in females in our study as intermittent rather than constant , cumulative uvr exposure is implicated in the pathogenesis of bcc .
this female predilection may also be attributed to the changes in cultural practices like veil custom ( figure 5 ) , structurally thinner skin with lower collagen density in the dermis when compared to men .
the most commonly affected age group in our study was 6180 years ( 47.2% ) followed by 4160 years ( 38.95% ) , 2140 years ( 8.3% ) , and 81100 years ( 5.6% ) .
the cases belonged to age ranging from 29 to 92 years which is similar to study published from north india .
higher rates of occurrence of bcc among elderly may be due to cumulative uvr induced dna damage as well as reduced efficiency of immune - surveillance and dna repair mechanisms with aging . in our study , higher frequency among rural inhabitants was seen when compared to urban residents .
this can be explained on the basis of more outdoor activities ( as agriculture is the main occupation ) , changes in clothing preferences , illiteracy , and infrequent use of sunscreens .
the rural patients regard initial lesions of bcc as a minor cosmetic problem with insignificant impact on health and seek medical advice only when lesions become symptomatic or disfiguring .
a study done in punjab regarding cancer found that tap water contains high content of arsenic , chromium , iron , and mercury , whereas ground water has abundance of arsenic , chromium , nickel , and iron .
tseng et al . found a dose - dependent relation between arsenic levels in drinking water and the prevalence of skin cancers .
thus , exposure to harmful metals and pesticides may also add to the risk of skin cancers , but further clinical and research studies are needed to confirm their role in the pathogenesis of bcc and to delineate underlying mechanisms .
occupations at risk of bcc that are highlighted in our study include agricultural workers and housekeepers .
immunocompromised patients like hiv positive patients or organ transplant recipients have a markedly increased risk of both typical and highly invasive nmsc .
interesting fact is that while the bcc / scc incidence ratio is approximately 4 : 1 in the general population , sccs become more prevalent in the transplant population with a bcc / scc ratio of approximately 1 : 2 .
some studies refute any relationship between smoking and risk of bcc , while boyd et al . found that bcc in young women is linked with past or current smoking .
smith and randle described an increased prevalence of bcc larger than 1 cm in diameter among the smokers .
other iatrogenic risk factors associated with bcc include treatment with psoralens and uva therapy and nbuvb for various ailments .
none of the patients in our study had received such treatments . in a retrospective ,
nation - wide cohort study of patients with psoriasis subjected to climatotherapy at the dead sea , it was found that the overall risk of cancer in patients treated at the dead sea was higher than that expected in the general population , owing to an excess risk of nonmelanoma skin cancer ( nmsc ) , with multiple lesions being more common and predilection for younger individuals . the most common location in our study was head and neck area ( 97.2% ) which is close to what was observed by malhotra et al . .
this pigmentation might be misleading as , clinically , bcc may be misdiagnosed as melanoma . although most bccs are slow - growing , relatively nonaggressive tumors , a minority have an aggressive behavior with local tissue destruction and , rarely , metastasis .
risk factors for development of metastatic bcc include large primary tumor ( > 2 cm ) , location in head and neck region , long standing lesion , multiple primary tumors and recurrences , prior radiation therapy , large tumor depth , invasion of perineural space and blood vessels , fair skin , male gender , and immunosuppression .
this study highlights a paradoxically increasing trend of bcc with female predilection and higher percentage of pigmented lesions in indians .
major contributory risk factors include intermittent rather than constant uv exposure , cultural and lifestyle changes , cosmetic indifference , possible role of arsenic and pesticides , improved clinical awareness , and diagnostic facilities .
the increasing cancer burden calls for the need of introduction of national screening program including mandatory annual skin examination by trained health professionals at the national level . since early detection and treatment of lesions
are crucial to decrease functional and cosmetic morbidity and costs , this study highlights the importance of improving awareness among general practitioners , public health workers , and general population .
the clinical and epidemiological data collected in this study would serve as a reference for future research and may be helpful in the development of preventive and educational strategies .
Output:
| objectives .
although the incidence of skin cancers in india ( part of south asia ) is low , the absolute number of cases may be significant due to large population .
the existing literature on bcc in india is scant .
so , this study was done focusing on its epidemiology , risk factors , and clinicopathological aspects .
methods .
a hospital based cross - sectional study was conducted in punjab , north india , from 2011 to 2013 .
history , examination and histopathological confirmation were done in all the patients visiting skin department with suspected lesions . results .
out of 36 confirmed cases , 63.9% were females with mean sd age being 60.9 14.2 years .
mean duration of disease was 4.7 years .
though there was statistically significant higher sun exposure in males compared to females ( p value being 0.000 ) , bcc was commoner in females , explainable by intermittent sun exposure ( during household work in the open kitchens ) in women .
majority of patients ( 88.9% ) had a single lesion .
head and neck region was involved in 97.2% of cases , with nose being the commonest site ( 50% ) with nodular / noduloulcerative morphology in 77.8% of cases .
pigmentation was evident in 22.2% of cases clinically .
nodular variety was the commonest histopathological variant ( 77.8% ) .
conclusions .
this study highlights a paradoxically increasing trend of bcc with female preponderance , preferential involvement of nose , and higher percentage of pigmentation in indians . |
PubmedSumm4854 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input:
Output:
| this review presents a brief overview of the health effects and exposures of two criteria pollutants -- ozone and particulate matter -- and two toxic air pollutants -- benzene and formaldehyde .
these pollutants were selected from the six criteria pollutants and from the 189 toxic air pollutants on the basis of their prevalence in the united states , their physicochemical behavior , and the magnitude of their potential health threat .
the health effects data included in this review primarily include results from epidemiologic studies ; however , some findings from animal studies are also discussed when no other information is available .
health effects findings for each pollutant are related in this review to corresponding information about outdoor , indoor , and personal exposures and pollutant sources.imagesfigure 3figure 8figure 9 |
PubmedSumm4855 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: anesthesia has the potential to induce physiological changes that may lead to morbidity and mortality . as a result
a number of investigators , however , have reported that anesthesia - related mortality rates have declined over the past two decades .
this decrease has been attributed to a variety of safety improvements including improved monitoring techniques , the development and widespread adoption of practice guidelines , and other systematic approaches to error reduction.1,2 nonetheless , trends in the frequency of anesthesia - related mortality remain controversial . according to a recent review,3 the literature reports a wide range of perioperative mortality rates , which is probably due to variable methodologies and differences in operational definitions and reporting sources , as well as a lack of appropriate risk stratification .
numerous studies have examined perioperative mortality.331 in these reports , the definitions for deaths in which anesthesia was the primary or a contributing cause335 varied widely , as did the time windows for the considered perioperative period .
the perioperative period has been defined as intraoperative only,12,14,16,24,33 intraoperative and recovery from anesthesia,24,29,31 the first 12 postoperative hours,34 the first 24 postoperative hours,5,7,8,11,13,18,20,22,26,28,30,32,33 two or three postoperative days,3,9,10,17,35 or seven postoperative days.6,19,21,23,25 furthermore , mortality incidence may depend on the surgical population .
several studies examined all types of surgery,35,713,1532 , 35 while others excluded surgeries in asa v patients,34 cardiac surgeries14,24,33 or obstetric surgeries.6 these wide variations based on methodological differences as reported in the literature make it impossible to detect trends in anesthesia safety.3 large - scale and national studies of anesthesia - related mortality have been performed in some countries to confirm whether the mortality rate has indeed decreased.11,17,20,21,23,25,26,35 in brazil , reliable data on anesthesia - related mortality have been collected,2731 but no nationwide study has been undertaken .
the purpose of our study was to perform a systematic review of the brazilian and worldwide literature in order to evaluate the incidence and causes of perioperative and anesthesia - related mortality .
the medline ( via pubmed ) and scielo databases were searched using the subject keywords mortality , cardiac arrest and anesthesia . we also used the related articles
publications were included in our review if their titles or abstracts were available in english or portuguese and suggested a perioperative mortality rate related to anesthetic management in a general patient population over a specific period of time based on original data from at least 25,000 anesthetics .
publications were excluded if the anesthetic management was limited to a particular technique or the patient population was limited to a particular procedure , associated disease state , or age group .
mortality - triggering factors were assigned to one of three groups : ( i ) surgery - related ; ( ii ) related to patient disease or condition ; or ( iii ) anesthesia - related when anesthesia was the major contributor or represented an additional factor associated with patient disease condition or surgical factor .
each publication was reviewed in order to identify the author(s ) , study period , data source , perioperative mortality rate ( including all death - triggering factors ) , and anesthesia - related mortality rate .
database queries identified 33 publications reporting anesthesia - related mortality data , 28 from international investigators ( tables 1 and 2 ) and 5 publications by brazilian investigators ( table 3 ) .
comparison of the literature data reported by investigators from different countries between 1954 and 1989 with those obtained from 1990 to 2006 showed that anesthesia - related mortality rates decreased from 0.30 7.91 per 10,000 anesthetics413 ( table 1 ) to 0.10 5.70 per 10,000 anesthetics3,1426,3235 ( table 3 ) .
however , the highest anesthesia - related mortality rates were observed between 1990 and 2006 ( 3.3 to 5.7 per 10,000 anesthetics ) and reported in studies performed in developing countries18,26 ( table 2 ) . in brazil , reported anesthesia - related mortality rates also declined from 2.28 per 10,000 anesthetics in 198627 to 0.12 1.12 per 10,000 anesthetics between 1998 and 20062831 ( table 3 ) .
comparison of the literature reported by worldwide investigators from 1954 to 1989 with papers published between 1990 and 2006 demonstrated that perioperative mortality rates declined from 2.4 188.9 per 10,000 anesthetics413 ( table 1 ) to 1.41 28.2 per 10,000 anesthetics3,1423,25,26 ( table 2 ) .
once more , the highest anesthesia - related mortality rates for the 19902006 period ( 20.14 to 28.2 per 10,000 anesthetics ) were reported by investigators from developing countries15,18,26 ( table 2 ) .
the studies conducted in brazil between 1986 and 2006 also revealed increased perioperative mortality rates varying from 19.1 to 51.0 per 10,000 anesthetics2731 ( table 3 ) . in both brazilian28,30,31 and worldwide3,9,15,17,2022,26 studies , the patient / disease condition represented the major perioperative mortality - triggering factor , followed by surgery and anesthesia .
the incidence of mortality caused by surgical factors declined significantly during the last few decades.17 cardiovascular effects caused by the administration of anesthetic drugs and inadequate blood management during hemorrhage and anemia have been the major contributing factors to anesthesia - related mortality during the past twenty years , followed by airway management failure.3,20,24,31,3537 of the factors associated with the patient condition/ disease or surgery , both brazilian29,31 and worldwide22,26 studies have pointed to trauma as the major cause of perioperative mortality , followed by end - stage liver disease and liver transplantation - related complications , complications associated with cardiac surgery , and exsanguinating hemorrhage at operation associated with the primary disease . in newborns and children under one year11,14,2123,30 as well as in the elderly , mortality rates were higher than in young adults.11,12,17,2123,28,35 poorer american society of anesthesiologists physical status ( asa iii to v)11,14,29,31,34,35 and emergency surgery11,12,17,21,22,27,29,31 have been considered risk factors for perioperative mortality . in addition , higher perioperative mortality incidence has been reported in males.22,28,30,31,35 with regard to anesthesia type , perioperative mortality has been reported to be higher in patients undergoing general anesthesia as compared to those undergoing neuraxial anesthesia.20,27,30,31,35 mortality incidence during surgeries carried out under plexus block has been reported as practically zero.29,31,34 a higher number of intraoperative deaths have occurred during cardiac surgeries , followed by thoracic , vascular , gastroenterologic , pediatric , and orthopedic surgeries.20,22,28,30,31,35
substantial differences in methodology make it very difficult to compare anesthesia - related mortality rates among studies.3 despite the difficulties , studies undertaken in different countries ( tables 1 and 2 ) suggest that anesthesia - related mortality rates are lower today than they were 20 years ago . the pioneering study of beecher and todd ( 1954),4 which covered the period between 1948 and 1952 , reported an anesthesia - related mortality rate of 6.40 per 10,000 anesthetics . over the past two decades ,
most of the published studies have reported anesthesia - related mortality rates ranging from 0.5 to 1.0 per 10,000 anesthetics 3,14,22,34,35 or even lower,1517,19,2325,33 which is at least a ten - fold improvement . in support of this assertion , the authors of a nationwide survey performed in france in 199935 reported that , in comparison with data obtained in a previous nationwide study ( 19781982 ) , anesthesia - related mortality in france seemed to be reduced ten - fold in that country .
some brazilian studies conducted at the same kinds of institutions point to the same trend . according to these studies
, anesthesia - related mortality rates decreased from 2.28 per 10,000 anesthetics in the period of 1982198427 to 0.77 per 10,000 in 1995,28 and to 0.12 per 10,000 in 19981999.30 other brazilian studies in another institution reported lower and stable anesthesia - related mortality rates ranging from 0.85 per 10,000 anesthetics in 1988199529 to 1.12 per 10,000 anesthetics in 19962004.31 considering the differences in patient risk and complexity of surgery five decades ago , it may be easy to conclude that anesthesia safety has dramatically increased over the past two decades .
however , surveys of anesthesia - related mortality carried out in developing countries over this period18,26 report rates of 3.30 to 5.70 per 10,000 anesthetics . according to lagasse ( 2002),3 the number of anesthesia - related deaths worldwide
has not yet stabilized and one can not detect trends in anesthesia safety until the causes of variation among studies have been fully understood and factored out .
lagasse highlights the fact that the causes of variation could represent real differences in anesthesia safety or just differences in the tools used to measure anesthesia - related mortality in the various studies .
although anesthesia - related mortality has been reduced in recent decades , such a reduction is insufficient because , as articulated by macintosh in 1948,36 the ideal goal is that zero anesthesia - related deaths should occur .
unfortunately , anesthesia still contributes to major and avoidable adverse effects and deaths,3739 and is still not completely safe in asa i or ii status patients.3 in developed countries , perioperative - related mortality also seems to have decreased from 133.4 per 10,000 anesthetics administered in 194819524 and 188.9 per 10,000 in 196519695 ( table 1 ) to fewer than 20 per 10,000 anesthetics3,17,22 and even fewer than 10 per 10,000 anesthetics14,16,1921,23,25 ( table 2 ) . nonetheless , brazilian studies suggest no reduction in perioperative - related mortality rates .
one study,27 covering the period between 1982 and 1984 , reported a perioperative mortality rate of 19 per 10,000 anesthetics , while studies performed in the last two decades reported higher incidences ranging from 21 to 51 per 10,000 anesthetics.28,31 studies in developing countries have also reported high perioperative mortality rates ( 20.14 to 28.2 per 10,000 anesthetics).15,18,26 certain pre - existing morbidities such as trauma , sepsis , and multiple organ failure , which seem to occur at a high incidence in brazil,40 and in developing countries as well,4143 have certainly influenced perioperative mortality rates . thus , weaker clinical statuses of patients undergoing anesthesia seem to be the main factor contributing to the higher perioperative - related mortality rates reported by authors from developing countries in comparison with studies from developed countries .
the higher perioperative mortality rates observed among young adult males both in brazil2931 and in several other countries20,22,24,35,44 can be explained by the fact that men are more predisposed to trauma , violence , and vascular disease than women .
poorer asa physical status and emergency surgery have been reported as risk factors for perioperative mortality11,22,35 and are the only predictive factors of mortality after cardiac arrest.45 some investigators have reported an increased incidence of perioperative mortality in neonates and infants.11,14,2123,30 prematurity , congenital neurological disease , congenital heart disease , and other congenital defects place neonates and infants at a higher anesthesia risk than older children and adults.45 on the other hand , more recent studies20,24,30,34,45 have reported lower perioperative mortality rates in children from 1 to 12 years old .
some reports11,12,17,2123,28,35 have identified advanced age ( 7080 years ) as a risk factor . however , in one report,21 age itself was not found to be an independent risk factor .
anesthesia - related cardiac arrest and deaths in 7080 year old patients seem to be increasing , especially during hip arthroplasty surgery.17,24,34 in france , the annual rate of anesthetic procedures between 1980 and 1996 increased from 6.6 to 13.5 per 100 people .
increases were greater in the elderly and in those with higher asa physical status.46 if this trend were global , it could indicate improvements in anesthesia safety because instead of an increase , a decrease in anesthesia - related mortality rates has been reported over the past 20 years in france.35 studies suggest that mortality is higher during general anesthesia than during neuraxial anesthesia.24,34,47,48 however , this may reflect the fact that patients with hemodynamic instability and a wider variety of more complex cases are surgically treated under general anesthesia .
likewise , there may be a bias towards general anesthesia in emergency settings or for patients with coexisting medical conditions .
improved knowledge of neuraxial block physiology and the use of new and safer local anesthetics for the cardiovascular and central nervous systems , together with routinely used oxygen monitoring through pulse oximetry , have all decreased the frequency of major complications during neuraxial anesthesia.49 on the other hand , mortality rates of zero have been observed during plexus block .
studies have shown that because there are no major respiratory and cardiovascular changes in plexus block mortality rates can be almost nil , and these low rates happened mainly after the introduction of newer local anesthetics with low myocardial toxicity,.29,31,34,47 deaths caused by airway management failures seem to have decreased.11,20,35 morray et al.45 suggested that the predominance of cardiovascular events in anesthesia - related cardiac arrest and mortality may be related to the frequent use of pulse oximetry and capnography and monitoring hardware that may be more effective in preventing respiratory rather than cardiovascular events . in 24 cases reported by the danish
closed claims registry , four cases were related to airway management and two to ventilation management.38 a review of pediatric anesthesia malpractice claims showed that the frequency of respiratory events as primary causes of cardiac arrest has decreased from 51% in the 1970s to 41% in the 1980s and to 23% in 19902000.47 on the other hand , cardiovascular events joined respiratory causes as major risk sources in the 1990s.50 medication - related problems have been reported as predominant factors in cardiovascular events as primary causes of mortality .
findings of the pediatric perioperative cardiac arrest ( poca ) registry reveal that the rate of medication - related cardiac arrests decreased from 37% ( 19941997 ) to 18% ( 19982004 ) .
this decrease was attributed to the increased use of sevoflurane , which is a less severe myocardial depressant than halothane.51 in addition , drug error in anesthesia practice is still a matter of concern and can lead to major problems and deaths.29,37 in a study of 6,894 cases of the american society of anesthesiologists closed claims project covering the period between 1975 and 2000 , the proportion of claims for respiratory - related damaging events decreased , while the proportion of claims for cardiovascular - related damaging events increased so that by the period 19922000 , they occurred at the same frequency ( 28% ) .
this trend was associated with an increase in the use of pulse oximetry and end - tidal carbon dioxide monitoring . however ,
the increase in monitoring and the decrease in death or permanent damage rates seemed unrelated.52 improvements should focus on these two most important areas in order to reduce the number of perioperative deaths .
however , one study demonstrated that poor practical application rather than lack of knowledge leads to critical incidents.53 major improvements in terms of perioperative morbidity and mortality seem possible with the application of simple anesthesia management principles , such as the routine use of an equipment checklist with documentation of the equipment check , direct availability of an anesthesiologist to lend a hand or troubleshoot when needed , no change of anesthesiologist during anesthesia , the presence of two anesthesia team members in emergency rooms , monitoring neuromuscular blockade , and when necessary , using muscle relaxant and opiate reversal to reduce perioperative morbidity and mortality after surgery and anesthesia.53 a period of monitoring in a post - anesthesia care unit is now mandatory following all general , neuraxial , and regional anesthetics
. for high - risk patients , continued monitoring in an intensive care unit may reduce anesthetic mortality . inability to provide or failure to use these facilities may increase anesthesia - related mortality rates .
for example , we fail to consider anesthesia - related mortality reported prior to 1966 because of the temporal limitations of the medline database .
it is , therefore , difficult to verify that all relevant studies predating the medline database ( 1966 ) studies and even after this date have been considered . in conclusion
, our systematic review of the literature confirms that perioperative mortality rates are higher in brazil and other developing countries than in developed countries .
anesthesia - related mortality rates in brazil and in developed countries are similar and lower than 1 per 10,000 anesthetics .
major risk factors for mortality are apparent for newborns , children under 1 year of age , the elderly , males , patients of asa iii or poorer physical status , emergency surgeries , during general anesthesia , and in cardiac , vascular , thoracic , gastroenterologic , orthopedic , and pediatric surgeries .
medication - related cardiocirculatory events and airway management accounted for the majority of the cases of anesthesia - related mortality
Output:
| this systematic review of the brazilian and worldwide literature aims to evaluate the incidence and causes of perioperative and anesthesia - related mortality .
studies were identified by searching the medline and scielo databases , followed by a manual search for relevant articles .
our review includes studies published between 1954 and 2007 .
each publication was reviewed to identify author(s ) , study period , data source , perioperative mortality rates , and anesthesia - related mortality rates .
thirty - three trials were assessed .
brazilian and worldwide studies demonstrated a similar decline in anesthesia - related mortality rates , which amounted to fewer than 1 death per 10,000 anesthetics in the past two decades .
perioperative mortality rates also decreased during this period , with fewer than 20 deaths per 10,000 anesthetics in developed countries .
brazilian studies showed higher perioperative mortality rates , from 19 to 51 deaths per 10,000 anesthetics .
the majority of perioperative deaths occurred in neonates , children under one year , elderly patients , males , patients of asa iii physical status or poorer , emergency surgeries , during general anesthesia , and cardiac surgery followed by thoracic , vascular , gastroenterologic , pediatric and orthopedic surgeries .
the main causes of anesthesia - related mortality were problems with airway management and cardiocirculatory events related to anesthesia and drug administration .
our systematic review of the literature shows that perioperative mortality rates are higher in brazil than in developed countries , while anesthesia - related mortality rates are similar in brazil and in developed countries .
most cases of anesthesia - related mortality are associated with cardiocirculatory and airway events .
these data may be useful in developing strategies to prevent anesthesia - related deaths . |
PubmedSumm4856 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: a functioning vascular access is essential for effective delivery of hemodialysis and , understandably , lack of vascular access or complications developing in an existing vascular access are associated with significant patient morbidity .
thrombosis is one of the most common complications associated with autologous arteriovenous fistula ( avf ) for hemodialysis and often results in failure of avf .
here we report , to our knowledge for the first time in india , salvage of a thrombosed avf using early thrombolytic therapy ( tt ) alone , when interventional treatment option was not available .
a 48-year - old man with end stage renal disease ( esrd ) , on regular thrice - a - week hemodialysis for 4 years , noticed that his avf for dialysis vascular access had stopped working and reported to the hospital .
he was on regular treatment for hypertension for 17 years before he was detected as having deranged renal function and shrunken kidneys in 2009 .
he had no history of coronary artery disease , cerebrovascular accidents , peripheral vascular disease , or any other thrombotic events
the side to side radio - cephalic avf on the right side was created in 2010 , following primary failure of left radio - cephalic avf .
he received hemodialysis thrice a week for 4 h each ; the avf was cannulated by the step ladder technique with the proximal needle being placed more than 5 cm from the avf anastomosis site .
the avf supported a blood flow of 300 - 350 ml / min consistently over the past 3 years .
one year back , on a day when he was due for hemodialysis , he noticed the absence of thrill over the avf and he reported to the surgeon who created the avf , in another city .
the dialysis session got over by 10:00 pm and the fistula bands were removed by 1:00 am .
he did not notice any abnormality with the avf the next day morning , when he woke up from sleep . at about 4:00 pm in the evening
, he noticed that the avf appeared collapsed and on palpation found the thrill to be absent .
he denied any history of trauma or prolonged pressure over the avf , he had mild pain , and noticed a small swelling over the avf anastomosis site . on examination , there was no bruit over the avf .
after discussing the available and feasible treatment options with the patient , thrombolysis of the blocked avf was attempted .
written informed consent was taken after explaining the procedure and the possible benefits and risks involved .
an 18 g intravenous cannula was placed in the avf , with the tip of the cannula reaching the thrombus at the anastomotic site [ figure 1 ] .
flushing was done with 20 ml sterile normal saline to ensure that there was no counter - puncture and resultant extravasation of the thrombolytic agent .
tissue plasminogen activator ( tpa - injection actilyse , boehringer ingelheim india ) was reconstituted to a concentration of 0.5 mg / ml . a tourniquet was placed proximal to the iv cannula to prevent the injected tpa from reaching the systemic circulation .
a volume of 4 ml ( 2 mg ) of the reconstituted tpa was injected through the iv cannula into the avf segment , close to the thrombus .
manual manipulation of the anastomotic site where the thrombus was lodged was carried out , during and following injection of tpa , to soften the thrombus .
since the thrill remained feeble , another injection of 4 ml ( 2 mg ) tpa was administered , along with manual manipulation , 5 min after the first injection .
a prominent thrill reappeared promptly , and the avf venous segment demonstrated evidence of good blood flow .
the patient was advised limb exercise with a soft ball , and he was started on infusion of unfractionated heparin and tablet aspirin .
right forearm of the patient having the arteriovenous fistula ( avf ) with the thrombus ( solid arrow labeled a ) , 18 g iv cannnula placed in the avf with its tip close to the thrombus ( oblique arrow labeled
c ) and a tourniquet applied proximally using a fistula band ( transparent arrow labeled b ) an angiogram of the right upper limb ( radial artery and the avf ) was performed the next day morning by the cardiologist and showed excellent flow across the avf anastomotic site with no evidence of stenosis at the anastomotic site or in the venous system , with small thrombus at avf [ figure 2 ] .
he underwent hemodialysis the same day afternoon , with the avf supporting blood flow > 300 ml / min .
he was treated with anticoagulation with heparin for 5 days and discharged with advice to continue aspirin and clopidogrel .
fistulogram after thrombolytic therapy with tissue plasminogen activator showing the radial artery ( thick arrow labeled a , the arterialized cephalic vein ( arrow labeled b ) and a small mobile thrombus near the anastomotic site of the arteriovenous fistula ( oblique arrow labeled c )
vascular access is the achilles heel of hemodialysis and absence or loss of vascular access is often associated with significant morbidity and mortality . even though the thrombosis rate of autologous avf is one - sixth that of av graft
thrombosis is usually the consequence of some sort of anatomic abnormality , like stenosis , in the proximal venous segment ; problems with the arterial segment account for only about 17% of avf thrombosis , but systemic abnormalities in hemostasis like protein c and s deficiency , factor v leiden , antiphospholipid antibodies , etc . , may also contribute .
the results of treatment of thrombosed avf have significantly improved in recent times , with long - term patency reports at 63 - 89% at 3 months , 52 - 74% at 6 months , and 27 - 47% at 1 year .
delay in instituting treatment may result in extension of the thrombus , making subsequent intervention or surgical procedures more difficult and less successful .
delay in treating the thrombus also allows a longer period of contact between the thrombus and the vessel wall , making subsequent extraction of thrombus more traumatic to the vessel wall , which in turn could predispose to thrombotic events in the future .
most importantly , early resolution of the thrombosis may allow uninterrupted use of the same avf for dialysis , avoiding intercurrent use of a venous catheter and attendant morbidity , like in our case .
treatment options available for thrombosed avf are : ( 1 ) percutaneous intervention with thrombectomy and angioplasty of any stenosis detected ; ( 2 ) surgical thrombectomy ; ( 3 ) declotting by mechanical techniques ( dilatation and aspiration ) ; ( 4 ) tt ; and ( 5 ) combined mechanical declotting and tt . in the absence of robust comparative trials , clinical practice is usually dictated by local expertise and available facilities .
percutaneous intervention is the most preferred option and is usually performed by an interventional radiologist or an interventional nephrologist .
percutaneous interventions as well as surgical thrombectomy were not immediately possible in our patient due to logistic issues .
we referred the patient to an intervention center in another city , but the patient refused .
hence it was decided to try tt in his case , in a desperate attempt to salvage the access .
only tpa is fda approved for treatment of thrombosis in hemodialysis catheters ( not avf ) in the us and almost all recent reports of tt in clotted avf also employed tpa .
we could not find reports of thrombolysis of avf using sk after 1995 and the immediate patency rate reported in previous studies was about 50% .
the available literature on the use of tpa reported a short - term patency of 90% or even more .
based on this , we felt that tpa probably offered better chances of success and decided to employ it in our case .
it may be prudent to point out that the success in our case may not be generalizable to all cases of clotted avf .
our patient promptly recognized the absent thrill and reported to hospital within a couple of hours , he had an isolated thrombus at the anastomotic site with the rest of the avf bearing no thrombi , and we could institute tt within about 4 h of detection of catheter malfunction - all of which likely contributed significantly to the success of the treatment .
Output:
| a functioning vascular access is crucial to the wellbeing of patients on hemodialysis .
thrombosis is the most common complication of arteriovenous fistula ( avf ) resulting in late fistula failure ; its treatment is difficult , and results are often suboptimal .
interventional treatment of avf thrombosis may not be available all the time , and timely application of an available noninterventional treatment may salvage the fistula .
we report the successful treatment of avf thrombosis using local thrombolytic therapy using tissue plasminogen activator in a patient , for the first time in india . |
PubmedSumm4857 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: host - seeking mosquitoes were collected in and around grand forks , north dakota , by using mosquito magnet traps ( american biophysics corp . , north kingston , ri , usa ) for 4 transmission seasons , from early summer 2002 through fall 2005 .
mosquitoes were sorted by species and tested for wnv by using reverse transcriptase pcr assays .
passerine birds in and around grand forks were surveyed for antibodies to wnv for 3 transmission seasons : june 24october 27 , 2003 , april 4july 7 , 2004 , and may 17august 11 , 2005 . in 2003 and early 2004 ,
birds were captured by using mist nets , blood ( < 0.1 ml ) was obtained by brachial venipuncture , and birds were released . later in 2004 and in 2005 , necropsies were performed on dead birds .
samples were tested for anti - wnv antibodies by using a qualitative epitope - blocking elisa ( 3 ) .
this is the first report of seroprevalence of wnv in passerines in the northern prairies .
a total of 277 birds ( 11 species ) were tested ( table 1 ) . in 2003 , seroprevalence was relatively low ( 17% ) .
the first seropositive bird was captured july 24 , 2003 , 4 days after the first wnv - positive pool of cx .
most seropositive birds ( 11 of 14 ) were collected in september , when migratory species were leaving and vector populations were waning .
thus , a lag occurred between peak abundance of infected vectors in mid- to late august 2003 ( 2 ) and seroconversion of passerines .
seroprevalence rates were significantly higher in 2004 and 2005 than in 2003 ( table 1 , fisher exact tests , p<0.0001 ) and were higher than most seroprevalences reported for passerines in the eastern and southeastern regions of the united states ( 46 ) .
all passerine species sampled in 2004 and 2005 contained seropositive birds , which indicated that all these species were preyed on by vectors regardless of differences in their nesting habitats ( e.g. , cattail marshes , peridomestic ) .
american robins , common grackles , and red - winged blackbirds showed increased seroprevalence from 2003 to 2004 .
high seroprevalence was maintained in passerines in 2005 despite low wnv activity ( i.e. , low natural boosting ) during 2004 ( 2 ) , which suggests that passerine immunity to wnv may last longer than a single season ( 7,8 ) .
previous laboratory and field studies have indicated that most american crows die so quickly from wnv infection that they never have time to seroconvert ( 911 ) . why crows in the red river valley survive wnv infection is not known .
one possibility is that wnv has undergone genetic changes with a concurrent loss in virulence as it spread westward from forest ecosystems with cx .
annual data on seroprevalence in passerines , environmental temperatures , reporting of human cases , and minimum infection rates ( mir ) in vector populations are summarized in table 2 .
time between first and last appearances of host - seeking culex tarsalis mosquitoes in mosquito magnet traps .
data from north dakota department of public health ( 15 ) . # no . of wnv - infected cx .
environmental conditions from 2002 to 2005 produced a natural field experiment , which demonstrated the differing magnitudes by which environmental temperature and host immunity affected local wnv activity . despite warm temperatures and high vector abundance , wnv activity was low during its introductory year ( 2002 ) , as indicated by low numbers of human cases , undetectably low seasonal mir , and by low seroprevalence in passerines in 2003 .
because wnv had only recently arrived , presumably there was neither sufficient time nor number of infection nidi to promote extensive amplification cycles . however , 2003 was an epidemic year for wnv , as indicated by the increased number of human cases statewide and the high mir in the local vector population .
the relatively low level of immunity in passerines at the time also likely contributed to the epidemic . in 2004 , unusually cool environmental temperatures prolonged vector larval development , adult emergence , and the arboviral extrinsic incubation period . as a result ,
duration of the 2004 transmission season was nearly half that of the preceding seasons ( table 2 ) .
thus , wnv activity during 2004 was low ( i.e. , reduced vector abundance , number of human cases , and seasonal mir ) , and the virus had insufficient time to undergo extensive amplification cycles , similar to the situation that occurred during the introductory year of 2002 .
however , the epidemic conditions of 2003 had produced a high level of herd immunity in the local bird population in 2004 .
( note : most migratory passerine species live for several years and return each year to the same general locale to breed . ) in 2005 , environmental temperature , length of transmission season , and vector abundance were all nearly identical to those of the epidemic year of 2003 . yet
the high prevalence of immunity during 2005 may have contributed to preventing another epidemic , but it did not totally eliminate wnv activity .
levels of wnv activity during 2005 ( as measured by human cases and mosquito mir ) were intermediate between those of the epidemic year ( 2003 ) and both the introductory year ( 2002 ) and the coldest year ( 2004 ) .
thus , environmental temperature dictated the ultimate success ( or more precisely , the failure ) of wnv amplification within the central red river valley during 2004 , whereas even high levels of herd immunity among the reservoir population exerted only a moderating effect on wnv activity during 2005 . whether the level of wnv activity observed during 2005 will be representative of the arbovirus 's natural equilibrium within the central red river valley remains to be seen .
is wnv reintroduced every spring through infected migratory birds or wind - blown mosquitoes from the south ? or does wnv survive the harsh winters inside mosquitoes undergoing diapause , only to reemerge in the spring ? either or both of these scenarios could be correct , but one conclusion is certain : the incidence of wnv disease in horses from north dakota during june of 2002 and again in may of 2005 ( 15 ) indicates that wnv becomes active in the northern great plains well in advance of the first summer brood of its primary vector , cx .
Output:
| west nile virus ( wnv ) epizootiology was monitored from 2002 through 2005 in the area surrounding grand forks , north dakota .
mosquitoes were tested for infection , and birds were surveyed for antibodies . in 2003 , wnv was epidemic ; in 2004 , cool temperatures precluded wnv amplification ; and in 2005 , immunity in passerines decreased , but did not preclude , wnv amplification . |
PubmedSumm4858 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input:
Output:
| after intravenous administration of bacterial lipopolysaccharide ( lps ) to rats , polymorphonuclear neutrophils ( pmns ) rapidly accumulate in the liver , and midzonal hepatic necrosis is prominent by 6 hr .
pmns are required for the development of hepatic injury in rats .
certain polychlorinated biphenyls ( pcbs ) can activate pmns , resulting in production of superoxide anion ( o2- . ) and release of cytolytic factors from granules .
this raises the possibility that pcb exposure might enhance pmn - mediated tissue injury , such as lps - induced hepatotoxicity .
we treated female sprague - dawley rats with a minimally toxic dose of lps in saline ( 2 mg / kg , intravenous ) and 90 min later exposed them to aroclor 1248 ( 50 mg / kg , intraperitoneal ) , a mixture of pcbs . the animals were killed 6 hr after lps administration , and hepatic injury was assessed .
neither lps nor aroclor 1248 alone produced liver injury .
co - treatment with lps and aroclor 1248 resulted in pronounced liver injury as demonstrated from increased activities of alanine aminotransferase and isocitrate dehydrogenase in plasma .
histological evaluation indicated increased severity of hepatic necrosis in rats receiving both lps and aroclor 1248 .
hepatic accumulation of pmns , normally observed after lps , was not altered by co - exposure to pcbs .
aroclor 1248 stimulated rat pmns in vitro to produce o2- . and to degranulate .
in addition , pmn - mediated cytotoxicity to isolated rat hepatocytes in culture was increased upon addition of aroclor 1248 .
pcbs activate pmns in vitro and increase pmn - dependent hepatocellular damage in vitro and after lps treatment in vivo .
pcbs may act in vivo as an additional inflammatory stimulus to activate pmns to become cytotoxic , resulting in increased tissue injury.imagesfigure 1.figure 2 .
afigure 2 .
bfigure 3.figure 4 .
afigure 4 .
bfigure 5.figure 6 . |
PubmedSumm4859 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: keishibukuryogan ( kbg , gui - zhi - fu - ling - wan in chinese ) is one of the kampo medicines , and has been widely administered to patients with blood stagnation for improving blood circulation .
it was reported that kbg improves conjunctional microcirculation in patients with cerebrospinal vascular diseases , thus suggesting that it may have beneficial effects on hematological parameters such as blood viscosity and red blood cell deformability [ 24 ] .
moreover , matsumoto et al . have explored a proteomic approach for the diagnosis of blood stasis in rheumatoid arthritis patients treated with kbg .
in addition , kbg is used to treat symptoms of peripheral ischemia such as cold extremities .
furthermore , we recently reported that kbg is effective in patients with chronic pigmented purpura , a group of skin vascular disorders of unknown etiology .
kbg is composed of five medicinal plants , cinnamomum cassia blume ( cinnamomi cortex ) , paeonia lactiflora pallas ( paeoniae radix ) , paeonia suffruticosa andrews ( moutan cortex ) , prunus persica batsch ( persicae semen ) and poria cocos wolf ( hoelen ) ( table 1 ) .
paeoniae radix and moutan cortex have many known active components in common , including paeoniflorin , paeonol , oxypaeoniflorin , benzoylpaeoniflorin , and palbinone .
paeoniflorin is a characteristic main principal bioactive component of paeoniae radix , which included approximately 5.57% ( w / w ) paeoniflorin , and moutan cortex , which included approximately 3.96% ( w / w ) paeoniflorin .
paeoniflorin has been reported to have many pharmacological effects , such as anti - inflammatory and antiallergic effects .
recently , zheng and wei reported that the total glucosides present in the moutan cortex , which contain paeoniflorin as the principle bioactive component , inhibited primary and secondary inflammation in both collagen - induced arthritis and adjuvant - induced arthritis .
up until now , topical and oral corticosteroids , oral bioflavonoids , ascorbic acid , griseofulvin , and cyclosporine have been suggested as treatments for chronic pigmented purpura [ 13 , 14 ] . however , none of these treatments have proven to be satisfactory .
human dermal microvessel endothelial cells ( hdmecs ) are the prominent cells in dermal skin .
hdmecs produce inflammatory cytokines , such as interleukin ( il)-6 and il-8 when they are exposed to lipopolysaccharide ( lps ) .
we therefore consider that examinations of the effects of kbg and paeoniflorin on hdmecs are important for the therapeutic studies of chronic pigmented purpura in vitro . in this study
, we aimed to evaluate the role of kbg and paeoniflorin , ininhibiting the production of inflammatory cytokines using hdmecs .
kbg ( tj-25 ) was obtained from tsumura & co. ( tokyo , japan ) .
kbg was suspended in cs - c complete medium containing 10% fetal calf serum and 1% penicillin and csc growth factor ( cell systems inc , wa ) and was rotated at 4c overnight .
then , the suspension was centrifuged , and the supernatant was filtered through a 0.45 m - pore membrane .
the following materials were obtained from commercial sources : the isogen rna extraction kit was obtained from nippon gene ( tokyo , japan ) ; m - mlv reverse transcriptase was from gibco ( grand island , ny ) ; taq dna polymerase was from perkin - elmer ( norwalk , co ) ; lps was purchased from sigma ( st . louis ) ; nylon membranes were from schleicher & schuell ( keene , nh ) ; the anticyclooxygenase-2 ( cox-2 ) polyclonal antibody ( pab ) was purchased from cell signaling technology , inc .
( boston ) ; antiinducible nos ( inos ) pab was purchased from enzo life sciences international inc .
; mif , il-6 , and il-8 elisa kits were obtained from r&d systems ( minneapolis ) ; and the western blot detection system was obtained from cell signaling technology ( beverly , ma ) .
primary human dermal endothelial cells ( hdmecs ) were obtained from cell systems inc ( wa ) .
hdmecs were cultivated in conditioned endothelial culture medium ( cs - c complete medium ) containing 10% fetal calf serum and 1% penicillin and csc growth factor at 37c in a 5% co2 atmosphere .
cell viability before treatment was always over 95% as evaluated by trypan blue dye exclusion test . on the day of the experiment ,
cells were collected and suspended in fresh culture medium at a concentration of 1 10 cells / ml . the cells were divided into 4 groups : a control group , a group receiving 10 mg / ml of kbg or 100 g / ml of paeoniflorin as previously described [ 9 , 15 ] , a group treated with 1 g / ml of lps , and another group treated with the combination .
the cells were treated with the various agents , and analyses were performed as described for each procedure .
the number of cells was measured by an mtt assay . in brief , the media were removed by aspiration , and then the cells were treated with 0.5 mg / ml dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide ( mtt , sigma ) in culture medium for 4 hours at 37c . after being washed with pbs once , isopropanol/0.04 m hcl was added , and od570 was measured , and the value of blank was subtracted .
rna reverse transcription was performed with m - mlv reverse transcriptase using random hexamer primers , and subsequent amplification was done using taq dna polymerase .
pcr was carried out for 30 cycles with denaturation at 94c for 30 seconds , annealing from 52 to 64c for 1 minute and extension at 72c for 30 seconds using a thermal cycler ( pe applied biosystems gene amp pcr system 9700 ) .
the human mif primers used were 5-atgccgatgttcatcgtaaac-3 ( forward ) and 5-ggcgaaggtggagttgttcca-3 ( reverse ) .
supernatants were collected after 24 h of incubation with lps ( 1 g / ml ) and/or kbg ( 10 mg / ml ) and paeoniflorin ( 100 g / ml ) .
mif , il-6 , and il-8 were assayed by elisa , according to the manufacturer 's instructions .
the cells were lysed at a density of 110 cells/50 l of ripa buffer ( 1 m tris - hca , 5 m nacl , 1% nonidet p-40 ( v / v ) , 1% sodium deoxycholate , 0.05% sds , 1 mm phenylmethyl sulfonyl fluoride ) for 20 minutes . after brief sonication
, the lysates were centrifuged at 12,000 rpm for 10 minutes at 4c , and the protein content in the supernatants was measured using a bio - rad protein assay kit ( bio - rad , hercles , ca ) .
the protein lysates were denatured at 96c for 5 min after mixing with 5 l of sodium dodecylsulfate ( sds ) loading buffer , applied on an sds polyacrylamide gel for electrophoresis , and transferred to nitrocellulose membranes .
western blot analysis was carried out to detect the expression levels of cox-2 and inos using specific antibodies .
band signals were visualized on x - ray film using chemiluminescence ecl detection reagents ( amersham biosciences , buckinghamshire , uk ) .
the relative amounts of proteins associated with specific antibodies were normalized according to the intensities of -actin .
the values are expressed as the means sd of the respective test or control group .
statistically significant differences in the stimulation with lps in the groups treated with kbg or paeoniflorin were evaluated by the nonparametric mann - whitney u test .
lps plays a fundamental role in the pathogenesis of a number of inflammatory diseases by inducing a distinctive pattern of inflammatory cytokine release .
the cells were incubated with or without 1 g / ml of lps or 10 mg / ml of kbg for 6 or 24 h , and the cell viability was assessed .
none of the treatments elicited cytoxicity in the cells at the tested concentrations and incubation times ( figure 1(a ) ) .
we examined the anti - inflammatory effects of kbg on the induction of inflammatory cytokines by lps stimulation .
lps - induced protein levels of mif , il-6 , il-8 , and tnf- were significantly inhibited by kbg ( figure 1(b ) ) .
treatment of the cells with 1 g / ml of lps increased in mrna levels of these cytokines from 6 h after stimulation , but these mrna levels were decreased by kbg ( figure 1(c ) ) .
the cells were incubated with or without 1 g / ml of lps or 100 g / ml of paeoniflorin for 6 or 24 h , and the cell viability was assessed .
figure 2(a ) reveals that the incubation with paeoniflorin did not elicit toxicity in cells at the tested concentration at either incubation time .
lps - induced protein levels of mif , il-6 , il-8 , and tnf- were significantly inhibited by paeoniflorin , and the inhibitory effect was stronger than that of kbg ( figure 2(b ) ) . moreover , to examine the effects of paeoniflorin on the mrna levels of inflammatory cytokines , cells were treated with lps for 6 h in the presence of 100 g / ml of paeoniflorin .
the lps - induced mif , il-6 , il-8 , and tnf- mrna levels were decreased by paeoniflorin ( figure 2(c ) ) .
western blot analyses revealed that the expression of cox-2 and inos was increased by lps stimulation in hdmecs whereas the treatment with paeoniflorin resulted in a decrease in cox-2 and inos expression ( figure 3 ) .
among traditional japanese medicinal compounds , kampo formulas originated from ancient chinese medicine , and are currently recognized and reimbursed by the health ministry in japan for the treatment of a wide variety of conditions .
the kampo formula kbg is frequently used in traditional japanese and chinese medicine to treat several symptoms , including skin diseases .
the preparation has demonstrated anti - inflammatory and free - radical scavenging effects . in the present study , we have demonstrated that kbg treatment significantly suppressed the protein and mrna levels of mif , il-6 , il-8 , and tnf- in lps - stimulated cultured hdmecs .
chronic pigmented purpura is a disease complex characterized by capillaritis and lymphocytic capillary damage in the papillary dermis .
several lines of evidence suggest the involvement of humoral or cellular immunity , as well as hemostasis , in the pathogenesis of this disease .
indeed , our previous data support the effectiveness of kbg , which led to a significant improvement in patients with chronic pigmented purpura .
it is reported that kbg can prevent the progression of atherosclerosis , and preserve vascular endothelial function in cholesterol - fed rabbits and in hypertensive rats .
furthermore , in diabetic rats , it was demonstrated to have protective effects against vascular injury , and to delay the development of diabetic kidney disease [ 22 , 23 ] .
moreover , kbg has a favorable effect on impaired glucose metabolism in type 2 diabetes by improving glucose intolerance , and it has been suggested that some of this effect is derived from the reduction of tnf- content in skeletal muscle .
accordingly , kbg may exert beneficial effects that result in the inhibition of inflammatory cytokines in hdmecs .
it was recently reported that mif induces the endothelial expression of il-8 , thus resulting in leukocyte recruitment .
since mif is an initiator of other proinflammatory cytokines such as il-6 , il-8 , and tnf- , and regulates the induction of these cytokines [ 26 , 27 ] , we hypothesized that kbg may inhibit mif - regulated inflammatory mediators .
we also demonstrated that paeoniflorin , a bioactive compound contained in kbg , suppressed the mrna levels of these inflammatory cytokines in lps - stimulated cultured hdmecs , similar to the effects of kbg .
it is known that paeoniflorin has anti - inflammatory and antiallergic activities [ 28 , 29 ] .
in addition , paeoniflorin has reportedly exhibited immunoregulatory effects [ 30 , 31 ] , analgesic effects , neuromuscular blocking [ 33 , 34 ] , cognition enhancement , and steroid protein binding inhibition .
many studies have demonstrated that overproduction of nitric oxide and inflammatory prostaglandins such as pge2 , mainly via inos and cox-2 , respectively , plays an important pathophysiological role in the development of inflammation .
kim and ha reported that paeoniflorin treatment significantly attenuated lps - induced no and pge2 production .
moreover , the extract of kbg has been shown to have cox-2 and inducible inos inhibitory activities . in this context
, we suggest that kbg and paeoniflorin induce their anti - inflammatory effects by inhibiting both proinflammatory cytokines and inhibiting the cascade of the overproduction of cox-2 and inos in hdmecs .
taken altogether , these findings suggest that kbg may be useful to improve microvascular inflammation in patients with skin diseases such as chronic pigmented purpura .
Output:
| keishibukuryogan ( kbg ) is one of the traditional herbal formulations widely administered to patients with blood stagnation for improving blood circulation ; currently , it is the most frequently prescribed medicine in japan .
kbg has been reported to improve conjunctional microcirculation .
the aim of this study was to evaluate the role of kbg and paeoniflorin , a bioactive compound of kbg , in inhibiting the production of inflammatory cytokines using human dermal microvessel endothelial cells ( hdmecs ) .
the authors observed that lipopolysaccharide ( lps ; 1 g / ml ) stimulated the secretion of proinflammatory cytokines in hdmecs .
kbg treatment ( 10 mg / ml ) significantly suppressed the mrna levels of migration inhibitory factor ( mif ) , interleukin ( il)-6 , il-8 , and tumor necrosis factor ( tnf)- in lps - stimulated cultured hdmecs . similarly , paeoniflorin significantly suppressed the mrna levels of these cytokines in lps - stimulated cultured hdmecs .
elisa showed that kbg and paeoniflorin suppressed the production of mif , il-6 , il-8 , and tnf- in lps - stimulated hdmecs .
moreover , kbg and paeoniflorin decreased the expression of cyclooxygenase-2 and inducible nitric oxide synthase ( inos ) in these cells .
these results suggest that kbg may be useful for improving microvascular inflammation in patients with skin diseases . |
PubmedSumm4860 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: spondylocostal dysostosis ( scdo ) is a rare , heritable axial skeleton growth disorder characterized by malformed vertebral column and ribs , abridged thorax , and kyphoscoliosis .
we present here an infant with scdo with neural tube defect who underwent lipomyelomeningocele excision and detethering of the cord .
an 8-month - old male child was admitted with a history of soft , nonprogressive swelling in the lower back since birth .
this child was a product of nonconsanguinous marriage , born full term by cesarean section .
the fetus was diagnosed to have neural tube defect on antenatal scan , but the pregnancy was deemed precious and hence continued .
the first female child was 3 years old and did not have any congenital abnormality .
both the father and mother did not have any other comorbid conditions . on examination ,
examination of the thorax revealed a shortened thorax with deficient rib cage on the left side .
second , a soft , mid - line swelling was present in the lumbosacral region , which was non - compressible and nontransilluminant with no overlying skin defect or leak .
physical examination did not reveal any associated stigmata such as short neck , abnormal facial feature , thoracic asymmetry , polythelia , inguinal swelling , undescended testis or anal atresia .
chest x - ray displayed absent left sixth to eighth ribs and fan like configuration of ribs , seventh and ninth butterfly shaped thoracic vertebrae and mild scoliosis of the thoracolumbar spine [ figure 1 ] .
magnetic resonance imaging revealed lumbosacral lipomyelomeningocele with low lying cord at l4l5 level with tethered cord [ figure 2 ] .
he underwent excision and repair of lipomyelomeningocele and detethering of cord under general anesthesia in the prone position with appropriate padding to avoid direct pressure on the heart .
both the intraoperative and postoperative period was uneventful without any further deterioration in neurological function .
chest x - ray : absent left 6 to 8 ribs with its fan like configuration , 7 and 9 butterfly shaped thoracic vertebrae and mild scoliosis of thoracolumbar spine magnetic resonance imaging spine : ( a ) t1-weighted sagittal image and ( b ) t2-weighted sagittal image displaying lumbosacral lipomyelomeningocele with low lying cord at l4l5 level with tethered cord and deformed 7 and 9 thoracic vertebrae ( c ) t2-weighted axial image at l4l5 spinal level showing lipomyelomeningocele communicating through vertebral defect ( d ) short inversion time inversion recovery coronal image demonstrating deficient and malformed rib cage on left side
spondylocostal dysostosis is a rare anomaly caused due to defective embryological development of the axial skeleton during early stages of gestation . in 1938 , saul jarcho and paul levin at john hopkins university had first described a pattern of vertebral and costal anomalies distinctly different from the well - known klippel feil syndrome . since then jarcho levin syndrome ( jls )
eponym has been used for varied malady like hereditary multiple hemivertebrae , spondylocostal dysplasia , spondylothoracic dysplasia , costovertebral anomalies and costovertebral dysplasia .
eponym was used by many authors for scdo before the introduction of genetic based classification .
scdo1 and scdo4 have been found to be associated with neural tube defects like spina bifida , meningocele , meningomyelocoele , lipomyelomeningocele , and diastematomyelia .
scdo1 is caused by an abnormality in the dll3 gene located on chromosome 19 at 19q13 .
scdo4 is caused by an abnormality in the hes7 gene located on chromosome 17 at 17p13 . according to dias and walker ,
split cord malformations and related malformations occur as a result of embryological failure of the mid - line axial integration during gastrulation .
the common association of segmental costovertebral malformations with neural tube defects could be related to an early gastrulation genomic defect or one after gastrulation when there are two independent somatic columns .
lipomyelomeningocele results due to premature disjunction during primary neurulation . due to ingression of adjacent mesenchymal cells ( sclerotome ) into the central canal of developing neural tube ,
this would form an abnormally widened spinal canal with numerous associated vertebral segmentation anomalies , including sagittal cleft ( butterfly ) vertebrae or hemi vertebrae . and thus due to deficient sclerotome for embryogenesis ,
the patients with scdo are prone to respiratory insufficiency and repeated respiratory infections ( pneumonia ) because the vertebrae are fused and the ribs fail to develop properly and the chest cavity is too small to accommodate the growing lungs . other abnormalities associated with
this syndrome includes chiari malformation , renal / urinary tract abnormalities , hydrocephalus , hydroureteronephrosis . till date
, about 17 cases of scdo with neural tube defects have been described in the literature as reckoned in the table [ table 1 ] . amid these only three cases of scdo reported had lipomyelomeningocele , which encompasses one by duru et al . and two cases by nadkarni et al .
he presented with rib defect on the left side making the heart vulnerable to any direct injury .
in such patients , care has to be taken during surgery in the prone position to avoid direct pressure on the heart and also parents need to be counseled about the same .
sometimes these patients because of the shortened thorax and its asymmetry , weaning may be difficult , and this may result in respiratory complications and increase in ventilator days .
these patients should be thoroughly investigated for other associated anomalies before taking up for surgery . as these patients may be associated with renal abnormalities ,
perioperative hemodynamics and urine output monitoring are mandatory to prevent any insult to the kidneys .
it is important to thoroughly investigate the neural tube defect patient and to rule out the associated abnormalities .
management of such patients should aim at aggressive neonatal care and prevention of respiratory infections .
also , precautions must be taken to prevent direct trauma to heart or lungs in view of deficient rib cage .
additional genetic and embryological studies are necessary to provide evidence of an etiological link between scdo and neural tube defect .
Output:
| spondylocostal dysostosis ( scdo ) is rare anomaly caused due to flawed embryological development of the axial skeleton during preliminary stages of gravidity , characterized by malformed vertebral column and ribs , abridged thorax and kyphoscoliosis .
this entity was also reported as a jarcho levin syndrome
eponym by erstwhile authors , before the introduction of genetic based classification .
a literature review showed only three cases of this clinical entity with lipomyelomeningocele .
we report the fourth case report of an infant with scdo with lipomyelomeningocele .
his chest x - ray displayed absent left side 6th8th ribs with peculiar fan like configuration , making the heart vulnerable to any direct injury .
special care has to be taken for such patients who need surgical procedure in the prone position . |
PubmedSumm4861 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: since the introduction of two cognitive - behavioral models of social anxiety in the 1990s ( clark and wells 1995 ; rapee and heimberg 1997 ) , a proliferation of studies have focused on the cognitive aspects of social anxiety as described in these models ( schultz and heimberg 2008 ) .
the cognitive - behavioral models describe what happens to an individual during , or in anticipation of , a socially threatening situation , in terms of cognitive , behavioral and physical processes ( clark and wells 1995 ; rapee and heimberg 1997 ) .
clark and wells ( 1995 ) primarily focus on socially anxious individuals beliefs about the danger inherent in social situations and the processes that prevent them from changing their beliefs and ultimately , reducing their social anxiety .
the core feature of rapee and heimberg s ( 1997 ) model is the mental representation formed by the individual of his / her external appearance and behavior as seen by the audience .
this mental representation is compared with the individual s perception of the audience s standard for evaluation . the extent to which the mental representation of performance
does not meet the audience s perceived standards determines the likelihood of negative evaluation and experience of anxiety .
of key importance in the context of the studies reviewed in this article is the way in which the cognitive models describe how socially anxious persons tend to engage in distorted processing of information related to a social - evaluative situation . because socially anxious individuals are greatly concerned about the possibility of negative evaluation from others ( clark and wells 1995 ) and assume that other people are inherently critical ( rapee and heimberg 1997 ) , they take a negative view of social situations and the accompanying behavioral , cognitive and somatic responses within themselves .
the assumption that socially anxious persons negative view is a distortion of reality underpins the treatment approach of cognitive behavioral therapy ( cbt ) as one of the main principles of cbt is to try to alter the individual s negative perceptions of social situations . in the present review , the tendency toward a negative perspective of social situations is investigated in two domains .
these domains are ( a ) interpretation of ambiguous social situations and ( b ) self - evaluation of social skills and nervous behaviors ( see fig . 1 ) .
this review also aims to ascertain the extent to which socially anxious persons negative perspective is justified ; this is addressed in the cognitive models but is not discussed extensively ( clark and wells 1995 ; rapee and heimberg 1997 ) .
do socially anxious individuals have good reason for their negative perceptions , that is , is there a kernel of truth in their negative social cognitions ? or , are their perceptions a distortion of reality and their thoughts negatively biased ?
this review focuses mainly on studies that investigated youth samples because a key feature of social anxiety , fear of negative evaluation , increases in the adolescent period ( e.g. , weems and costa 2005 ; westenberg et al .
2004 ) and the clinical manifestation of social anxiety , social phobia , typically has its onset in early to mid adolescence ( rapee and spence 2004 ) . we organize the review around studies recently conducted in our laboratory and also draw from a sample of studies in the extant literature.fig .
1socially anxious individuals perceptions and negative bias in social situations in relation to the evaluation of their behavior by others .
representation of the main variables ( rectangular boxes ) and measures ( ovals ) discussed in the paper socially anxious individuals perceptions and negative bias in social situations in relation to the evaluation of their behavior by others .
representation of the main variables ( rectangular boxes ) and measures ( ovals ) discussed in the paper in sum , the current review aims to address the following research questions in socially anxious youth : is there evidence for negative perceptions in relation to interpretation of ambiguous social situations and self - evaluation of social performance?are the negative perceptions actually justified by sources of information other than socially anxious youth themselves , such as independent observers and fellow age peers ? or are the negative perceptions of socially anxious youth really unwarranted as based on these other sources of information ?
is there evidence for negative perceptions in relation to interpretation of ambiguous social situations and self - evaluation of social performance ?
are the negative perceptions actually justified by sources of information other than socially anxious youth themselves , such as independent observers and fellow age peers ? or are the negative perceptions of socially anxious youth really unwarranted as based on these other sources of information ? in this review we will first present studies that investigated negative social cognitions in the two domains previously described with a particular focus on studies that employed youth samples . following this
finally , we will close the article with clinical and theoretical implications of the reviewed studies and suggestions for future research .
the two leading cognitive models assume that socially anxious persons interpret social situations in a threatening way and that their interpretations are more negative than non - socially anxious persons interpretations ( clark and wells 1995 ; rapee and heimberg 1997 ) .
for example , imagine a person has just given a speech in front of a large audience and at the end of the speech nobody in the audience asks a question .
for a person without strong socially anxious feelings the lack of questions is likely to be interpreted in a positive or neutral manner .
for example , that the speech was very clear , or due to the speech taking place at the end of the day all audience members were too tired to ask a question .
however , for a socially anxious person it is likely that the lack of questions would be interpreted as meaning that something was wrong with their speech ; it was unclear , or difficult to follow . this tendency to place a negative meaning on an ambiguous social cue
highly anxious children and adolescents interpret ambiguous situations as more threatening ( negative ) than non anxious peers ( e.g. , barrett et al .
1996 ; bgels and zigterman 2000 ; bgels et al . 2003 ; creswell et al . 2005 ; chorpita et al .
2000 , 2003 ) . however , the studies that specifically addressed interpretation bias in socially anxious youth are scarce ( see also muris 2010 ) . in one study , bgels et al .
( 2003 ) compared children s ( aged 712 years ) interpretations of different situations , reflecting social , separation and generalized anxiety , and using a generalized anxious , social phobic and separation anxious group .
children in the social phobia group made significantly more negative interpretations of social situations and significantly fewer negative interpretations of separation stories compared to the separation anxiety group .
thus , the socially phobic group s interpretations were partly specific to social situations and partly more general in nature .
vassilopoulos and banerjee ( 2008 ) evaluated cognitive biases in a sample of 1113 year old children who were presented with descriptions of positive and mildly negative social situations .
these authors found a significant positive relationship between social anxiety level and the tendency to interpret negative social events in a catastrophic fashion .
this relationship held after controlling for children s level of self - reported depression as measured by the short form of the children s depression inventory ( cdi ; kovacs 1992 ) .
social anxiety was not related to interpretations of positive social situations . in a training study ,
2009 ) presented 1011 year old high socially anxious children with descriptions of social situations together with a negative and a benign interpretation of that situation .
after the children had indicated which interpretation was describing how they would think in that situation , they were given feedback on what was the correct
it was found that the training not only reduced the negative interpretations of the children in the experimental group , but also reduced their social anxiety . in a study by miers et al .
( 2008 ) the presence of an interpretation bias was tested in a non - clinical adolescent sample and a number of issues central to the study of this bias using self - report methods were investigated .
these issues were derived from the main findings in the adult literature and concern the following : ( a ) whether the interpretation bias reflects a real propensity to favor negative explanations for ambiguous social situations over positive ones , or , whether it reflects a lack of positive explanations ( amir et al .
; stopa and clark 2000 ) . that is , are positive explanations absent or are they given less importance than negative interpretations in the minds of socially anxious adolescents ?
( b ) whether a socially anxious person s belief in a particular interpretation is as important as the likelihood of the interpretation coming to mind ( clark et al .
some research has shown that negative interpretations of social situations are also characteristic of individuals with depression ( e.g. , franklin et al . 2005 ) .
is interpretation bias particular to social anxiety or is it a feature of an underlying negative affect common to anxiety and depression ? and ( d ) the content - specificity of interpretation bias ; do socially anxious individuals show an interpretation bias only in social situations or is it also present in non - social situations ? miers et al .
( 2008 ) developed the adolescents interpretation and belief questionnaire ( aibq ) to measure interpretation bias .
the aibq required participants to indicate how likely it is that a particular interpretation for an ambiguous social or non - social situation would pop up in their mind .
the aibq was modeled on two self - report instruments used in the adult literature ( stopa and clark 2000 ; voncken et al .
three different interpretations of each ambiguous situation , a positive , a neutral and a negative one were rated separately on a five point likert scale according to the likelihood that the interpretation would pop up in the participant s mind .
second , participants had to choose which of the three interpretations they believed to be the most correct with a higher score indicating belief in a more negative interpretation . in line with the authors expectations , socially anxious adolescents rated negative interpretations of social situations as more likely to come to mind than adolescents with moderate social anxiety .
the socially anxious group was also more likely to believe the negative interpretation for social situations as compared to the moderate social anxiety group ( miers et al .
2008 ) . however , the effect for negative interpretations coming to mind was stronger than for belief in the negative interpretation .
to suggest that the strength of belief in a negative interpretation is less important than the likelihood of that interpretation coming to mind , at least for adolescent social anxiety . to the best of our knowledge
, no other study has examined this issue in socially anxious youth ; hence we can not as yet draw firm conclusions . in relation to the first issue , miers et al .
( 2008 ) showed that socially anxious adolescents are more likely to make negative interpretations of social situations but are not less likely to have positive interpretations of these situations .
similarly , vassilopoulos and banerjee ( 2008 ) found support for the presence of a negative bias rather than the absence of positive interpretations in their sample ; however their measurement of interpretation bias was slightly different .
children rated how likely a neutral explanation would come to mind in response to a mildly negative social event .
because of the nature of mildly negative events , positive interpretations would not be plausible ; hence neutral interpretations are a suitable comparison to the positive explanations in the aibq .
the weak and non - significant correlation between neutral interpretations of negative events and social anxiety reported by vassilopoulos and banerjee ( 2008 ) corroborates the findings of miers et al .
( 2008 ) that socially anxious children are as likely as non - anxious children to interpret ambiguous social events in a neutral way . to address the third issue miers et al .
( 2008 ) measured negative affect using the positive and negative affect scale ( panas ; watson et al .
1988 ) . after controlling for levels of negative affect the differences between high socially anxious and moderate anxious youth on negative interpretations coming to mind and belief in negative interpretations of social situations remained ( miers et al .
this indicates that the negative interpretations are not a consequence of a general negative affect factor associated with other emotional disorders , such as depression . in the adult literature
the tendency to interpret ambiguous social situations negatively has frequently been shown to be specific to social anxiety , rather than a feature of negative affect associated with anxiety and depression ( amir et al .
1999 ) were either measured using self - report instruments or groups of socially anxious , non - anxious and depressed persons were compared in clinical ( voncken et al .
( 2008 ) and in the study of vassilopoulos and banerjee ( 2008 ) for youth samples converge with those from studies with adult samples and indicate that interpretation bias is particular to social anxiety . in terms of the fourth issue , miers et al .
thus , socially anxious adolescents were not more likely than their non - anxious peers to rate negative explanations of non - social situations as coming to mind , after statistically accounting for negative affect levels .
content specificity has been widely studied in adult populations and the findings suggest that the interpretation bias is indeed specific to social situations and does not extend to non - social situations ( amir et al . 2005 ; constans et al .
in general , these findings paint a pretty dim picture of the way in which youth with high levels of social anxiety interpret ambiguous cues in social situations , particularly as social situations are generally full of ambiguities .
this would make daily life quite distressing for socially anxious youth if they indeed perceive negative reasons for unclear behavior toward them . in the interpretation bias literature
it is assumed that a bias is present when socially anxious persons perceptions diverge from those of individuals with low to moderate social anxiety .
however , this comparison does not really provide enough information to decide whether the negative perceptions are indeed distortions of reality or grounded in actual negative experiences in social situations .
socially anxious youth might perceive social cues in a negative manner simply because they are socially inadequate and , as a result , receive negative feedback from others .
hence , to determine whether or not their negative perceptions in relation to interpretation of ambiguous social situations are based on a kernel of truth , actual social behavior and interpersonal relations should be measured ( vassilopoulos and banerjee 2008 ) . in the following section ,
we describe the predominant theoretical perspective on socially anxious individuals negative cognitions of social performance before reviewing the results of studies that measured actual social behavior .
the cognitive models assume that socially anxious individuals evaluate their performance in social situations more negatively than persons without social anxiety ( clark and wells 1995 ; rapee and heimberg 1997 ) .
in addition , the models also raise the question whether socially anxious persons tendency to be more negative about their performance is warranted ; do socially anxious persons really perform more poorly than their non - anxious counterparts in different social situations ?
clark and wells ( 1995 ) state that the negative performance thoughts are partly distorted
similarly , rapee and heimberg ( 1997 ) propose that the negative mental representation of socially anxious persons could be a result of actual deficits
thus , these authors propose that although socially anxious persons are likely to overestimate how poor their performance is , there is still some degree of truth in their evaluations .
studies measuring actual social behavior of socially anxious youth tend to differentiate between two components of social performance , actual social skills and overt nervousness ( e.g. , inderbitzen - nolan et al .
some studies report findings that are consistent with the social skills deficit hypothesis , that is , the negative evaluations of social performance are based on a social skills deficiency and therefore reflect a kernel of truth ( e.g. , alfano et al . 2008 ; inderbitzen - nolan et al . 2007 ;
however , other studies with youth samples do not find social skills differences between high and low socially anxious groups ( e.g. , cartwright - hatton et al .
studies show that socially anxious youth overestimate how nervous they appear during a social - evaluative task ( cartwright - hatton et al .
socially anxious youth s ratings of nervousness appear to be a distortion of reality , as compared to the evaluations of independent observers .
however , the findings concerning whether evaluations of social skills are distorted or a reflection of reality appear to be mixed . in a study described in miers et al . ( 2009 ) a possible explanation for the inconsistent findings was investigated . miers et al .
( 2009 ) proposed that negatively biased self - evaluations of social performance are related to performance level .
performance level , as judged by independent observers , may vary among socially anxious individuals .
two studies have shown that , according to independent observers , some socially anxious individuals perform well in social situations whilst others have a poorer social performance ( morgan and banerjee 2006 ; rodebaugh and rapee 2005 ) . if a socially anxious individual s performance level is judged as poor their negative self - evaluations are likely to be more or less correct . however , if a socially anxious individual s performance level is good , the negative self - evaluations are likely to be incorrect and biased
( 2009 ) investigated social performance evaluations in a group of high socially anxious youth ( versus low socially anxious youth , aged 917 years ) , differentiating between the two aspects of social performance , social skills and overt nervousness .
the anxiety groups were selected according to self - reported scores on the social anxiety scale for adolescents ( sas - a ; la greca and lopez 1998 ) with the high anxious group scoring > 1 sd above the mean .
selection of the low anxious group began with scores in the second decile and continued until the same number of boys and girls were included as in the high anxious group .
high and low socially anxious youth evaluated how well they performed during a short speech .
audio - visual recordings of the speeches were made and shown to independent observers ( i.e. , blind to anxiety group membership ) who also evaluated the performances using the same questionnaire as participants .
( 2009 ) found that high socially anxious youth evaluated their performance in the leiden public speaking task ( leiden - pst ; westenberg et al .
( 2009 ) also found that , according to independent observers the high anxious youth did not appear more nervous , stutter more or show more physical signs of nervousness such as blushing .
thus , it seems that for nervousness , high anxious youth s negative perceptions were distorted and were not matched by the other information source : adult observers .
this is in line with current literature ( e.g. , alden and wallace 1995 ; cartwright - hatton et al .
2005 ; norton and hope 2001 ) and the cognitive models of social phobia in which concern about anxiety symptoms is prominent for socially anxious persons .
moreover , in that study self - evaluations of nervousness were not related to performance level ; all high socially anxious youth had negatively biased perceptions regardless of how well they were judged to perform ( miers et al .
participants and independent observers were in agreement about the poorer social skills of high anxious youth .
after teasing apart the good performing from the poor performing youth in order to examine the relation with performance level , the authors showed that the self - perceptions were justified only for some socially anxious youth , namely the poor performers . those high anxious youth who were judged as performing relatively poorly had reasonably accurate self - evaluations of social skills .
however , the good performing high anxious youth evaluated their skills as poorly as the poor performers ; hence their perceptions were unwarranted and distorted .
this finding is in line with results from studies investigating the effectiveness of video feedback on self - evaluations ( morgan and banerjee 2006 ; rodebaugh and rapee 2005 ) . in these studies ,
video feedback improved the self - evaluations of only the skilled participants ( morgan and banerjee 2006 ) or the participants with larger underestimations of performance ( rodebaugh and rapee 2005 ) .
hence , the findings are consistent with the notion that a bias in relation to self - evaluations of social skills exists for some , but not all , socially anxious individuals .
the cognitive models of social phobia give an indication as to the origin of these negative social performance evaluations .
they state that prior social experience influences the socially anxious person s beliefs about the social world ( clark and wells 1995 ) or their mental representation in a social situation ( rapee and heimberg 1997 ) .
hence , it is very likely that the negative self - evaluations of socially anxious youth reflect unsuccessful social interactions with peers .
a number of studies using a range of methodologies , including observations in the school environment ( blte et al .
2007 ; spence et al . 1999 ) , sociometric nomination ( gazelle and ladd 2003 ; greco and morris 2005 ) and peer liking conducted in the laboratory ( verduin and kendall 2008 ) clearly show that socially anxious youth receive negative feedback , are disliked and neglected by their peer group .
the literature to date therefore suggests that socially anxious youth have good reason to think about their social performance in a negative way . a study described by miers et al .
( 2010 ) explores whether unfamiliar same age peers perceive the social skills of socially anxious youth as poorer than the skills of their non - anxious counterparts . using same age peers as observers of social skills instead of adults
is considered important because peers might be more sensitive to slight digressions in the behavior of other youth .
furthermore , peer relations take on increasing dominance and importance in the adolescent period ( e.g. , brown 2004 ; hartup 1996 ) suggesting that evaluations from peers might be more relevant to the child s developing awareness of social self - worth . if socially anxious youth are perceived as lacking in social skills this might be a reason for their poor treatment , and in turn , their negative self - evaluations . in miers et al .
( 2010 ) a group of high ( n = 20 ) and low ( n = 20 ) socially anxious adolescents ( age range 1317 years ) who took part in the leiden - pst ( westenberg et al .
( 2010 ) specifically chose unfamiliar age peers as raters in order to remove the influence of a child s longstanding social reputation in a peer group on reactions to that child s behavior ( verduin and kendall 2008 ) .
a minimum of 20 peer raters per high or low anxious speaker was included and these peers rated the speakers in their own school classrooms .
this approach was chosen in order to reflect an average reaction from a group within a normal school classroom situation .
peer raters were of a comparable age to the high and low anxious speakers and attended the same education levels .
the speech recordings of high and low socially anxious adolescents were rated on four social skills : clarity of speech content , use of facial expressions , posture and body movement and way of speaking .
these four skills capture the most important verbal and nonverbal behaviors of a speech performance and have been shown to differentiate socially anxious from non - anxious adults ( baker and edelmann 2002 ) .
( 2010 ) study reported large , significant differences between high and low socially anxious speakers : unfamiliar peers evaluated high anxious speakers as giving a poorer speech in terms of content , facial expressions , posture , and way of speaking .
furthermore , for all skills except facial expressions , the anxiety group difference could not be accounted for by high levels of depression in the high socially anxious group .
these results are consistent with previous studies that revealed more negative treatment of socially anxious as compared to non - anxious children and adolescents in the school environment ( blte et al . 2007 ; spence et al .
1999 ) and greater disliking of children with social anxiety disorder than those without as rated by unfamiliar age peers ( verduin and kendall 2008 ) . in the context of peer relations ,
then , high socially anxious youth s negative self - evaluations of social skills might in fact be justified and accurate .
it is possible that , as a result of their inadequate social skills as perceived by peers , these peers react in a different , less pleasant manner towards them as compared with low anxious youth .
this differential treatment is in turn noticed by the socially anxious youth , who may then come to expect negative outcomes from all types of social situations as a result of this repeated exposure to unpleasant social interactions .
perhaps this bias is underpinned by high anxious youth s exposure to negative outcomes from social relations with peers and should therefore be seen as based on truth , rather than a distortion of reality .
the first question asked whether there is evidence for negative perceptions in relation to interpretation of ambiguous social situations and self - evaluation of social performance in socially anxious youth . to sum up the findings reviewed here with respect to the first research question
, it appears that during social situations , socially anxious youth do have negative perceptions in relation to , respectively , the interpretation of ambiguous situations ( miers et al . 2008 ; vassilopoulos and banerjee 2008 ) and self - evaluation of performance ( cartwright - hatton et al . 2005 ; inderbitzen - nolan et al . 2007 ; miers et al . 2009 ) .
the second research question asked whether these negative perceptions are justified by sources of information other than the socially anxious youth themselves , such as independent observers and fellow age peers . in terms of this second question the studies here reviewed suggest different answers for the different perceptions . in relation to the negative interpretation bias
we can only speculate that socially anxious youth s negative interpretations of ambiguous social cues are at least partly based on a kernel of truth , due to their experience of poor peer interactions ( e.g. , blte et al .
however , because the reviewed studies did not disentangle the process of receiving negative feedback from one s social environment from the development of negative interpretations we do not know whether one precedes the other and hence to what extent the negative interpretations are distorted . as regards self - evaluations of how nervous one appears during a social - evaluative task the findings overall are in support of biased processing of nervousness .
this is evident from the overestimations of the visibility of anxiety related symptoms and behaviors as compared to independent observers evaluations ( cartwright - hatton et al .
. for self - evaluations of social skills the findings indicate at least a partial justification for the low self - evaluations of socially anxious youth , as compared to adult observers ( miers et al .
2009 ) ; and a suggestion of wholly warranted low perceptions , as compared to peer observers ( miers et al .
the studies reviewed in this article may be used to inform treatment of youth with clinical levels of social anxiety . before attempting to modify an interpretation bias
it would seem important to first identify the quality of socially anxious youth s peer relations and possible reasons for peer rejection
. it might be fruitless to modify the interpretation bias without increasing the chance that the socially anxious youth receives positive feedback from others . in the context of continuing poor peer relations
peer - perceived social skills deficits of socially anxious youth may be the reason for previously observed negative treatment and disliking ( blte et al .
the present article is unable to definitively make this conclusion ; however it is quite plausible that less adequate social skills are at least one aspect of high socially anxious youth s behavior that elicits negative responses from their peers ( verduin and kendall 2008 ) .
schneider ( 2009 ) showed that the behavior of socially withdrawn 1012 year olds in trusted close friendships is characterized by unassertiveness , passivity and uncommunicativeness .
whether it is a lack of specific skills or a general reticent nature that hinders the prolongation of successful peer relations , it is clear that the behavior of socially anxious youth makes this group a target for peer exclusion . with this in mind ,
assertiveness training , targeted improvement of particular social skills or even attention to general appearance may all contribute to forming more constructive and positive social relationships . in terms of negative perceptions of social performance , as suggested by the studies of miers et al .
( 2009 ) , morgan and banerjee ( 2006 ) , and rodebaugh and rapee ( 2005 ) a one size fits all technique to correcting social skills evaluations might not be appropriate .
socially anxious youth who perform poorly are not likely to benefit from video feedback or cognitive strategies to correct their negative perceptions .
a behavioral component would be preferable for these individuals in order to improve their social skills , followed by the cognitive method if required .
for those evaluated as good performers , video feedback could be a key component of treatment .
( 2010 ) advocates including the perceptions of age peers to inform the treatment of socially anxious youth s social skills .
improving social skills in a manner that elicits positive feedback from age peers , rather than adults , might be more effective at breaking the cycle of ineffective social interactions , expectations of negative social outcomes and fear of negative evaluation .
the other side of the social performance coin is nervousness : the visibility of one s anxious behaviors ( e.g. , stuttering , blushing ) . a number of studies ( e.g. , cartwright - hatton et al . 2005 ; miers et al .
2009 ) imply that all socially anxious youth would benefit from being made aware that their anxious behaviors in a social - evaluative event are normal and are not more visible than the anxious behaviors of their non - anxious peers .
moreover , it would be important for therapists to emphasize that visible nervousness does not detrimentally affect other people s impressions of social performance ( blte et al .
the findings reviewed in this article and those from several other studies ( e.g. , siegel et al . 2009 ; spence et al .
1999 ; verduin and kendall 2008 ) suggest that the theories of clark and wells ( 1995 ) and rapee and heimberg ( 1997 ) could be expanded into development models whereby the role of peer relations and interactions on the development of children and adolescents negative social perceptions is included .
for example , clark and wells ( 1995 ) refer to previous experience interacting with innate behavioral predispositions as key to the development of social phobics negative assumptions of the social world . similarly , rapee and heimberg ( 1997 ) state that prior experience and feedback in a social situation is one source of information that is used to develop the mental representation of the self in social situations .
the experience referred to in both models should incorporate social interactions with age peers , particularly in adolescence , as this period is associated with both an increase in the importance of peers to emotional development ( la greca and prinstein 1999 ) , and fears for social - evaluative situations ( weems and costa 2005 ; westenberg et al .
it seems important for models to consider how feedback from peers impacts upon the child s perceptions of the social world and their idea of how others perceive their social behavior . in this vein , it would be important to investigate whether negative or unsuccessful peer interactions merely serve to confirm pre - existing beliefs about one s social inadequacy or if they actually play a greater role in shaping the child s perceptions , and consequently the likelihood of developing severe social anxiety .
furthermore , from the current literature it is still unclear exactly why socially anxious youth are less liked than their non - anxious age peers ( verduin and kendall 2008 ) .
2010 ) , however it could be that the peers react to attractiveness , general appearance or the use of safety behaviors as opposed to basic skill deficits .
hence further research is required to tease apart the influence of these factors on peer judgments of socially anxious youth .
a new developmental model would also need to address the question of how negative perceptions , social skills and negative peer interactions influence each other in the formation of youth social anxiety .
the studies reviewed here can not inform about the order in which these factors occur and there may be several possibilities .
for example , as suggested in the current review a lack of basic social skills may lead to the formation of negative social cognitions through negative feedback received by peers . in this case , the negative cognitions would be based on actual social skill inadequacies and unbiased .
alternatively , negative social cognitions may have already been passed on to the developing youth by their parents ( creswell and oconnor 2006 ; lester et al .
2010 ) , which could increase feelings of anxiety about social situations and lead to overestimations of poor social performance .
these biased cognitions may , however , in time come to reflect a kernel of truth .
negative thoughts about one s social performance and accompanying anxious feelings may hinder the youth s ability to perform skillfully in social situations .
negative peer responses to unskilled social behavior would then serve to reinforce the pre - existing negative social perceptions and enhance socially anxious feelings , in a vicious circle . in order to disentangle the influences of poor social skills , negative cognitions , familial processes and peer feedback on the development of social anxiety in youth future studies could use a longitudinal design in which a group of children are followed from an age that temporally precedes the onset of social anxiety disorder .
these different factors could be measured at predetermined and frequent intervals in order to document the formation of negative perceptions and/or social skills deficits over time .
alternatively , using cross - sectional data , structural equation modeling could test different models in which the order of social skills , negative perceptions and negative peer interactions in their influence on social anxiety are varied , and the models evaluated in terms of their fit to the data . a point on which the two leading cognitive models differ is the role of attentional processes in the maintenance of social fear ( schultz and heimberg 2008 ) .
clark and wells ( 1995 ) propose that upon entering a social situation attention is directed to the self , which prevents social phobics from perceiving information from the social environment that is inconsistent with their fear ( hence , this information from the external environment is suggested to reflect positive behaviors from other people ) , and simultaneously enhances awareness of the feared anxiety responses .
rapee and heimberg ( 1997 ) in contrast advocate that attentional resources are allocated both to aspects of the self and to potential external threat such as negative behaviors by audience members .
the findings presented in this review article are more in line with monitoring of both internal and external social cues as advocated by rapee and heimberg ( 1997 ) . in miers et al .
( 2010 ) unfamiliar age peers readily perceived inadequacies in the social skills of high socially anxious adolescents .
2007 ; siegel et al . 2009 ) suggests that , contrary to clark and wells ( 1995 ) theory , attention to the external environment would often confirm socially anxious youth s fear of negative responses from others .
it therefore seems likely that socially anxious youth attend to information in the social environment , particularly from their age peers , and that this information plays a role in the formation of socially anxious youth s negative social cognitions . in relation to
socially anxious youth s negative perceptions of how nervous they look the cognitive models also propose that socially anxious individuals distort and exaggerate their physiological symptoms of arousal during social situations .
clark and wells ( 1995 ) model states that during social situations somatic changes occur and that these changes are interpreted as evidence of danger and anxiety .
for example , an increased heart rate is perceived as losing control . for rapee and heimberg ( 1997 ) information from the autonomic nervous system feeds into the mental representation and this may be depicted as visible , for example a slight warm feeling in the cheeks would be represented as obvious blushing ( voncken and bgels 2009 ) . because physical symptoms of arousal are seen as key candidates for negative evaluation ( e.g. , sweating , heart pounding ) the socially anxious person will overestimate these symptoms . hence , the cognitive models assume that socially anxious persons also perceive their arousal in perhaps a rather negative manner , and distort the degree to which they actually experience physiological symptoms . a number of studies conducted with adult samples ( e.g. , mauss et al .
2004 ) and one study with high and low socially anxious adolescents ( anderson and hope 2009 ) indicate that socially anxious persons perception of arousal during an anxiety evoking social task indeed does not match their actual symptoms , that is , subjective and objective physiological arousal do not correspond .
this suggests that perceptions of physiological arousal are not based on truth ; however , this should be replicated in youth populations .
one reason for exaggerating their physiological responses is the use of self - monitoring processes by socially anxious persons ( clark and wells 1995 ; rapee and heimberg 1997 ) .
the cognitive models describe how socially anxious individuals monitor different types of internal information , such as thoughts , somatic responses and images when under the threat of negative social evaluation .
future research should investigate whether high socially anxious persons perception of physiological arousal is influenced by these increased self - monitoring processes rather than the actual physiological changes that take place .
finally , it is recommended that research into socially anxious youth s perceptions of social situations be sure to include the perceptions of persons relevant to the anxious youth s daily social environment .
inherent to the social environment are parents and family members , and other influential adults such as a teacher or mentor . however , because of the nature of peer relationships and their increasing importance during the adolescent period ( brown 2004 ; hartup 1996 ) it is crucial that age peers are included in research ( verduin and kendall 2008 ) . how age peers perceive ( miers et al .
2007 ; spence et al . 1999 ) , socially anxious youth is very likely to be critical to understanding the youth s social context and the etiology and maintenance of their own perceptions of the social context .
indeed , evaluations from age peers are particularly relevant to the question of whether socially anxious youth s negative social cognitions reflect a distorted reality or a kernel of truth .
Output:
| we review studies that investigate negative social cognitions of socially anxious youth in relation to two specific domains : interpretation of ambiguous social situations and self - evaluation of social performance , including social skills and nervous behaviors . in this review ,
we address the question whether socially anxious youth s negative perceptions are distortions of reality or reflect a kernel of truth as compared to other sources of information including independent adult observers and age peers .
studies key to this question are those that investigate not only the social perceptions themselves but also the social behavior of socially anxious youth .
hence the selection of studies for the review was based on this criterion . from the relevant literature
it is , as yet , unclear whether the negative interpretations of ambiguous social situations shown by socially anxious youth are distorted or a reflection of reality .
socially anxious youth s self - evaluations of social skills appear partly distorted and partly true , depending on the person judging the social skills . in contrast , self - evaluations of nervous behaviors appear distorted .
the studies reviewed indicate that research would benefit from including a wider range of perceptions from persons relevant to the socially anxious youth s daily social environment , not only parents and teachers but also their age peers . |
PubmedSumm4862 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: neurilemmoma is defined as " a neoplasm that arises from schwann cells of the cranial , peripheral , and autonomic nerves " .
clinically , these tumors may present as cranial neuropathy , abdominal or soft tissue mass , intracranial lesion , or spinal cord compression .
the terminology regarding neurilemmoma may be confusing with neurinoma , neurocytoma , peripheral glioma , perineurial fibroblastoma and schwannoma . today ,
they are the most common type of peripheral nerve sheath tumor ( pnst ) , but they are rarely found in deep peroneal nerve sensory branch9121617 ) .
we report an interesting case of neurilemmoma of deep peroneal nerve sensory branch that triggered sensory change with compression test on lower leg and induced changes on pre- and post - operative infrared ( ir ) thermographic images .
ir thermography was taken at 23. it is the first to document a case of thermal change arising from neurilemmoma with compression test .
a 52-year - old woman had complained of pain at lower back and right leg for 9 months .
a local clinician made a diagnosis of herniated lumbar disc ( hld ) and performed a pain block on the patient 's spine .
the symptoms persisted , however , and a mass sized approximately 2 cm by 2 cm was palpated on the lateral side of leg , between right side of tibia and fibula , about 3.5 cm proximal to lateral malleolus .
she was subsequently referred to our hospital . upon visiting our hospital , she initially presented with sensory change on the dorsal side of the right foot , particularly the big toe .
percussion of the mass caused severe pain at fibular area , dorsal side of the right foot , and the big toe .
no neurologic signs were examined except for sensory change with compression test and mild numbness at the fibula and dorsal area of foot .
ultrasonography of the lower extremity discovered an oval - shaped mass sized 1.42 cm by 0.77 cm by 1.12 cm , considered as probably benign pnst arising from the right deep peroneal nerve sensory branch ( fig .
after 1 month , the low back pain was relieved by medication , but right leg pain remained , and an excision of the mass was planned .
a computed tomography ( ct ) scan with contrast of the both lower extremities was taken , which revealed a soft tissue mass within the sensory branch of right deep peroneal nerve ( fig .
when the palpable mass was compressed , the patient complained of sensory change , severe pain on fibula ( upward from mass to below the knee ) and dorsal area of foot , especially on fibular area and big toe . at that time , a thermal change was found on ir thermograpy , 31.83 at fibular area , 31.45 at dorsal area : specifically , the temperature of the fibular area was elevated by 0.75 and dorsal area was decreased by 0.15 ( fig .
a vertical skin incision was made under spinal anesthesia , and sharp and blunt dissection was used to expose the mass .
gross identification demonstrated a mass sized 1.4 cm by 1.2 cm and shaped like a pigeon egg ( fig .
4 ) . the tumor capsule was incised parallel to the running direction of nerve , and totally enucleated , with special attention paid to deep peroneal nerve sensory branch in order to avoid damaging the nerve .
the patient complained of mild sensory change on dorsum of foot , which was relieved partially over 1 month and completely over 2 months of period .
when the excision site was compressed , temperature was 31.49 at fibular area , 31.32 at dorsal area ( table 1 ) .
there is no severe sensory change , except mild op wound pain , and thermal elevation like pre - op status .
the temperatures at dorsal foot area do not show any significant difference in pre- and post - op status .
neurilemoma , also known as schwannoma , is a common benign tumor of the peripheral nerve1119 ) .
neurilemmomas usually arise at the intracranial cavity but may be found on other sites of the body .
odom et al.14 ) reviewed previous literature and reported that schwannoma of the leg comprise about 7.09% of all cases .
the initial impression of our case was herniated lumbar disc ( hld ) , which was ultimately found to be incorrect .
there has been a previous case where a patient with schwannoma of the peroneal nerve presented with sciatica , which was initially misdiagnosed as hld13 ) .
this patient 's perceived sciatic pain or l5 dermatomal pain could have lead to the misdiagnosis . in our case ,
the patient underwent several sessions of pain block in a local hospital , and there was no clear sign of improvement of low back pain .
causes of nerve irritational symptom include hld , ischialgia , piriform muscle syndrome , polyneuropathy , pernoneal nerve trauma , pressure upon peroneal nerve due to wearing immobilization , fracture or expansive process in the region of tibial head , lipoma , ganglioma , synovial cysts from popliteal region , anatomic variability , and others14 ) , and differential diagnosis should be made after considering the innervation of the deep peroneal nerve .
the diagnostic modalities available for the differential diagnosis include ct scan , ultrasonography , magnetic resonance imaging , and electromyography , among other31420 ) .
simple radiographs are not of much value when a patient presents with neurologic symptoms . ultrasonography has been considered as a useful screening tool3 ) , but it is difficult to perform such costly examination from the onset .
this examination measures the change in temperature radiating from the body resulting from alteration of subcutaneous capillary blood flow .
thus , for the precise examination , it is important to maintain a constant temperature and environment in thermography laboratory .
this was first used by lawson in 1956 for the diagnosis of breast cancer8 ) and is now being used as a novel method objectively quantifying the subjective sense of pain2 ) . in order to minimize the errors , our thermography lab maintains temperature at 23 , we use difference between temperature of before and after compression of the lesion .
the ir thermograpy demonstrated thermographic changes when the neurilemoma induced sensory change with compression test on the fibular area , dorsal side of foot , and the big toe .
the area of thermographic change was found to be related to the path of deep peroneal nerve sensory branch . in hld accompanied by leg pain ,
hyperthermic regions resulting from local dilation arise on the posterior lumbar skin that correlates to anatomic site of the compressed nerve due to antidromic stimulation .
the information is transmitted to the recurrent meningeal nerve , or sinuvertebral nerve , located at the spinal cord , and consequently , the autonomic output caused by the reflex arc leads to local vasoconstriction and hypothermia28 ) . in our case , however , there was greater blood flow at the pain site , which further increased upon inducing sensory change with compression test , resulting in hyperthermia ( fig .
while the degree of pain intensified in accordance with compression test , vasodilation and increased temperature of the skin was observed , rather than hypothermia and vasoconstriction caused by sympathetic nerves as seen in hld .
this may be explained by autonomic dysfunction following nerve injury ( in this case , tumor growth on peroneal nerve sensory branch ) , including changes of the sympathetic tone and norepinephrine synthesis1 ) .
sympathetic nervous system usually induces vasoconstriction by secretion of adrenaline , but sometimes , the cholinergic fibers within the sympathetic nerves releases acetylcholine , which may cause vasodilation and diaphoresis1015 ) .
the former may be more significant in hld , whereas in our case , the latter may have been the stronger factor .
vasodilation resulting from the stimulation of the dorsal root , which is thought to be a separate entity from sympathetic nervous system , has been discovered .
this arises from spinal gray matters , and the preganglionic fibers passes the dorsal root and dorsal root ganglions , changing postganglionic fiber and ultimately , peripheral ganglions and skin temperature21 ) .
furthermore , parasympathetic nerves are also involved in regulation of skin temperature , which may be a clue explaining the rise in temperature at fibular area and cutaneous blood flow following sensory change with compression test .
interestingly the temperatures at dorsal foot area do not show any significant changes and were elevated more than fibular area . the study performed by zhang et al.21 )
presents thermal data of the upper body measured indoor at 23. in this case , the mean temperatures of upper body sectors are distributed from 29 to 32. this study demonstrates lower extremity temperature of our case , being maintained at 31.08 to 31.83 regardless of compression . in other words ,
our case of ir thermography data follows the temperature distribution pattern obtained at 23 indoor . the magnitude temperature of difference between left and right side of the same anatomic location was 0.1 , 0.2 , 0.3 , and 0.4 regardless of indoor temperature ( 20 or 23 ) , in both 1995 and 1999 study21 ) .
the elevated temperature of the foot dorsum compared to the fibula before the surgery ( table 1 ) may be attributed to tumor effect .
the situation where the temperature of dorsum was 0.58 higher instead of 0.3 was determined as abnormal6 ) .
this is also well demonstrated in uematsu , where carpal tunnel syndrome was correlated with electromyography ( emg)18 ) .
the degree of median nerve lesion was classified as mild , moderate , or severe according to emg findings , and mild and moderate compression group demonstrated thermal elevation while in severe compression group , both thermal elevation and depression was observed . in other words ,
palmar temperature rises as the severity of median nerve compression increases and then drops as thenar muscle atrophy develops as the result of chronic severe carpal tunnel syndrome . since peripheral nerves include sympathetic nerves involved in vasoconstriction of the anatomic area , the tumor located at sensory branch of the deep peroneal nerve may have suppressed the vasoconstriction of the surround area , resulting in vasodilation and the following hyperthermia of the right dorsum and toe compared to the left side . there are numerous other factors influencing skin temperature , including emotional stress and depression , which can affect autonomic dysfunction4 ) , as well as the circadian rhythm , which results in diurnal variation of body temperature7 ) .
it shows temperature change according to autonomic nervous system tone or change in circulation caused by various etiologies . therefore , although it shows temperature changes , it does not clarify what the nature of the causative lesion is .
considering these variables , future studies and analyses controlling for these factors may be needed .
when the mass , pnst , was compressed , there is a ir thermographic - thermal elevation at pnst proximal part with subjective pain .
mass excision relieves the patient 's symptom , and there is no definite thermal change at post - operative ir thermograpy .
however , tumors that occurred in peroneal nerve have a similar symptoms with hld , or symptoms caused by nerve irritation or compression .
although , ir thermographic findings are not specific , as discussed previously , there are differences in ir thermography , and it is useful and supportive in our case . therefore , there are possible usefulness of ir thermography in evaluating symptoms caused by nerve irritation or compression , and possible limitation from various etiologies .
further study will be needed to clarify which range of temperature change can be interpreted as significant result and to get specific result without numerous other factors influencing skin temperature .
Output:
| we report a case of neurilemmoma of deep peroneal nerve sensory branch that triggered sensory change with compression test on lower extremity .
after resection of tumor , there are evoked thermal changes on pre- and post - operative infrared ( ir ) thermographic images . a 52-year - old female presented with low back pain , sciatica , and sensory change on the dorsal side of the right foot and big toe that has lasted for 9 months .
she also presented with right tibial mass sized 1.2 cm by 1.4 cm .
ultrasonographic imaging revealed a peripheral nerve sheath tumor arising from the peroneal nerve .
ir thermographic image showed hyperthermia when the neurilemoma induced sensory change with compression test on the fibular area , dorsum of foot , and big toe .
after surgery , the symptoms and thermographic changes were relieved and disappeared .
the clinical , surgical , radiographic , and thermographic perspectives regarding this case are discussed . |
PubmedSumm4863 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: recently , nanostructure mesoporous materials have attracted much attention for development of catalytic and adsorption systems .
mesoporous materials have often been functionalized by adding noble ligands to improve their physical and chemical properties [ 13 ] .
santa barbara amorphous ( sba-15 ) is a highly ordered material possessing a regular two dimensional array of channels .
it is similar in structure to the better known mcm-41 , however , due to its larger pore size and thicker pore walls it has the ability to capture larger molecules and chemical complexes and has also greater stability in aqueous solutions .
this mesoporous material typically has a pore diameter in the order of 710 nm , which is twice that of mcm-41 .
we used the functionalized sba-15 as a sorbent for removal of some lanthanides from wastes , because of its promising abilities .
so , for evaluation the stability of functional group of aurintricarboxylic acid on the sba-15 the sorbent was irradiated .
high - level radioactive waste generated by commercial reprocessing facilities contains cesium , strontium , lanthanides , actinides , and other elements .
long - lived radioactive lanthanide species are present at very low concentrations in wastes and the radioactivity of lanthanides is low .
selective removal of these species could greatly reduce the volume of materials for long - term storage .
the adsorbent must be selective for the target species among other interfering cations and/or competing ligands .
thus both hard ness of anionic ligands and ligand synergy are important attributes in designing effective complex agents for these species .
the aurintricarboxylic acid ligand has been synthesized and loaded as monolayer on an extended family of highly ordred mesoporous silicates such as santa barbara amorphous ( sba ) [ 7 , 8 ] .
these silicates have been developed as high - performance sorbent materials whose functional groups can be tailored to selectively sequester many target species .
the high surface area of the nanopore support coupled with the dense monolayer coating provides high binding capacity and the rigid open pore structure allows for rapid sorption kinetics .
the lanthanides are considered only slightly toxic in the hodge - sterner classification system and are safely handled with ordinary care .
the effect of atomic weight of rare - earth elements on lethality is difficult to assess , but the medium rare - earth elements appear to have a lesser toxicity than light or heavy rare - earth elements .
the presented research investigates the normal sba-15 and functionalized sba-15 mesopore with aurintricarboxylic acid after -irradiation by fourier - transform infrared spectroscopy and describes a novel functionalized sba-15 which was used for sorption of praseodymium and lutetium ions from nuclear waste waters in batch ( static ) techniques .
standard solution of lanthanides was prepared by icp- standard solution grade . in this study sba-15
was synthesized using a triblock copolymer - poly ( ethylene glycol)-block - poly ( propylene glycol)-block - poly ( ethylene glycol ) -as a templating agent and coated with aurintricarboxylic acid by contacting the mesoporous silicate with its solution .
normal and functionalized sba-15 mesopore were then exposed to co -irradiation ranging from 1 kgy to a cumulative dose of up to 15 kgy . for this study ,
about 50 g of sba-15 powders was mixed with 188 ml of molar aurintricarboxylic acid solution in a 250 ml polypropylene bottle and agitated for 3 days .
after being allowed to settle for 24 h , the clear supernatant solution was discarded and the residue was collected by vacuum filtration through a 0.45 m nylon membrane .
the solid residue was returned to the treatment bottle and agitated with 200 ml of double - distilled water for 24 h to remove the excess of aurintricarboxylic acid .
the precipitate was washed and collected by vacuum filtration , and the sba-15 functionalized by aurintricarboxylic acid ligand was dried at room temperature .
the ftir spectra of irradiated samples were also studied using kbr ( 0.01 g powder + 0.5 g kbr ) pellet technique in the range of 5004000 cm . to evaluate the efficiency of sorbent for separation of trace amounts of lanthanides from waste waters distribution coefficient ( kd )
was determined by exposing the functionalized mesopore sba-15 to solutions containing lanthanides in definite concentrations ranging from 1 ppb to 300 ppm .
the method was used to evaluate the absorption potential of sorbent under batch operation . for this purpose , 0.2 g of functionalized sba-15
was mixed with 50 ml of solutions containing lanthanides at 25 c for 270 min .
the liquid phase was separated by filtrations concentration of lanthanides in the liquid phase was determined by an inductively coupled plasma- atomic emission spectrometer ( icp - aes , liberty 150 ax turbo ) and ultraviolet visible spectrophotometer ( uv / vis , hp- 8453 ) .
the effect of some parameters such as amount of functionalized mesopore , concentration of lanthanides , and shaking time were investigated by determination of kd and percent of sorption in various conditions .
the surface modified sba-15 was loaded with a chelating agent and assessed for its potential as a highly metal selective adsorbent material for industrial and analytical laboratory applications .
the effect of -irradiation on normal and functionalized sba-15 mesopore before and after -irradiation was investigated ( with up to 15 kgy dose ) .
1ftir specters of -irradiated sba-15 ( a ) , -irradiated functionalized sba-15 ( b ) , sba-15 before irradiation ( c ) and functionalized sba-15 before irradiation ( d ) ftir specters of -irradiated sba-15 ( a ) , -irradiated functionalized sba-15 ( b ) ,
sba-15 before irradiation ( c ) and functionalized sba-15 before irradiation ( d ) the results of experiments showed that normal and aurintricarboxylic acid functionalized sba-15 mesopore remained unchanged up to 15 kgy and it is suitable for applying in lanthanides separation .
ftir spectrum of functionalized sba-15 was significantly influenced by the underlying silicate surface , whilst the aurintricarboxylic acid coating produces lower transmittance values and new peaks in the fourier - transform infrared spectrum at higher wave numbers . according to the results of transmission electron microscope ( tem ) of sba-15 pore size distribution was around 25 nm .
uv - vis absorption spectrum of aurintricarboxylic acid ligand is shown in fig . 2
. maximum absorption of this ligand is appeared in wavelengths of 207 and 310 nm.fig .
2ultraviolet and visible spectra of aurintricarboxylic acid ultraviolet and visible spectra of aurintricarboxylic acid the distribution coefficient ( kd ) was calculated using the following equation:\documentclass[12pt]{minimal }
\usepackage{amsmath }
\usepackage{wasysym }
\usepackage{amsfonts }
\usepackage{amssymb }
\usepackage{amsbsy }
\usepackage{mathrsfs }
\usepackage{upgreek }
\setlength{\oddsidemargin}{-69pt }
\begin{document}$$ k_{\text{d } } = [ ( c_{i } - c_{f } ) /c_{f } ] v / m $ $ \end{document}where ci and cf are the initial and the final concentration of target ion respectively , m is the mass of functionalized sba-15(g ) and v is the volume of lanthanides solution ( ml ) .
there are some factors which can affect the sorption of praseodymium and lutetium by functionalized sba-15 , for this reason , the operating conditions should be optimized . for this purpose ,
the results of distribution coefficients of different lanthanides with concentration of 100 ppm are shown in fig .
the main criterion for selection of functionalized sba-15 as a prospective sorbent is their higher distribution coefficients.fig .
3distribution coefficients of lanthanides using functionalized mesopore ( with ion concentration of 100 ppm ) distribution coefficients of lanthanides using functionalized mesopore ( with ion concentration of 100 ppm ) according to figs . 4 , 5 , 6 ,
10 g of modified mesopore is the best value of sorbent in its different concentrations.fig .
4relation between the amounts of modified mesopore and absorbance in a constant concentration of lutetium ion ( 100 ppb ) at wavelength of 208 nmfig .
5relation between the amounts of modified mesopore and absorbance in a constant concentration of lutetium ion ( 50 ppb ) at wavelength of 208 nmfig .
6relation between the amounts of modified mesopore and absorbance in a constant concentration of lutetium ion ( 10 ppb ) in wavelength of 208 nm relation between the amounts of modified mesopore and absorbance in a constant concentration of lutetium ion ( 100 ppb ) at wavelength of 208 nm relation between the amounts of modified mesopore and absorbance in a constant concentration of lutetium ion ( 50 ppb ) at wavelength of 208 nm relation between the amounts of modified mesopore and absorbance in a constant concentration of lutetium ion ( 10 ppb ) in wavelength of 208 nm extraction time is one of the most important factors in the most of the extraction methods ; the effect of contact time of praseodymium and lutetium with functionalized sba-15 was examined in the range of 230 min in constant experimental conditions ( figs . 7 and 8).fig .
8relation between distribution coefficient of lutetium ion and shaking time relation between distribution coefficient of paraseodyum ion and shaking time relation between distribution coefficient of lutetium ion and shaking time the results show that 1230 min is best time for this purpose .
the distribution coefficients of praseodymium and lutetium in different concentrations on the functionalized sba-15 mesopore have shown in figs . 9 and 10.fig .
10relation between distribution coefficients of lutetium ion and its concentrations relation between distribution coefficients of paraseodyum ion and its concentrations relation between distribution coefficients of lutetium ion and its concentrations the distribution coefficients decreased by increasing concentration of praseodymium and lutetium ions .
ftir spectra of normal and surface functionalized sba-15 revealed that sorbent remained unchanged by -irradiation , so , it can be promising sorbent to remove radioactive ions . based on the results , the selectivity of functionalized sba-15 decreased with increasing concentration of praseodymium and lutetium ions .
this can be considered as a result of the nature of kd formula , which implies that the sorbent shows higher affinity to the praseodymium and lutetium ions at lower concentration .
subnanomolar concentrations of praseodymium and lutetium can be removed and measured in a short time with a desirable efficiency ; so , functionalized sba-15 can be used to develop a simple and extremely sensitive method for rapid analysis of praseodymium and lutetium ions in waste water , where removal of trace concentration is a big deal for scientists working in the field of liquid waste management .
it was not found any other patented or published experiences regarding to praseodymium and lutetium sorption on the sba-15 grafted with aurintricarboxylic acid ligand worldwide .
further investigation is required to determine their uptake behavior in a dynamic flow conditions . in this concern , it is necessary to consider the effect of some other parameters such as media ph , reaction temperature , stream flow rate for column test , etc .
Output:
| in the present work , results of -irradiation on normal and functionalized sba-15 by aurintricarboxylic acid have been reported .
characterization of normal and functionalized sba-15 particles before and after -irradiation was carried out using fourier - transform infrared technique .
aurintricarboxylic acid ligand connected to sba-15 was also analyzed using uv / vis spectrophotometer .
the modified sorbent was then used as a new sorbent for separation of trace amounts of praseodymium and lutetium ions from nuclear waste waters in batch techniques .
based on the results of distribution coefficients determination , and investigation of sorption process in various conditions , the parameters were optimized for separation lanthanides .
it can be concluded that the functionalized sba-15 is a promising sorbent for praseodymium and lutetium cations . |
PubmedSumm4864 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: kyrle 's disease ( kd ) is a rare skin disorder characterized by transepidermal elimination of abnormal keratin .
it is classified as a subtype of acquired perforating dermatosis along with reactive perforating collagenosis , elastosis perforans serpiginosa and perforating folliculitis .
it is commonly seen in patients with diabetes , renal disease and rarely in liver disease .
kd is regarded as a genetically determined disease with onset during adulthood usually between the age of 30 and 50 years but onset as early as age 5 years and as late as 75 years has been reported with female - to - male ratio of up to 6:1 .
it presents as multiple discrete , eruptive papules with a central crust or plug , often on the lower extremities .
the first line therapy of kd is keratolytics ( salicylic acid and urea ) followed by electrocautery or radiocautery .
a 64-year - old male presented to skin department with complaints of lesions over body since 1 month with severe itching .
the lesions initially began over right leg which progressed to involve both lower limbs , back , hands , face and scalp .
he was a known case of diabetes and hypertension since 25 years on regular treatment .
patient was on hemodialysis since 1 year ( twice a week ) for chronic renal failure . on investigations
his serum creatinine was 15.45 mg / dl , serum uric acid was 9.1 mg / dl , and hba1c was 7.8% .
urine routine and microscopy showed glucose 2 + and protein 3 + , fasting blood sugar 180 mg / dl and post - prandial blood sugar 200 mg / dl . ultrasonography of abdomen and pelvis revealed right kidney size to be 8 3 cm and left kidney size to be 8.5 3 cm .
multiple , large , discrete hyperpigmented , hyperkeratotic papules with central crusted keratotic plugs over bilateral extremities [ figure 1 ] , back , neck , face and scalp were seen .
linear distribution of lesions was seen over bilateral thighs showing koebnerization [ figure 2 ] .
biopsy taken from one of the papule from right leg showed irregular epithelial hyperplasia with follicular cornified plug and focal parakeratosis .
multiple discrete hyperkeratotic papules on bilateral lowerlimbs koebnerization over right lateral thigh follicular cornified plug with focal parakeratosis ( h and e , 4 ) the patient was seen after 15 days with symptomatic improvement in the form of reduced intensity of itching .
kyrle first described this disorder in 1916 under the name hyperkeratosis follicularis et parafollicularis in cutem penetrans .
perforating disorders ( pd ) are a heterogeneous group of disorders which are categorized into four types based on physical and pathological investigations sharing the common characteristics of transepidermal elimination as elastosis perforans serpiginosa , reactive perforating collagenosis , perforating folliculitis and kd .
kasiakou et al . , suggested an infectious etiology while abnormal keratinization been proposed by tappeiner et al .
detmar et al . , suggested that defective differentiation of the epidermis and the dermoepidermal junction owing to alteration of the underlying glycosylation process may be responsible for the lesions .
elevated serum and tissue concentrations of fibronectin may be responsible for inciting increased epithelial migration and proliferation , culminating in perforation was suggested by morgan et al .
it has been found to be associated with renal failure and diabetes , shown by the report of saray et al . , in which among 22 patients with pd , 72% had chronic renal failure and 50% had diabetes . among patients with diabetes and pd , 90% had chronic renal failure .
in a report involving 21 cases of kd , 19 cases presented with a renal disorder and 12 cases had diabetes . the pathogenesis associated with diabetes mellitus
is unknown , it may be an outcome of changes in the epidermis or dermis leading to metabolic derangements and a cutaneous response to the superficial trauma and vasculopathy arising from products of oxidative damage or endoplasmic stress like advanced glycation end products and oxidized low - density lipoprotein ( ldl ) .
the mode of inheritance of kd is unclear as both autosomal dominant and autosomal recessive patterns have been reported .
it is characterized by hyperkeratotic papules and nodules , with a central keratotic plug most commonly on the lower extremities with marked disposition for calf , tibial region and posterior aspect .
arms , head and neck region are also involved while palms and soles are involved rarely .
koebner phenomenon has been noted in some cases like in our case . along with diabetes mellitus and chronic renal failure ,
it is also seen with tuberculosis , pulmonary aspergillosis , scabies , atopic dermatitis , aids , neurodermatitis , malignancy , hepatic disorders , congestive heart failure and endocrinological disorders .
it occurs in 10% of dialysis patients like our case nine cases of kd among 200 patients underwent hemodialysis because of chronic renal failure a keratotic plug is seen histologically in an atrophic epidermis penetrating papillary dermis with underlying dermal histiocytic and lymphocytic infiltrate , which constitutes the foreign body granulomatous reaction .
transdermal elimination of collagen , elastic fibers and degenerated follicular contents with or without collagen or elastic fibers is seen in rpc , eps and pf , respectively while transdermal elimination of keratotic material with no collagen or elastic fibers is observed in kd .
the first line therapy for treatment of kd is keratolytics ( salicylic acid and urea ) followed by electrocautery , cryotherapy or co2 laser surgery .
other options include ultraviolet irradiation after curetting the hyperkeratosis along combination of oral retinoids and psoralen plus ultraviolet a radiation .
emollients and oral antihistamines are useful in relieving pruritus . oral clindamycin ( 300 mg )
kd is a rare entity which has potential to adversely affect the quality of life .
therefore physicians need to have high index of suspicion for kd in patients with diabetes along with concomitant renal disease .
any suspicious lesion should be biopsied , sent for histopatholgy , to confirm the diagnosis and start the treatment at the earliest .
Output:
| kyrle 's disease ( kd ) is an acquired perforating dermatosis associated with an underlying disorder such as diabetes mellitus or chronic renal failure .
it presents as multiple discrete , eruptive papules with a central crust or plug , often on the lower extremities .
a keratotic plug is seen histologically in an atrophic epidermis and may penetrate the papillary dermis with transepidermal elimination of keratotic debris without collagen or elastic fibers .
various therapies have been reported that include cryotherapy , laser therapy , narrow - band ultraviolet b and use of topical or systemic retinoids .
hereby a case of 64-year - old male , a known case of diabetes mellitus , hypertension and chronic renal failure who developed kd is presented . |
PubmedSumm4865 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: lipomasare slow growing fatty tumours of mesenchymal origin and can occur in any organ of the body .
spindlecell lipomas ( scls ) are lipoma variants which have the potential of neuromuscular invasion despite their benign histopathology .
this case report highlights a spindle cell lipoma variant in the supraclavicular area found intraoperatively to invade both the paravertebral muscles and the brachial plexus .
computerised tomography ( ct ) and magnetic resonance imaging ( mri ) findings were suggestive of possible malignancy but the biopsy and immune - histochemical stains confirmed the diagnosis as scl . this report highlights the need for making a preoperative diagnosis of spindle cell lipoma .
this ensures accurate patient consent and appropriate preoperative surgical planning including surgical approach and extent of surgery .
a - sixty - three - year - old gentleman presented with a two - year history of a left supraclavicular mass which had increased in size over the previous three months prior to presentation .
he was a smoker with a past medical history of hypertension and type 2 diabetes mellitus . on examination
, there was a large tennis ball sized swelling in the left neck level v area with no palpable cervical lymphadenopathy .
fine needle aspiration ( fna ) of the mass was performed but it was nondiagnostic .
ct neck showed a 46 69 91 mm left supraclavicular mass posterior to the sternocleidomastoid muscle and superficial to the paravertebral muscles , of fatty density with fine internal septations ( figures 1 and 2 ) .
the radiological appearance was suggestive of a lipoma but a low - grade liposarcoma could not be excluded due to the internal complexity confirmed on mri .
the case was discussed at the multidisciplinary meeting and due to the suspicion of malignancy , and a nondiagnostic fna , excision biopsy was recommended .
the operation was technically difficult because the mass invaginated around the brachial plexus and extended posteriorly through the prevertebral fascia .
complete excision of the mass was undertaken with mobilisation and preservation of the brachial plexus .
histological examination showed mature adipocytes interspersed with fibrous septa containing bland spindle cells with focal pseudo - angiomatous arrangement .
there was the presence of ropey collagen , a very characteristic finding in spindle cell lipoma .
no lipoblasts were seen and the spindle cells showed strong uniform immuno - histochemical positivity for cd34 .
subsequent review also showed negative staining for cdk4 and p16 , supporting the diagnosis of spindle cell lipoma , and excluding atypical lipomatous neoplasm .
spindle cell lipoma ( scl ) is a benign tumour which typically occurs on the posterior neck , shoulder , or upper back in predominantly elderly males .
there is a marked male predilection especially in the sixth decade which may be partly explained by androgen receptors reactivity .
other rare reported sites of occurrence in the head and neck region include the face , suprasellar region , buccal fat pad , oesophagus , nasal vestibule , the tongue [ 7 , 8 ] , floor of mouth , vallecula and parotid gland .
histologically it consists of a proliferation of mature adipocytes , collagen fibres , and spindle cells within a myxoid stroma ( figure 3 , 4 , 5 , 6 , and 7 ) and can infiltrate between skeletal muscle fibres .
on immuno - histochemistry , the spindle cells express cd34 and they are negative for s-100 protein .
they are however desmin negative tumours and this may help differentiate them from other cd34 positive tumours .
differential diagnoses include atypical lipomatous tumour / well - differentiated liposarcoma , pleomorphic lipoma , neurofibroma , nuchal fibroma , lipoblastoma , hibernoma , cellular angiofibroma , extramammary myofibroblastoma , and solitary fibrous tumour .
it is important to note that reactivity to cd34 immuno - histochemical stain is not specific to only spindle cell lipoma as other entities can demonstrate immunoreactivity to cd34 such as atypical lipomatous neoplasm ( aln)/well - differentiated liposarcoma ( wdl ) .
aln / wdl is the most common form of liposarcoma seen in late adult life with equal gender affectation generally .
they contain a significant component of mature fat and tend to have less well - defined borders than lipomas .
the favoured sites for aln / wdl are deep soft tissues of extremities and retroperitoneum compared to scl that favour the subcutis of the posterior neck , back and shoulders .
this coupled with the usual absence of giant marker and ring chromosomes that are typically seen in atypical lipomatous tumour / well - differentiated liposarcoma supports their distinction .
immunostaining for mdm2 and cdk4 has been shown to be a relatively sensitive and specific means of identifying and separating atypical lipomatous neoplasm / well - differentiated liposarcoma from various benign lipomatous lesions [ 15 , 16 ] . in this case report
, histologic findings did not demonstrate sufficient nuclear atypia to suggest a diagnosis of atypical lipomatous tumour and further immuno - histochemical markers that would make such a diagnosis possible ( cdk4 , p16 ) were found to be negative .
scl shares overlapping clinical , morphologic , and immuno - histochemical findings with pleomorphic lipoma as well as the same cytogenetic aberrations .
it however typically arises in the dermis , often in younger patients and lacks the characteristic ropey collagen of scl .
schwannoma and neurofibroma have a similar striking nuclear palisading and conspicuous mast cell infiltrate present in some scl .
scl may also be mistaken for several sarcomas , including myxoid liposarcoma or spindle cell liposarcoma .
the presence of multinucleated floret - like giant cells is characteristic of pleomorphic lipoma and is occasionally seen in atypical lipomatous tumour / well - differentiated liposarcoma . in this case report , the spindle cell lipoma presented a diagnostic and management dilemma as it could not be clinically differentiated from a liposarcoma which would require a more radical approach to treatment .
the radiologic findings of a complex internal architecture with fine septations allowed differentiation of the preoperative differential diagnosis from a benign lipoma or possible malignancy but could not differentiate between a liposarcoma or a spindle cell lipoma .
the authors suggest that when radiologic findings suggest a complex internal architecture suspicious for a diagnosis of a possible lipomatous tumour , it is imperative to obtain a biopsy prior to definitive surgery .
histologic interpretation is crucial and this can be supported by the use of immune - histochemical stains .
immuno - histochemical stains demonstrating positivity for cd34 can be helpful in diagnosis of cd34 positive tumours such as spindle cell lipoma , and the differential diagnoses discussed such as atypical lipomatous tumour and dermatofibrosarcoma protuberans ( dfsp ) .
as discussed , further differentiation can be made based on clinical presentation , immunoreactivity for actin or desmin , s-100 protein staining of mature lipocytes , the presence / absence of ropey collagen bundles , multinucleated floret - like giant cells and cytogenetic aberrations . in difficult cases ,
a preoperative diagnosis of spindle cell lipoma is crucial to surgical management as it impacts on the consent process , surgical approach , extent of surgery , and management . in making a preoperative diagnosis ,
however , it is important to note that fna may be nondiagnostic as it was in this case , because the specimen consisted largely of fatty cells .
core biopsy is preferable and can be obtained by an initial procedure under anaesthesia prior to definitive surgery based on a histological diagnosis .
a preoperative diagnosis will guide the consent process as such patients can be warned of the risks of neurovascular injury as well as determining the extent of surgery .
Output:
| background . spindle cell lipoma ( scl ) is a benign lipomatous tumour , typically occurring in the posterior neck , shoulder or upper back of elderly males .
they compose of fat , cd34 positive spindle cells , and ropey collagen on a myxoid matrix .
this case highlights a rare presentation of scl and the need for pre - operative diagnosis .
case report .
a 63-year - old gentleman presented with a pre - existing left supraclavicular mass that had recently increased in size .
fna and ct scans were performed and results discussed in the mutidisciplinary team meeting .
excisional biopsy was recommended .
radiology .
ct neck showed a left supraclavicular mass of fatty density with fine internal septations .
a low - grade liposarcoma could not be excluded .
histopathology .
fna was indeterminate .
histology of specimen showed bland spindle cells with no evidence of malignancy .
immuno - histochemistry showed scl with cd34 positivity and negative staining on cdk4 and p16 .
management .
excision biopsy of the mass was performed which was technically difficult as the mass invaginated around the brachial plexus .
the patient recovered well post - operatively with no neurological deficits .
conclusion .
spindle cell lipoma is a rare benign tumour and a pre - operative diagnosis based on the clinical context , imaging and immuno - histochemistry is crucial to management . |
PubmedSumm4866 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: we conducted a preliminary comparison of the relative sensitivity of a cross - section of published hrv - specific pcr primer pairs ( most of which were first published before hrv - c was reported ) , independent of most variables described above , by testing a panel of 57 clinical specimen nucleic acid extracts from combined nose and throat swabs from preschool children with colds and influenza - like illnesses in melbourne , australia .
the panel included representatives of the 3 hrv species ( figure ) , human enteroviruses ( hevs ) , and extracts negative for picornaviruses .
the hrvs had been previously detected by using a nested primer pair ( table a1 ) ( 5 ) .
we used 10 different hrv primer pairs and also retested specimens by using the original primer pair with our standard reagents and equipment ( 5 ) .
the original descriptions of primer pairs 7 and 10 ( table a1 ) lacked tm information , and after in - house calculations , we used tms of 50c and 58c , respectively .
we also deliberately standardized the reagents ( onestep rt - pcr kit , qiagen , doncaster , victoria , australia ) and thermal cyclers used ( veriti , applied biosystems , foster city , ca , usa ) for conventional pcr and the rotorgene 3000 real - time cycler ( qiagen ) .
because primer pair 1 had a published history of detecting types from all hrv species , we chose it to genotype hrv - positive samples by sequencing the amplified products .
distribution of human rhinovirus ( hrv ) and human enterovirus ( hev ) sequences used for primer pair studies .
the hrv and hev genotypes from the testing panel ( indicated by filled circles ) were aligned with the central 154 nt of the 5 untranslated region ( utr ) region of all complete hrv genomes and poliovirus-1 .
hrv - ca and hrv - cc refer to hrv - cs with 5 utr sequences that have phylogenetic origins from either hrv - as or hrv - cs , respectively .
the tree was constructed by neighbor joining of maximum composite likelihood distance implemented in mega ( www.megasoftware.net ) .
we found that no primer pair detected the same hrvs and hevs typed when the original pair ( 5 ) or pair 1 ( table a1 ) was used .
five primer pairs , including real - time pcr ( rtpcr ) pair 5 , did not amplify the hevs , a positive feature for hrv - specific studies . only 2 primer pairs amplified anything from a specimen that was positive for both hrv and hev , a problem for accurate estimation of the frequency of co - detections .
the original primer pair screen detected 3 untypeable picornaviruses , which were not detected by any other pair or by repeat testing using the same pair .
only the second - round amplicon of the 3 nested sets of nested primer pairs ( 2,3 , and,9 ) was considered because the second round increased the total number of positive specimens over the first round .
the longest amplicon , produced by primer pair 7 , was also a valuable genotyping target , but it detected only 14 of the original 27 hrv - positive specimens in this population .
we next selected 4 frequently published primer pairs ( 1,5,7 , and,8 ) to examine 44 picornavirus - positive specimens ( 39 hrvs , 3 hevs , and 2 untypeable picornaviruses ) from nonhospitalized children with acute asthma exacerbation ( 6 ) .
as before , primer pair 1 detected the greatest number of hrv- and hev- positive specimens and all positive specimens detected by other primer sets ( n = 41 ) , followed by pair 7 ( n = 40 ) , pair 5 ( n = 36 ) , and pair 8 ( n = 31 ) .
most notably , primer pair 7 performed better than it had in the previous population , detecting only 1 fewer hrv than primer pair 1 and 9 more hrvs than pair 8 .
no species - specific bias was apparent , but generally , a specimen with a lower rna concentration , as indicated by the cycle threshold from primer pair 5 , was less likely to be detected or typed by using other primer pairs .
we noted in both populations that primer pair 1 sometimes amplified a region of human genomic dna from chromosome 6 ( gq497714 ) , for which amplicon size was indistinguishable from that expected due to hrv .
it was not possible to use the precise conditions reported for the 10 compared assays ; 1 was published > 2 decades ago and used phenol chloroform extraction .
some of the original enzyme formulations or reagents are no longer available , and production processes have changed in the interim .
in addition , the previously published primers were used in assays divided between those using 1-step rt - pcr and those using a separate rt cdna synthesis step .
a review of studies that detected hrvs with adequately described conditions during 20092010 found that fewer used a single - tube rt - pcr approach than a 2-step system .
we conducted single - tube rt - pcr to maintain the benefits of the so - called closed amplification system of rtpcr .
thus , we chose to use a single common set of reagents as the fairest way to compare the primer pairs examined in this study .
we believe the nature of this relative comparison best reflects performance for the likely end users : clinical microbiology laboratories or researchers .
we compared primers rather than assay function using clinical material instead of cultured virus , plasmid or synthetic rna standards , or screening contemporary or archived extracts , which are sometimes of low viral load . when picornavirus epidemiology is the primary research focus , we recommend using > 2 primer pairs to maximize the detection of hrvs . under our conditions ,
pairs 14 returned the highest number of positive results , and the rtpcrs behaved similarly but with reduced sensitivity .
many possible reasons could cause discrepant virus testing results between different sites , including changes to specimen integrity resulting from transport and variable amplification resulting from low viral loads .
the effects of viral load can be seen in this study : specimens in population 1 that were positive with multiple ( > 6 separate pairs ) primer pairs had a mean cycle threshold of 33.3 ( combining results from both rtpcrs ) , whereas those with < 6 positive results had means of 39.3 cycles .
amplification variability can also be attributed to the substantial nucleotide sequence diversity between hrvs and the different temporal and clinical characteristics of the 2 specimen populations we used .
our selection of published primer pairs includes those from studies that have informed our current understanding of hrv epidemiology . finding such a high degree of variability in performance was thus noteworthy .
comparison of data between different hrv studies is confounded as are data from studies seeking to determine the effects of other respiratory viruses .
the prevalence , seasonality , transmission , and clinical effects of hrv types and species require reexamination with tools that have been comparatively validated to ensure their sensitivity .
Output:
| we conducted a preliminary comparison of the relative sensitivity of a cross - section of published human rhinovirus ( hrv)specific pcr primer pairs , varying the oligonucleotides and annealing temperature .
none of the pairs could detect all hrvs in 2 panels of genotyped clinical specimens ; > 1 pcr is required for accurate description of hrv epidemiology . |
PubmedSumm4867 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: during the first decade of the 21st century , global health became prominent on the international political agenda ( fidler , 2005 ) and international financial assistance for health increased substantially ( institute for health metrics and evaluation , 2010 ) . according to fidler ( 2005 )
this was nothing less than a global health revolution , which perhaps came to an end with the global financial crisis that started in 2008 ( fidler , 2008 ) .
but there is a widely shared belief that maternal health missed the boat : a report developed under the auspices of the united nations secretary general in september 2010 argues that the 5th millennium development goal ( mdg ) focusing on maternal health has shown the least progress ( united nations secretary general , 2010 ) .
that same report launched a global strategy for women s and children s health , also known as the every woman every child initiative , which attracted some us$40 billion worth of pledges , to be spent between 2011 and 2015 ( every woman every child , 2010 ) .
if these pledges translate into actual funding , by 2015 maternal health will have caught up with other global health concerns in terms of the volume of funding .
will maternal health really catch up by 2015 ? to answer the question , we will analyse four hypotheses about why it has been lagging behind , and how the every woman every child initiative will address those issues . but first , we want to clarify that this is a paper about global financing for maternal health , and why .
we do not think that financing is the only or even the main factor influencing health outcomes , and we do not think that global financing is more important than national financing .
but we do believe that financing is important , and that global financing creates particular challenges which deserve to be discussed separately .
we do agree with austveg , who regrets that in the global health debate , sexual and reproductive health has been side - lined and that maternal health was singled out as a priority , while maternal health itself has been detached from the comprehensiveness of reproductive health and framed solely in relation to motherhood
maternal health has been singled out , separated from far more contentious issues like abortion and birth control presumably to enhance its attractiveness to international assistance contributors and was nonetheless relatively unsuccessful at attracting funding .
probably the most comprehensive effort to track international assistance for health over the past decades is conducted by the institute for health metrics and evaluation ( ihme ) .
the ihme s financing global health 2010 report contains data about international assistance for health from 1990 to 2008 , adding rough estimates for 2009 and 2010 ( institute for health metrics and evaluation , 2010 ) .
fidler ( 2008 ) argues that the global health revolution unfolded over the preceding 10 - 15 years , and in keeping with this definition we will briefly examine the evolution of global health financing from 1999 to 2008 .
the ihme disaggregates international assistance for health into six specific categories hiv / aids ; maternal , new - born , and child health ; malaria ; health sector support ; tuberculosis ; noncommunicable diseases while the remainder is allocated to another ( less important ) category or considered unallocable. as figure 1 illustrates , a substantial amount of international assistance for health is considered either unallocable or other , that is allocated to a category other than one of the six mentioned above . furthermore
thus there are two considerable margins of error : the unallocable / other assistance that may or may not include support for maternal health efforts , and the unknown weight of maternal health within the category of maternal , new - born and child health . keeping the margins of error in mind , the ihme data does seem to confirm that maternal health has missed the boat .
the total amount of international assistance for health was $ 9,630 million in 1999 and increased to $ 23,870 million in 2008 : or international assistance for health in 2008 reached 248% of its 1999 level .
international assistance for maternal , new - born and child health increased too , but by a smaller percentage : its level in 2008 corresponds to 202% of the 1999 level .
international assistance to fight aids , international assistance to fight tuberculosis , and international assistance to fight malaria all increased by a factor 10 or more . rather than talking about a global health revolution , it may be more accurate to talk about a global aids , tuberculosis and malaria ( atm ) financing revolution , and ask why the fire from that revolution did not jump to maternal health . or perhaps the fire did jump ?
the every woman every child initiative attracted $ 40 billion worth of pledges for maternal , new - born and child health , to be spent between 2011 and 2015 , or $ 8 billion per year ( every woman every child , 2010 ) .
that level of commitment would exceed the volume of global financing to fight atm in 2008 . yet
will the every woman every child initiative effectively address the reasons why maternal health missed the boat until recently ?
we now turn to four hypotheses all seeking to explain why the atm financing revolution left maternal health behind .
several authors link the global atm financing revolution with exceptional aids activism ( ingram , 2009 ) , rooted in a human rights approach ( nixon & forman , 2008 ) . until the mid-1990s , the absence of effective treatment for aids meant that demanding respect for their dignity as humans and for their human rights was more or less the only strategy people living with hiv or aids had .
this human rights based approach evolved into an understanding that enhancing the human rights of people at higher risk of hiv infection could be an effective prevention strategy ( anonymous , 1996 ) . a further step on this human rights path was brazil invoking the right to health to justify its production of generic antiretroviral medicines , arguing that the right to health trumps the international intellectual property rights regime ( galvo , 2005 ) . moving from this position to arguing that the international community as a whole has a shared responsibility to finance life - saving medicines a responsibility shared with the governments of the countries where the people needing the medicines live
indeed , a july 2002 modification of the international guidelines on hiv / aids and human rights issued by the office of the united nations high commissioner on human rights ( ohchr ) and unaids , explicitly mentioned that states should ensure that international and bilateral mechanisms for financing responses to hiv / aids provide funds for prevention , treatment , care and support , including the purchase of antiretroviral and other medicines , diagnostics and related technologies
( office of the united nations high commissioner on human rights , unaids , 2006 ) . whereas the existence of international obligations to provide assistance for the realisation of the right to health remains somewhat controversial ( bueno de mesquita & hunt , 2008 ) , the principle has been quite firmly established for the global aids response .
somehow , aids activists seem to have succeeded in spreading the idea that an hiv positive person not having access to antiretroviral therapy is a human rights violation .
but if an hiv positive person not having access to antiretroviral therapy constitutes a human rights violation and we agree it does then surely every woman dying due to lack of access to emergency obstetric care constitutes a human rights violation too . why did maternal health activists not succeed in spreading that idea ?
it is certainly not because they failed to cast maternal health as a human rights issue they did cast maternal health as a human rights issue .
in fact , the historical relationship between human rights and maternal health , as described by gruskin et al .
both the 1994 international conference on population and development in cairo , egypt , and the 1995 fourth world conference on women in beijing , china two milestones in the advancement of maternal health were explicit about the need to promote and protect women s rights , particularly in matters relating to reproduction and sexuality to improve women s health
analysing factors shaping global political prioritisation of health issues , shiffman and smith mention policy community cohesion : the degree of coalescence among the network of individuals and organisations that are centrally involved with the issue at the global level , and having interviewed 23 individuals centrally involved in the safe motherhood initiative
they report a lack of consensus about appropriate interventions , in particular about emergency obstetric care ( shiffman & smith , 2007 ) . since the launch of the safe motherhood initiative in 1987 , maternal health advocates have been divided over this question , with some arguing that most maternal deaths can not be prevented without emergency obstetric care at the referral hospital ( access to transfusion and c - section ) , and others taking the position that there are more cost - effective interventions , like skilled attendance at delivery , which is about having access to health workers with midwifery skills ( at home or in primary health care centres ) .
although a consensus about the need to have both skilled attendants at birth and emergency obstetric care if needed was fostered by a series on maternal survival in the lancet in 2006 , shiffman and smith report that the divide is not completely over : some expressed strong concern about what to do in the interim , before such facilities could be established , in view of resource scarcity and the difficulty that poor countries faced in expanding care .
governments of countries providing international assistance , governments of countries receiving international assistance , and other actors like non - governmental organisations and international financial institutions generally dislike efforts that are clearly out of reach of the domestic financial capacity .
if a choice can be made between one particular effort that may work , perhaps , and that is cheap enough for the domestic financial capacity , and another effort that will almost certainly work much better but that creates dependency on international assistance , the cheaper intervention will most often be preferred ( ooms , 2006 ) . in the aids response ,
the provision of antiretroviral treatment was central , as there were no cheaper efforts that may have worked . for a few years
, there was a heated debate as to whether antiretroviral therapy should be provided at all with some arguing that using all available resources for prevention would save more lives in the long run ( marseille et al . , 2002a ) .
but among the people and organisations involved with the global aids response , there was consensus .
not aiming for antiretroviral treatment was a death sentence for millions of people , already infected with hiv but still alive . within weeks of publishing their plea for prioritising aids prevention , marseille and colleagues
felt compelled to clarify that both treatment and prevention were needed ( marseille et al . , 2002b ) . for people involved in the global aids response , long term dependency on international assistance is no longer a problem to be avoided , it is a problem to be managed .
( 2010 ) estimate the financing needs of the global aids response until 2031 under different scenarios and conclude that in any case , high burden low income countries will remain dependent on external funding for decades , creating major nancial risks over which they have little control , a problem indeed , but there is no alternative .
that kind of thinking has not yet been adopted by all involved in maternal health at the global level , as the interviews done by shiffman and smith reveal ( shiffman & smith , 2007 ) . as long as these hesitations remain
, international assistance may not increase as it is the demand for emergency obstetric care that will trigger the international assistance for emergency obstetric care .
the national intelligence council of the united states of america , in january 2000 , issued a report in which it stated : as a major hub of global travel , immigration , and commerce , along with having a large civilian and military presence and wide - ranging interests overseas , the united states will remain at risk from global infectious disease outbreaks , or even a bioterrorist incident using infectious disease microbes
the main focus of this report was the hiv / aids epidemic and its long - term consequences .
although recent findings suggest that the global hiv / aids epidemic does not constitute a security threat , the fear
back in 2000 may have contributed to the global atm financing revolution ( de waal , 2010 ) . as mcinnes ( 2009 ) argues , it is not
health that has been securitised , but rather a limited range of health issues , and maternal health was not one of them . the main causes of maternal death in developing countries are haemorrhage , hypertensive disorders , sepsis and infections , complications of unsafe abortion , obstructed labour , anaemia , and hiv / aids ( khan et al . , 2006 )
. most of these causes are not infectious and create no threat to countries providing international assistance .
if the securitisation of global health is what explains the global atm financing revolution , we should not expect anything similar to happen for maternal health , unless we can explain that maternal mortality does create a security threat ( which may require some imagination ) .
comparing former united nations secretary - general kofi annan s call , back in 2001 , for a war chest to fight aids
( stephenson , 2001 ) , with present united nations secretary - general secretary ban ki - moon s call for a strategy to improve women s and children s health ( united nations secretary general , 2010 ) , there are similarities but also striking differences .
a war chest not only sounds more determined than a strategy , it is a different thing .
a war chest was created : the global fund to fight aids , tuberculosis and malaria ( gfatm ) .
no global fund is being envisaged for maternal health . the every woman every child initiative created something else : a commission on information and accountability for women s and children s health .
this commission was not intended to become a permanent one ; it was tasked to develop a mechanism for holding donors accountable for their pledges and holding countries responsible for how well the money is spent , and it proposed an independent expert review group that will be reporting regularly to the un secretary - general on results and resources ( commission on information and accountability for women s and children s health , 2011 ) .
the seven members of the independent expert review group ( ierg ) were appointed in september 2011 .
none of them formally represents a government , which does not come as a surprise as it is supposed to be an independent group .
but that also means that they do not have it in their power to commit financial resources unlike members of the gfatm board .
it may seem illogical to consider that an organisation like the gfatm , merely a tool at the mercy of voluntary global financing , may have had a real impact on global financing
it seems logical to consider the tool as the result of a willingness to provide the global financing , and not the other way around .
allow us to explain this briefly in terms of demand and offer of international assistance .
demand : a need perceived by a country asking for assistance and acknowledged by a country providing the assistance , followed by an offer and discussions about the terms of agreement .
we discussed above that among those involved in the global aids response , there was a consensus about the need to provide antiretroviral treatment , even in low income countries , and even if that created long term dependency on international assistance .
if the global financing that funded antiretroviral treatment in low income countries had not started flowing in 2002 , very soon some people involved in the global aids response may have shifted their attention and energy to efforts that were feasible ( in the absence of additional funding ) .
thus the offer of international assistance for antiretroviral treatment sustained ( and increased ) the
demand. likewise , the existence of the gfatm demonstrated the feasibility of providing antiretroviral therapy and at the same time how inexpensive it was for high income countries : the gfatm showcased that a person needing antiretroviral treatment and not having access to it is a human rights violation . finally , at least some low income country governments were quite reluctant to provide antiretroviral treatment using international assistance . to acknowledge that real solutions require international assistance for decades to come is one thing ; to adopt those real solutions
it requires trust in the continuation of international assistance in the long run , and the track record of international assistance did not warrant such trust .
it was the adoption of antiretroviral treatment as an essential element of the appropriate response , by governments of low income countries , that created the demand but the
there is a promise of $ 40 billion for five years , or $ 8 billion per year , for maternal , new - born and child health ( every woman every child , 2010 ) . but
this promise includes domestic resources and pre - existing international assistance flows that have been confirmed or re - confirmed as serving maternal , new - born and child health purposes . according to some observers ,
the truly additional pledges account for $ 5 billion at best , or $ 1 billion per year ( bustreo & frenk , 2010 ) .
if this $ 1 billion is directed to low income countries arguably where it is most needed it means a little bit more than $ 1 per person per year .
will maternal health advocates have enough trust in the every woman every child initiative and in the ierg to leave their hesitations about the feasibility of emergency obstetric care behind ; to accept dependency on international assistance as a problem that needs to be managed but can not be avoided ; to confirm , loud and clear , that every woman dying because of not having access to emergency obstetric care is a human rights violation perpetrated by an international community unwilling to finance what it takes to avoid these deaths ?
the four hypotheses explained above do not constitute a comprehensive list of factors that may explain why a global atm financing revolution happened and why a global maternal health financing revolution did not happen .
none of the hypotheses can be dissociated from the others , and they can not be verified through some randomised controlled research .
but in as much as they capture part of what happened , they may be useful for forecasting what the future might hold with respect to the promised global maternal health financing revolution .
can maternal health activists be as loud , sharp and intense as aids activists are ?
can they ground their activism in a human rights approach ? the latter , they already have done .
the former seems to be a matter of political choices and willingness rather than ability .
it is more than twenty years since the safe motherhood initiative was launched and maternal health activism carries with it a history that is much older than the history of aids activism , a history that includes some fatalism about poverty being a complex multi - facetted fact of life .
maternal health activists must continue to reject what yamin ( 2008 ) rightfully characterised as failures of political will that are cloaked in claims of resource scarcity .
aids activists did not ignore poverty , but they firmly rejected the idea that poor countries had to aim for poor health care .
maternal health activists must reject any argument that low income countries can not afford to provide essential maternal health services .
but if security in the 21st century relies on cooperation between states , wealthier states can not reject responsibility for deaths due to poverty in poorer states , and at the same time expect poorer states and their inhabitants to feel responsible for deaths due to other causes in wealthier states ( ooms , 2010 ) .
it probably does matter that most causes of maternal death are not infectious and can not spread to wealthier countries .
but a broader perspective on security , one that acknowledges the need for cooperation between states and between humans across borders of states , not only allows us to cast maternal mortality as a security problem but also to highlight it as the most worrisome example of international indifference . can maternal health activists create something like the gfatm , but for maternal health ?
some may have hoped that the global fund for women that was created in 1987 long before the gfatm would assume that role ( global fund for women , 2011 ) .
others advocated for the gfatm to expand its mandate , and to embrace maternal and child health ( cometto et al . , 2009 ) .
but it appears that for the near future the every woman every child initiative may stand in the way of a global fund for women s health or a global fund for health : why create a global fund when we have $ 40 billion worth of pledges , and while the gfatm itself is facing financial difficulties ?
unfortunately , we are not optimistic about the promised global maternal health financing revolution . the gfatm is more than the result of a pre - existing willingness to increase international assistance ; it also was and remains , even in difficult times a mobilising factor ; it is the
offer that sustains the demand. without something similar , the global maternal health financing revolution will probably not occur .
not only should it track commitments and report on key indicators ; it should also critically assess the set - up of which it is part .
if a scheme of pledges without a central global fund does not generate enough trust in the reliability of international assistance , and therefore does not trigger the more ambitious strategies that are needed , the ierg should be the first to acknowledge that failing .
Output:
| the first decade of the new millennium saw an upsurge in global financing for health .
when the world took stock of progress on the millennium development goals in mid-2010 the one addressing maternal health showed the least progress .
did maternal health miss the boat ?
in mid-2010 the secretary - general of the united nations launched a global strategy for women s and children s health , also known as the every woman every child initiative . has the tide now turned in favour of maternal health ?
the authors try to answer this question by first examining whether maternal health really missed out with respect to increased global funding and why this may have occurred .
they then assess whether the new initiative will make a difference by comparing several elements of the approach taken by hiv / aids activist to that of maternal health activists .
they suggest that real progress requires international financing , thus pledges must become robust and reliable commitments .
they conclude that the absence of an organisational structure in the current initiative means the global maternal health financing revolution will probably not happen . |
PubmedSumm4868 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the intra - aortic balloon pump ( iabp ) is used to increase myocardial oxygen perfusion , while at the same time increasing cardiac output and decreasing the workload of the ventricle .
several parameters affect iabp treatment , such as the volume of the balloon , its location in the aorta , its rate of inflation and deflation , and the phase of iabp pumping .
several researchers have examined the effects of various parameters on iabp function in terms of increasing myocardial oxygen perfusion and decreasing the workload of the ventricle . when the volume of blood used to inflate and deflate the balloon increases ,
inflation of the iabp at end - systole and deflation of the iabp at end - diastole were the optimal pumping phase in order to decrease the ventricle workload and increase aortic pressure during diastole , thereby increasing myocardial oxygen perfusion ( 2 ) . to quantify the reduction in workload ,
indirect parameters are used , such as the mean systolic pressure ( 3 ) , product of heart rate and peak systolic pressure ( 3 ) , and pressure - volume area ( 4 ) .
no study has quantified the reduction in workload with iabp directly because experimental methods for documenting and evaluating myocardial energy consumption throughout the ventricular volume are hampered by low spatiotemporal resolution .
however , the previous computational models of the cardiovascular system and iabp used a simple lumped model of the cardiovascular system , which can not calculate the contractile cardiac energy consumption directly .
previously , we developed a computational model of left ventricular assist device support using a three - dimensional electromechanical model of failing canine ventricles together with a lumped model of the circulatory system ( 5 , 6 ) .
this model enabled us to quantify the changes in the local contractile energy consumption of the myocardium . in this study , we incorporated iabp function into the electromechanical model of a ventricle with a lumped model of the circulatory system .
then , we used the model to investigate the changes in the contractile energy consumption of the myocardium with an iabp using different inflation volumes .
the iabp - implanted cardiovascular system model was implemented by combining a three - dimensional ( 3d ) finite element ( fe ) electromechanical model of the failed heart , a lumped model of the circulatory system , and a model of iabp function .
1 shows a schematic of the integrated model ( a ) and myofilament dynamics , which were adapted from rice et al .
we used an anatomically accurate 3d - fe electromechanical model of failing canine ventricles , which incorporated a biophysical representation of cardiac myofilament dynamics ( 8) . the electrical model based on the membrane dynamic model of fox et al .
( 9 ) used magnetic resonance ( mr ) image - based canine ventricle geometry with approximately 1,400,000 nodes and 1,700,000 elements , which were developed using linear interpolation . the mechanical model based on the myofilament dynamic model of rice et al .
( 7 ) used the same canine ventricle geometry with 356 nodes and 172 elements , which were developed using hermite polynomials .
both meshes also have realistic fiber and laminar sheet structural information obtained from the diffusion tensor ( dt ) mr image .
the passive mechanical properties of the myocardium were assumed to be transversely isotropic , hyperelastic , and nearly incompressible , defined by an exponential strain energy function .
the local electrical activation times in the electrical mesh were mapped to the mechanical mesh .
2 shows the electrical activation time mapped to the mechanical mesh . here , the local electrical activation time is defined as the instant at which transmembrane voltage exceeds 0 mv . as an electrical wave propagates through the heart , the depolarization of each myocyte initiates the release of calcium ( ca ) from intracellular stores .
this is followed by the binding of ca to troponin c and cross - bridge cycling .
the cross - bridge cycling forms the basis for contractile protein movement and the development of active tension in the cell , resulting in deformation of the ventricles .
these physiological contractile mechanisms are considered in the myofilament model ( 7 ) . to consider remodeling of the passive electromechanical properties associated with heart failure ( hf )
first , we used the dilated geometry of a canine ventricle with heart failure ( hf ) ( 8) . then , the electrical conductivity was reduced by 30% , allowing for a total electrical activation time of 150 ms , according to the experimental results of helm et al . ( 10 ) .
third , to account for the increased stiffness of the failing myocardium , the passive scaling constant in the strain - energy function was increased fivefold ( 11 ) . finally , to introduce systolic dysfunction , the peak and time constant of the calcium transient function ( [ ca](t ) of eq .
( 7 ) ) , which served as an input , were reduced to 70% of the normal values .
this resulted in a calcium transient with a reduced peak and prolonged relaxation rate , which are the key features of the remodeled ca transient in hf ( 12 ) .
we combined the fe heart model with a lumped model of the circulatory system and iabp to predict the cardiovascular response during iabp therapy .
the model is formulated as an electrical analog model consisting of elements such as resistors , capacitors , and diodes . using the hemodynamic parameters related to blood circulation ,
this model calculates the pressure , volume , and blood flow for each of the six compartments making up the vascular system and atria ( fig .
1 ) : the systemic arteries and veins , pulmonary arteries and veins , left atrium , and right atrium .
individual elements in every compartment are modeled by considering the local resistance to blood flow and compliance of blood vessels .
the inertia of blood is ignored due to its relatively small effect on the canine cardiovascular response .
the four heart valves that surround the ventricles and control the blood flow direction are modeled by diodes and resistances .
briefly , the iabp component was modeled as the time - varying compliance of the systemic arteries . to generalize the patterns of inflation and deflation of an iabp ,
a harmonic waveform was used for the time - varying compliance of the systemic arteries .
the harmonic waveforms for the compliance of the aorta were expressed as follows : ( 1)csa , iabp(t)=csasfiabp(t ) here , csa , iabp is the time - varying compliance of the systemic arteries with the iabp , csa is the compliance of the systemic arteries without the iabp , sfiabp is a scale factor for the iabp , sf is the level of the scale factor , bcl indicates the basic cycle length of the ventricle , and indicates the time shift between the ventricular contraction cycle and iabp inflation cycle .
the sf is major parameter which is proportional to the stroke volume of iabp and related to the pumping compliance of iabp . in this study
, sf was given values of 0.05 , 0.1 , 0.15 , 0.2 , and 0.25 , and was set to 3.66 radians ( 350 ms shift ) , instead of end - systole .
the iabp - implanted cardiovascular system model was implemented by combining a three - dimensional ( 3d ) finite element ( fe ) electromechanical model of the failed heart , a lumped model of the circulatory system , and a model of iabp function .
1 shows a schematic of the integrated model ( a ) and myofilament dynamics , which were adapted from rice et al .
we used an anatomically accurate 3d - fe electromechanical model of failing canine ventricles , which incorporated a biophysical representation of cardiac myofilament dynamics ( 8) . the electrical model based on the membrane dynamic model of fox et al .
( 9 ) used magnetic resonance ( mr ) image - based canine ventricle geometry with approximately 1,400,000 nodes and 1,700,000 elements , which were developed using linear interpolation . the mechanical model based on the myofilament dynamic model of rice et al .
( 7 ) used the same canine ventricle geometry with 356 nodes and 172 elements , which were developed using hermite polynomials .
both meshes also have realistic fiber and laminar sheet structural information obtained from the diffusion tensor ( dt ) mr image .
the passive mechanical properties of the myocardium were assumed to be transversely isotropic , hyperelastic , and nearly incompressible , defined by an exponential strain energy function .
the local electrical activation times in the electrical mesh were mapped to the mechanical mesh .
2 shows the electrical activation time mapped to the mechanical mesh . here , the local electrical activation time is defined as the instant at which transmembrane voltage exceeds 0 mv . as an electrical wave propagates through the heart , the depolarization of each myocyte initiates the release of calcium ( ca ) from intracellular stores .
this is followed by the binding of ca to troponin c and cross - bridge cycling .
the cross - bridge cycling forms the basis for contractile protein movement and the development of active tension in the cell , resulting in deformation of the ventricles .
these physiological contractile mechanisms are considered in the myofilament model ( 7 ) . to consider remodeling of the passive electromechanical properties associated with heart failure ( hf )
first , we used the dilated geometry of a canine ventricle with heart failure ( hf ) ( 8) . then , the electrical conductivity was reduced by 30% , allowing for a total electrical activation time of 150 ms , according to the experimental results of helm et al . ( 10 ) .
third , to account for the increased stiffness of the failing myocardium , the passive scaling constant in the strain - energy function was increased fivefold ( 11 ) . finally , to introduce systolic dysfunction , the peak and time constant of the calcium transient function ( [ ca](t ) of eq .
( 7 ) ) , which served as an input , were reduced to 70% of the normal values .
this resulted in a calcium transient with a reduced peak and prolonged relaxation rate , which are the key features of the remodeled ca transient in hf ( 12 ) .
we combined the fe heart model with a lumped model of the circulatory system and iabp to predict the cardiovascular response during iabp therapy .
the model is formulated as an electrical analog model consisting of elements such as resistors , capacitors , and diodes . using the hemodynamic parameters related to blood circulation ,
this model calculates the pressure , volume , and blood flow for each of the six compartments making up the vascular system and atria ( fig .
1 ) : the systemic arteries and veins , pulmonary arteries and veins , left atrium , and right atrium .
individual elements in every compartment are modeled by considering the local resistance to blood flow and compliance of blood vessels .
the inertia of blood is ignored due to its relatively small effect on the canine cardiovascular response .
the four heart valves that surround the ventricles and control the blood flow direction are modeled by diodes and resistances .
briefly , the iabp component was modeled as the time - varying compliance of the systemic arteries . to generalize the patterns of inflation and deflation of an iabp ,
a harmonic waveform was used for the time - varying compliance of the systemic arteries .
the harmonic waveforms for the compliance of the aorta were expressed as follows : ( 1)csa , iabp(t)=csasfiabp(t ) here , csa , iabp is the time - varying compliance of the systemic arteries with the iabp , csa is the compliance of the systemic arteries without the iabp , sfiabp is a scale factor for the iabp , sf is the level of the scale factor , bcl indicates the basic cycle length of the ventricle , and indicates the time shift between the ventricular contraction cycle and iabp inflation cycle .
the sf is major parameter which is proportional to the stroke volume of iabp and related to the pumping compliance of iabp . in this study , sf was given values of 0.05 , 0.1 , 0.15 , 0.2 , and 0.25 , and was set to 3.66 radians ( 350 ms shift ) , instead of end - systole .
2 shows the simulated pressure waveforms in the lv and systemic artery under hf ( a ) , and hf with the iabp operating at level 1 ( sf=5% , b ) , 2 ( sf=10% , c ) , 3 ( sf=15% , d ) , 4 ( sf=20% , e ) , and 5 ( sf=25% , f ) .
the mean arterial pressure under hf was 125 mmhg , which matches that in congestive heart failure .
as the level of iabp treatment was increased , the aortic pressure during diastole , which is related to coronary perfusion , increased and the left ventricular peak pressure during systole , which is related to the after - load , decreased .
3 shows the calculated transmural distribution of the contractile atp consumption rates at end systole and end diastole for hf without an iabp ( fig .
3a ) , and the model with the iabp operating at level 5 ( fig .
the atp consumption rate changed significantly in the left ventricle rather than the right during systole .
the contractile atp consumption decreased significantly in the presence of the iabp . compared with the case involving hf without an iabp ,
the contractile atp consumption decreased by 12% with iabp therapy ( see the atp consumption rate in table 2 ) .
4 shows the calculated transmural distribution of the fiber strain at end systole and end diastole for hf without an iabp ( fig .
5 shows the pressure - volume curves for the six cases studied : hf without iabp therapy , and hf with the iabp at levels 1 to 5 .
6 ) ; this indicates that the iabp results in ventricular volume unloading by reducing the end - diastolic volume . table 2
shows the hemodynamic responses for hf and hf with the iabp at levels 1 to 5 .
while the cardiac output and stroke volume increased , the stroke work and atp consumption decreased with iabp therapy due to the pressure unloading effect .
the decreased left ventricular peak pressure also indicates the pressure unloading effect during iabp therapy .
this study investigated the changes in the contractile energy consumption of the myocardium with iabp with different inflation volumes using a cardiac electromechanical model with a lumped model of the circulatory system and iabp function . to generalize the patterns of inflation and deflation of the iabp , a harmonic waveform was used for the time - varying compliance of the systemic arteries . according to the iabp inflation volume , the arterial pressure increased during diastole , while the ventricular peak pressure decreased , which indicates improved coronary perfusion and ventricular unloading . to estimate the change in the ventricular workload
the transmural distribution of the mechanical strain was also compared between hf ventricles and hf ventricles with an iabp at level 5 in order to estimate the volume - unloading effect of the iabp ( fig .
, the sarcomere length affects the density of effective cross - bridges and therefore the contractile force ; this is known as the frank - starling law of the heart . a longer sarcomere length results in greater contractile atp consumption because of the greater density of the attached cross bridges in myocytes , as expressed in eq . 3 in the appendix .
previously , we demonstrated that myofibers in the endocardium have greater end - diastolic lengths than myofibers in the mid - myocardium and epicardium ( 6 ) .
4 also shows that the end - diastolic strain and atp consumption rate of the endocardial sarcomere are greatest .
this explains why the contractile atp consumption by the endocardium was greater than that at the mid - wall or epicardium ( figs . 3 and 4 ) . the cardiac output , stroke volume , stroke work , map , atp consumption rate , and ejection fraction
interesting point is that although the atp consumption is decreased significantly , stroke work is decreased only slightly , which indicates that the iabp helps the failed ventricle to pump blood efficiently .
we used an image - based electromechanical model of failing canine ventricles , in which the ventricular geometry , fiber architecture , and hemodynamics differ from those of human ventricles .
we also considered only the contractile atp consumption of the myocardium , although atp is used in other ways , such as by sarcoplasmic / endoplasmic reticulum calcium atpase ( serca ) , plasma membrane ca - atpase ( pmca ) , and na pumps .
finally , we did not considered remodeled electrical activities of myocardial cell in failing heart .
we assumed that the electrical conductivity changes in tissue level encapsulated those changes in cellular level .
we conclude that iabp improves coronary perfusion as well as pressure unloading and volume unloading and also helps the failed ventricle to pump blood more efficiently .
the contractile energy consumption of the myocardium was quantified by calculating the contractile atp consumption in the myofilament model of rice et al . ( 7 ) . the contractile atp consumption rate , e , per unit volume was calculated as a function of the atp - consuming cross - bridge detachment rate ( gxbt ) and the single overlap fraction of thick filaments ( sovfthick ) , where gxbt , which indicates the atp - consuming detachment transition rate , and sovfthick , which indicates the single - overlap fraction of the thick filament , were functions taken from the original myofilament model of rice et al .
then , gxbt can be derived as : the term xbmodspecies scales all cross - bridge cycling rates to account for species - based differences ( 0.2 for canines ) .
the temperature dependence of gxbt ( qgxbt ) is set to a default q10 value of 6.25 .
the term gxbt had strain dependence in the rate modifier gxbmd , defined as : where p and n set the effects of strain for positive and negative shortening velocities , respectively ; xo is the distortion of the cross - bridge head ; xxbpostr is the mean distortion of states xxbpostr , which is the probability of the transition to the post - rotated force - generating status .
the atp - consuming detachment transition rate gxbt is proportional to gxbmd , which depends on the strain of the cross bridges , and in turn , this strain depends on the velocity of contraction
finally , we calculated the atp consumption distribution by integrating the atp consumption rate with time for 600 ms and the atp consumption of the entire ventricle by spatially integrating the local atp consumption through the entire ventricular volume .
Output:
| to quantify the reduction in workload during intra - aortic balloon pump ( iabp ) therapy , indirect parameters are used , such as the mean arterial pressure during diastole , product of heart rate and peak systolic pressure , and pressure - volume area .
therefore , we investigated the cardiac energy consumption during iabp therapy using a cardiac electromechanics model .
we incorporated an iabp function into a previously developed electromechanical model of the ventricle with a lumped model of the circulatory system and investigated the cardiac energy consumption at different iabp inflation volumes .
when the iabp was used at inflation level 5 , the cardiac output and stroke volume increased 11% , the ejection fraction increased 21% , the stroke work decreased 1% , the mean arterial pressure increased 10% , and the atp consumption decreased 12% .
these results show that although the atp consumption is decreased significantly , stroke work is decreased only slightly , which indicates that the iabp helps the failed ventricle to pump blood efficiently . |
PubmedSumm4869 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: snoring is caused by vibration of the soft tissue during sleep while breathing within extrathoracal respiratory tract .
pathological reasons for the noise include tension loss in the oropharyngeal muscle due to disturbed innervation , degenerative processes , tumours , and changes in the mucous membranes . in general ,
the snorer 's sleep profile and the cardiovascular situation are undisturbed , thus snoring does not affect a snorer 's general health situation , but it can significantly impair social life and marital relation .
if , in addition to snoring , the patient complains about clinical symptoms such as excessive daytime sleepiness , reduced efficiency , morning headache , high blood pressure , and arrhythmias , a sleep - related breathing disorder should be suspected .
this disorder has a considerable and even life - threatening medical impact on a patient 's general health .
the correlation between increased morbidity and morality and moderate and severe expression of obstructive sleep apnoea syndrome has been proved .
therefore , the diagnosis must be made according to a differential diagnostic process . in the west , snoring is a common disorder , with an estimated prevalence of 28% in women and 45% in men in the age average of 30 to 60 years ; approximately 5% of these patients suffer from sleep disordered breathing .
the main risks for a sleep breathing disorder are an increased body mass index , increased age , and male sex .
a family predisposition , hormone status , the anatomy of the extrathoracal airway , the neck circumference and general behavioural factors such as alcohol consumption , use of sedatives , sleeping in a supine position , and a lack of general sleep hygiene can also trigger or cause sleep - disordered breathing .
when women go though the hormonal changes they too have a higher incidence of snoring . with most patients ,
sleep - disordered breathing is caused by partial or complete obstruction of the upper airways .
in rare cases it can also have centrally - placed source of obstruction . a precise , differential diagnosis is required before the onset of oral protrusive appliance treatment , since these devices are effective exclusively in obstructive sleep apnoea syndrome ( osas ) .
the diagnostic process in osas includes taking the medical history , physical examination , and a cardio - respiratory sleep study . in a cardio - respiratory sleep study , parameters such as the peripheral oxygen saturation and desaturation , pulse , oral and nasal flow , sleep position , paratracheal noises ; occasionally additional parameters are recorded . if cardio - respiratory sleep examination fails to provide a precise diagnosis , polysomnography in a sleep laboratory
this entails an electric encephalogram , so that the cardio - respiratory parameters can be analysed together with the patient 's sleep profile .
oral protrusive appliances are increasingly used in primary snoring and mild - to - moderate obstructive sleep disordered breathing .
an anterior and caudal movement of the mandible during sleep reduces the amount of nasopharyngeal obstructions and snoring in mild to moderate osa considerably .
a mandibular advancement enlarges the pharyngeal airway during sleep thus tightening and stabilising the pharyngeal soft tissue .
adjustment of the mandibular protrusion and pharyngeal opening is anatomically restricted to a certain degree .
described the positive effect of a mandibular advancement device , the so - called esmarch - orthese , on the respiratory situation during sleep for the first time .
the esmarch - orthese is designed like a modified function orthodontic appliance , since it moves the mandible into a protruded and fixed position . to date , other appliances , such as tongue - retaining devices , soft palatinal lifters , and functional training devices have not gained medical acceptance because there is still no adequate scientific proof that these appliances treat snoring and obstructive sleep apnoea effectively .
the mandibular protrusive appliances used for treating snoring and osas vary in their effectiveness , manufacture , material , ability to adjust mandibular protrusion , need of dental retention , durability , wearing comfort , expected side effects , efficacy , and expense ( table 1 ( tab .
the efficacy of two splints appliances fixed on the teeth of the upper and lower jaw has been proved .
the connection system should allow minor jaw movements and can be placed in anterior , buccal , interocclusal or palatinal position within the appliance ( figures 1 ( fig .
there is a vital clinical advantage that the patient can adjust the mandible protrusion himself according to need and his subjective tolerance .
to evaluate the efficacy of oral appliance treatment , parameters such as snoring noise , cardiovascular situation , and daytime sleepiness must be considered .
although oral appliances reduce habitual snoring considerably in some cases , snoring can persist during appliance use cause for this it are body position , alcohol , weight gain , and allergies . the data presented in the literature reveals great divergence regarding the therapeutic effectiveness of oral appliances .
treatment improvement varies from 40% to 83% when one considers the reference parameter rdi ( respiratory disturbance index ) and/or ahi ( apnea -hypopnea index ) .
the difference can be sufficiently explained by different patient selection , inclusion criteria , indications , and the polygraphic and polysomnographic control examinations employed .
oral protrusive appliances affect daytime systolic blood pressure and the diastolic pressure during 24-hour blood pressure recording .
the consistent application of an oral protrusive appliance during sleep reduces those blood pressure values significantly in patients with osas .
there has so far been present no systematically - controlled study examining the specific influence of the treatment modality in affecting in daytime sleepiness and sleep profile .
concerning side - effects caused by oral appliances , we must differentiate between discomfort and long term effects . at the beginning of treatment , patients may complain about increased salivation , tenderness in the masticatory muscle and temporomandibular joint , and occlusion disturbances .
these forces can lead to a retrusion of the upper front teeth and a protrusion of the lower front teeth as well as to an anterior and lateral bite opening .
in general , the extent of dental - side effects depends mainly on the extent of mandibular protrusion , the dental and periodontal situation at the onset of the treatment , and the length of time the appliance is used by the patient .
although side - effects appear frequently during oral appliance treatment ; they are usually mild and clinically acceptable .
if side - effects do occur , continuation of the treatment must be re - evaluated .
two splint appliances covering the entire dental arch of the clinical crowns seem to be superior to those fixed with clamps because of fewer dental side - effects .
dental side - effects can be reduced significantly via functional load on the teeth , e.g. by chewing hard chewing gum . to date , structural changes in the temporomandibular joint by mandibular protrusion during sleep have not been described in the literature .
removable dentures , periodontal diseases , acute infections , temporomandibular dysfunction , as well as epilepsy are regarded as contraindications for this kind of treatment .
a dental based contraindication was diagnosed in about 30% of those patients revered from the sleep - laboratory to a dentist for oral appliance therapy , .
the main advantages of oral appliances are the relative simplicity of the treatment , its non - invasiveness , its reversibility , and cost - effectiveness .
an appliance is easy to transport , to clean and maintain , and it require no electricity . in comparative studies of oral appliances and cpap ( continuous positive airway pressure ) ,
in summary , mandibular protrusive appliances remove or fundamentally reduce snoring 's frequency and volume . prior to initiating oral appliance use ,
however , the presence of characteristic of sleep apnoea syndrome must be examined by performing a sleep study .
oral appliances are indicated in snoring and mild - to - moderate osas only . from the dental point of view , adequate dental anchorage and a healthy stomatognathic situation
is required to guarantee adequate mandibular protrusion during sleep and to reduce dental side effects .
treatment efficacy should be evaluated in regular sleep studies with the patient wearing the appliance .
dental follow - ups are necessary with permanent use to monitor occlusion , the bite , and to ensure correct appliance fit . other less invasive treatment such as better sleep hygiene , positioning training , and weight reduction must be considered to minimise side - effects .
Output:
| oral appliances have long been used to treat snoring and mild to moderate obstructive sleep apnoea .
this kind of treatment is considered an alternative , non - invasive treatment option .
mandibular protrusive appliances enlarge and stabilise the oro- and hypo - pharyngeal airway space by advancing the mandible , and stretching the attached soft tissue , in particular the tongue , soft palate , uvula , and the pharyngeal tissues .
this article summarises the indications , contraindications , and possible side - effects of using oral appliances .
therapeutic efficacy is influenced by multiple parameters that are clinically difficult to control .
one major parameter is the patient`s stomatognathic situation of the patient .
thus oral appliances are restricted to patients whose dental retention is adequate for permanent treatment and who do not suffer from temporomandibular joint dysfunction .
regular follow - up sleep studies and dental evaluations are necessary to ensure adequate permanent treatment . |
PubmedSumm4870 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: as the global suicide rate increases by 60% in 50 years in the underdeveloped and developing countries , paraphenylenediamine ( ppd ) poisoning is emerging as an important etiological factor reported from india .
ppd ingestion is a very common form of poisoning in india as this compound is a component of hair dyes and is easily available .
it is brown or black colored solid substance , easily soluble in hydrogen peroxide and not in water .
it is a good hydrogen donor and metabolized by electron oxidation to an active radical by cytochrome p450 peroxidase to form a reactive compound called benzoquinone diamine .
this can be further oxidized to a trimer known as brandowaski 's base , a well known compound , reported to cause anaphylaxis and mutation .
it is traditionally used for dyeing palms and soles along with henna and to dye the hairs .
ingestion of ppd causes rapid development of edema of the face , neck , pharynx , tongue and larynx initially and rhabdomyolysis later
. finally , an acute renal failure supervenes as renal tubular necrosis occurs due the deposits of the toxic metabolites of ppd .
a 24-year - old young man who had ingested ppd pellets ( an exact amount could not be ascertained ) with suicidal intention .
he developed generalized itching and intermittent lacrimation for a few days and was treated symptomatically by a nearby medical practitioner from whom he concealed the history of consumption of ppd pellets .
he presented after 6 days with complaints of pain and stiffness of both lower limbs and passage of chocolate colored urine followed by anuria .
his blood urea and serum creatinine were 210 mg / dl and 12.4 mg / dl , respectively .
he was managed symptomatically with diuretics , phosphate binders , sodium bicarbonate , oral calcium and alkalization of urine . in view of his persistent oliguria and deranged metabolic parameters ,
myocarditis , myocardial rhabdomyolysis and shock have also been described in ppd poisoning . though the cervicofacial edema is also a common manifestation , it was not a prominent clinical feature in this case .
the alteration in the prominent clinical features may be due to the symptomatic management in the initial stages .
the major cause of mortality is respiratory distress due to edema , complications related to myocarditis and renal .
the cause of acute tubular necrosis in ppd poisoning , independent of rhabdomyolysis is due to concentration of ppd in the renal tubules .
this occurs due to aromatic structure of ppd , which makes it readily absorbable and concentrated in the tubules .
gastric lavage with 2% sodium bicarbonate is also effective . due to low molecular weight and hydrophilic nature
an acute renal failure is managed with adequate input and output charting , treating metabolic complications due to renal failure like hyperkalemia , hypocalcemia , hyperphosphatemia and metabolic acidosis by hemodialysis .
renal biopsy may be done when there is undue delay in recovery of renal function .
apart from an intentional or accidental excessive exposure to ppd , which results in above manifestations , routine use of this compound on regular basis for a long time can also lead to toxic effects .
association between personal hair dye use and non - hodgkin 's lymphoma , multiple myeloma , leukemia and other bladder cancer have been reported but have not been consistently observed .
however , the united states environmental protection agency has not classified ppd as a carcinogen . therefore , no warnings of toxicity are printed on boxes of hair dye .
but , in view of an easy availability and potential toxicity , awareness about the toxic effects of this compound and adequate warnings for the users may be useful .
Output:
| the commonest constituent of all hair dyes is paraphenylene diamine ( ppd ) .
hair dye poisoning is emerging as one of the emerging causes of intentional self - poisoning to commit suicide . in this article
, we report a case of ppd poisoning and the importance of clinical of hair dye poisoning .
the lack of specific diagnostic tests , a specific antidote for paraphenylene diamine poisoning and the importance of early supportive treatment modalities are also discussed . |
PubmedSumm4871 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: crystal nucleation in liquids has countless practical consequences
in science and technology , and it also affects our everyday experience .
one obvious example is the formation of ice , which influences global
phenomena such as climate change , as well as
processes happening at the nanoscale , such as intracellular freezing . on the other hand , controlling nucleation of molecular crystals
from solutions is of great importance to pharmaceuticals , particularly
in the context of drug design and production , as the early stages
of crystallization impact the crystal polymorph obtained .
even the multibillion - dollar oil industry is affected by the nucleation
of hydrocarbon clathrates , which can form inside pipelines , endangering
extraction .
finally , crystal nucleation is involved
in many processes spontaneously occurring in living beings , from the
growth of the beautiful nautilus shells to the dreadful formation in our own brains of amyloid fibrils ,
which are thought to be responsible for many neurodegenerative disorders
such as alzheimer s disease .
each
of the above scenarios starts from a liquid below its melting
temperature .
this supercooled liquid(12 ) is doomed , according to thermodynamics , to face a first - order
phase transition , leading to a crystal . before this
can happen , however , a sufficiently large cluster of crystalline atoms
( or molecules or particles ) must form within the liquid , such that
the free energy cost of creating an interface between the liquid and
the crystalline phase will be overcome by the free energy gain of
having a certain volume of crystal .
this event stands at the heart
of crystal nucleation , and how this process has been , is , and will
be modeled by means of computer simulations is the subject of this
review .
the past few decades have witnessed an impressive body
of experimental
work devoted to crystal nucleation .
for instance , thanks to novel
techniques such as transmission electron microscopy at very low temperatures
( cryo - tem ) , we are now able to peek in real time into the early stages
of crystallization
. a substantial effort
has also been made to understand which materials , in the form of impurities
within the liquid phase , can either promote or inhibit nucleation
events , a common scenario known as heterogeneous
nucleation . however , our understanding of crystal nucleation is far
from being complete .
this is because the molecular ( or atomistic )
details of the process are largely unknown because of the very small
length scale involved ( nanometers ) , which is exceptionally challenging
to probe in real time even with state - of - the - art measurements .
hence ,
there is a need for computer simulations , and particularly molecular
dynamics ( md ) simulations , where the temporal evolution of the liquid
into the crystal is more or less faithfully reproduced .
unfortunately ,
crystal nucleation is a rare event that can occur on time scales of
seconds , far beyond the reach of any conventional md framework . in
addition , a number of approximations within the computational models ,
algorithms , and theoretical framework used have been severely questioned
for several decades .
although the rush for computational methods able
to overcome this time - scale problem is now more competitive than ever ,
we are almost always forced to base our conclusions on the ancient
grounds of classical nucleation theory ( cnt ) , a powerful theoretical
tool that nonetheless dates back 90 years to volmer and weber .
in fact , these are exciting times for
the crystal nucleation community ,
as demonstrated by the many reviews covering several aspects of this
diverse field .
this particular review is focused almost exclusively on md simulations
of crystal nucleation of supercooled liquids and supersaturated solutions .
we take into account several systems , from colloidal liquids to natural
gas hydrates , highlighting long - standing issues as well as recent
advances .
although we review a substantial fraction of the theoretical
efforts in the field , mainly from the past decade , our goal is not
to discuss in detail every contribution .
instead , we try to pinpoint
the most pressing issues that still prevent us from furthering our
understanding of nucleation .
we
introduce the theoretical framework of cnt ( section 1.1 ) , the state - of - the - art experimental techniques
( section 1.2 ) , and
the md - based simulation methods ( section 1.3 ) that in the past few decades have provided
insight into nucleation . in section 2 , we put such computational approaches into context ,
describing both achievements and open questions concerning the molecular
details of nucleation for different types of systems , namely , colloids
( section 2.1 ) , lennard - jones
( lj ) liquids ( section 2.2 ) , atomic liquids ( section 2.3 ) , water ( section 2.4 ) , nucleation from solution ( section 2.5 ) , and natural gas hydrates ( section 2.6 ) . in the third
and last part of the article ( section 3 ) , we highlight future perspectives and open challenges
in the field .
almost
every computer simulation of crystal nucleation in liquids invokes
some elements of classical nucleation
theory ( cnt ) .
this theory has been discussed in great detail elsewhere , and we describe it here for the sake of completeness and also to
introduce various terms used throughout the review .
cnt was formulated 90 years ago
through the contributions of volmer and weber , farkas , becker and dring , and zeldovich , on
the basis of the pioneering ideas of none other than gibbs himself .
cnt was created to describe the condensation
of supersaturated vapors into the liquid phase , but most of the concepts
can also be applied to the crystallization of supercooled liquids
and supersaturated solutions . according to cnt ,
clusters of crystalline
atoms ( or particles or molecules ) of any size are treated as macroscopic
objects , that is , homogeneous chunks of crystalline phase separated
from the surrounding liquid by a vanishingly thin interface .
this
apparently trivial assumption is known as the capillarity approximation ,
which encompasses most of the strengths and weaknesses of the theory .
according to the capillarity approximation , the interplay between
the interfacial free energy , , and the difference in
free energy between
the liquid and the crystal , , fully describes the thermodynamics of
crystal nucleation . in three dimensions , the free energy of formation , , for a spherical crystalline nucleus of
radius r
can thus be written as the sum of a surface
term and a volume term1this function , sketched in figure 1 , displays a maximum corresponding
to the so - called critical nucleus size n*2where is the number density of the crystalline
phase .
the critical nucleus size represents the number of atoms that
must be included in the crystalline cluster for the free energy difference , , to match the free energy cost due to the
formation of the solid liquid interface .
clusters of crystalline
atoms occur within the supercooled liquid by spontaneous , infrequent
fluctuations , which eventually lead the system to overcome the free
energy barrier for nucleation3triggering the actual crystal growth ( see figure 1 ) .
sketch of the free energy
difference , , as a function of the crystalline nucleus
size n. a free energy barrier for nucleation , , must
be overcome to proceed from the ( metastable )
supercooled liquid state to the thermodynamically stable crystalline
phase through homogeneous nucleation ( purple ) .
heterogeneous nucleation
( green ) can be characterized by a lower free energy barrier , , and a smaller critical nucleus size , nhet * , whereas
in the case of spinodal decomposition ( orange ) , the supercooled
liquid is unstable with respect to the crystalline phase , and the
transformation to the crystal proceeds in a barrierless fashion .
the
three snapshots depict a crystalline cluster nucleating within the
supercooled liquid phase ( homogeneous nucleation ) or as a result of
the presence of a foreign impurity ( heterogeneous nucleation ) , as
well as the simultaneous occurrence of multiple crystalline clusters
in the unstable liquid .
this scenario is often labeled as spinodal
decomposition , although the existence of a genuine spinodal decomposition
from the supercooled liquid to the crystalline phase has been debated
( see text ) .
the kinetics of crystal
nucleation is typically addressed by assuming
that no correlation exists between successive events increasing or
decreasing the number of constituents of the crystalline nucleus .
in other words , the time evolution of the nucleus size
is presumed
to be a markov process , in which atoms in the liquid either order
themselves one by one in a crystalline fashion or dissolve one by
one into the liquid phase .
in addition , we state that every crystalline
nucleus lucky enough to overcome the critical size n * quickly grows to macroscopic dimensions on a time scale much smaller
than the long time required for that fortunate fluctuation to come
about .
if these conditions are met , the
nucleation rate , that is , the probability per unit time per unit volume
of forming a critical nucleus does not depend on time , leading to
the following formulation of the so - called steady - state nucleation
rate 4where kb is the
boltzmann constant and is a prefactor that we discuss
later .
the
steady - state nucleation rate is the central quantity in the description
of crystallization kinetics , as much as the notion of critical nucleus
size captures most of the thermodynamics of nucleation .
all
quantities specified up to now depend on pressure and most
notably temperature . in most cases , the interfacial free energy , ,
is assumed to be linearly
dependent on
temperature , whereas the free energy difference between the liquid
and solid phases , , is proportional to the supercooling , ( or the supersaturation ) .
several approximations
exist to treat the temperature dependence of ( 36 ) and , which can
vary substantially for different supercooled liquids . in any case
, it follows from eq 3 that the free energy barrier for nucleation , decreases with supercooling . in other words ,
the farther one is from the melting temperature , the larger the thermodynamic driving force
for nucleation is .
interestingly , in the case of supercooled
liquids , kinetics goes
the other way , as the dynamics of the liquid slow down with supercooling ,
thus hindering the occurrence of nucleation events .
in fact , although
a conclusive expression for the prefactor the latter is still lacking , it is usually written within cnt
as5where is the number of possible
nucleation sites
per unit volume , is the zeldovich
factor ( accounting for the fact that several postcritical
clusters might
still shrink without growing into the crystalline phase ) , and is a kinetic prefactor .
the latter should represent the attachment
rate , that is , the frequency with which the particles in
the liquid phase
reach the cluster rearranging themselves in a crystalline fashion .
however , in a dense supercooled liquid , also
quantifies the ease with which the
system explores configurational space , effectively regulating the
amplitude of the fluctuations possibly leading to the formation of
a crystalline nucleus . in short
, we can safely say that involves the atomic or molecular
mobility
of the liquid phase , more often than not quantified in terms of the
self - diffusion coefficient , which obviously
decreases with supercooling .
thus , for a supercooled liquid , the competing
trends of and lead , in the case of diffusion - limited
nucleation , to a maximum in the nucleation
rate , as depicted in figure 2 .
the same arguments apply when dealing with processes such
as the solidification of metallic alloys . in the case of nucleation from solutions , and
however ,
the dependence of the kinetic prefactor on supersaturation is much
weaker than the temperature dependence of characteristic
of supercooled liquids .
as a result
, there is usually no maximum in the nucleation rate as
a function of supersaturation for nucleation from solutions .
illustration of how certain quantities from cnt vary as
a function
of supercooling , t , for supercooled liquids .
the free energy difference between the liquid and the solid phase , the interfacial free energy , and the kinetic prefactor are reported as functions of t in a generic case of diffusion - limited nucleation , characterized
by a maximum in the steady - state nucleation rate .
is zero at the melting temperature , and is vanishingly
small at the glass transition
temperature .
although is supposed to play a minor role
compared
to the exponential term in eq 4 , the kinetic prefactor has been repeatedly blamed for the
quantitative disagreement between experimental measurements and computed
crystal nucleation rates .
atomistic simulations
could , in principle , help to clarify the temperature dependence as
well as the microscopic origin of and also
of the thermodynamic ingredients
involved in the formulation of cnt .
however , quantities such as are not only infamously
difficult to converge
within decent levels of accuracy but can even
be ill - defined in many situations .
for instance , it remains to be
seen whether , which , in principle ,
refers to a planar
interface under equilibrium conditions , can be safely defined when
dealing with small crystalline clusters of irregular shapes .
in fact ,
the early stages of the nucleation process often involve crystalline
nuclei whose size and morphology fluctuate on a time scale shorter
than the structural relaxation time of the surrounding liquid . moreover ,
the dimensions of such nuclei can be of the same order as the diffuse
interface between the liquid and the solid phases , thus rendering
the notion of a well - defined value quite dangerous .
as an example , joswiak
et al .
recently showed that , for liquid
water droplets , can strongly depend on
the curvature of
the droplet .
the mismatch between the macroscopic interfacial free
energy and its curvature - dependent value can spectacularly affect
water - droplet nucleation , as reported by atomistic simulations of
droplets characterized by radii on the order of 0.51.5
nm .
some other quantities , such as the size of the critical cluster ,
depend in many cases rather strongly on the degree of supercooling .
this is the case , for example , for the critical nucleus size n * , which can easily span 2 orders of magnitude in just
10 c of supercooling .
given the old
age of cnt , it is no surprise that substantial efforts have been devoted
to extend and/or improve its original theoretical framework .
the most
relevant modifications possibly concern the issue of two - step nucleation .
many excellent works have reviewed this subject extensively ( see ,
e.g. , refs ( 18 , 24 , 52 , and 53 ) ) , so that
we provide only the essential concepts here . in the original
formulation of cnt , the system has to overcome a single free energy
barrier , corresponding to a crystalline nucleus of a certain critical
size , as depicted in figure 3 . when dealing with crystal nucleation from the melt , it is
rather common to consider the number of crystalline particles within
the largest connected cluster , n , as the natural
reaction coordinate describing the whole nucleation process . in many
cases ,
the melt is dense enough that local density fluctuations are
indeed not particularly relevant and the slow degree of freedom is
in fact the crystalline ordering of the particles within the liquid
network .
however , one can easily imagine that , in the case of crystal
nucleation of molecules in solutions , for example , the situation can
be quite different .
specifically , in a realistically supersaturated
solution , a consistent fluctuation of the solute density ( concentration )
could be required just to bring a number n of solute molecules close enough to form a connected cluster . assuming
that the molecules involved in such a density fluctuation will also
order themselves in a crystalline fashion on exactly the same time
scale is rather counterintuitive .
schematic comparison of one - step versus
two - step nucleation for
a generic supersaturated solution .
( a ) sketch of the free energy difference
gn , n as a function of the number of solute molecules
in the largest connected
cluster ( they can be ordered
in a crystalline fashion or not ) ( n ) and of the number of crystalline molecules within the largest connected
cluster ( n ) .
the one - step mechanism predicted by
cnt ( purple ) is characterized by a single free energy barrier for
nucleation , gn , n,one - step*. in contrast , the two - step nucleation
requires a free energy barrier , gn,two - step * , to be overcome through a local density
fluctuation of the solution , leading to a dense , but not crystalline - like ,
precursor .
the latter can be unstable ( green ) or stable ( orange ) with
respect to the liquid phase , being characterized by a higher ( green )
or lower ( orange ) free energy basin .
once this dense precursor has
been obtained , the second step consists of climbing a second free
energy barrier , gn , two - step * , corresponding
to the ordering of the solute molecules within the precursor from
a disordered state to the crystalline phase .
( b ) one - step ( purple )
and two - step ( green and orange ) nucleation mechanisms visualized in
the density ( n)ordering
( n ) plane .
the one - step mechanism proceeds along
the diagonal , as both n and n increase at the same time in such a way that a single
free energy barrier has to be overcome . in this scenario ,
the supersaturated
solution transforms continuously into the crystalline phase . on the
other hand , within a two - step nucleation scenario ,
the system has
to experience a favorable density fluctuation along n first , forming a disordered precursor that , in
a second step , orders itself in a crystalline fashion , moving along
the ( n ) coordinate and ultimately leading to the
crystal .
in fact , the formation of crystals
from molecules in solution often
occurs according to a two - step nucleation mechanism that has no place
in the original formulation of cnt . in the prototypical scenario
depicted
in figure 3 , a first
free energy barrier , gn,two - step * , has to be overcome by means of a density
fluctuation of the solute , such that a cluster of connected molecules
of size n * is formed .
this object does not yet have any
sort of crystalline order , and depending on the system under consideration ,
it can be either unstable or stable with respect to the supersaturated
solution ( see figure 3 ) .
subsequently , the system has to climb a second free energy barrier ,
gn , two - step * , to order the molecules within the dense
cluster in a crystalline - like fashion .
a variety of different nucleation
scenarios have been loosely labeled as two - step , from crystal nucleation
in colloids ( see section 2.1 ) or lennard - jones liquids ( see section 2.2 ) to the formation of crystals of urea
or nacl ( see section 2.5 ) , not to mention biomineralization ( see , e.g. , refs ( 18 and 53 ) ) and protein crystallization ( see , e.g. , refs ( 54 and 55 ) ) . in all of these cases , cnt as it is formulated is simply
not capable
of dealing with two - step nucleation .
this is why , in the past few
decades , a number of extensions and/or modifications of cnt have been
proposed and indeed successfully applied to account for the existence
of a two - step mechanism . here , we mention the phenomenological theory
of pan et al . , who wrote an expression
for the nucleation rate assuming a free energy profile similar to
the one sketched in figure 3 , where dense metastable states are involved as intermediates
on the path toward the final crystalline structure .
the emergence
of so - called prenucleation clusters ( pncs ) , namely , stable states
within supersaturated solutions , which are known to play a very important
role in the crystallization of biominerals , for example , was also
recently fit into the framework of cnt by hu et al .
they proposed a modified expression for the excess free
energy of the nucleus that takes into account the shape , size and
free energy of the pncs as well as the possibility for the pncs to
be either metastable or stable with respect to the solution .
a comprehensive
review of the subject is offered by the work of gebauer et al .
it is worth noticing that these extensions of
cnt are mostly quite recent , as they were triggered by overwhelming
experimental evidence for two - step nucleation mechanisms .
cnt is
also the tool of the trade for heterogeneous crystal nucleation , that
is , nucleation that occurs on account of the presence of a foreign
phase ( see figure 1 ) .
in fact , nucleation in liquids occurs heterogeneously more often
than not , as in some cases , the presence of foreign substances in
contact with the liquid can significantly lower the free energy barrier .
a typical
example is given by the formation
of ice : as we shall see in sections 2.4.1 and 2.4.2 , it
is surprisingly difficult to freeze pure water , which invariably takes
advantage of a diverse portfolio of impurities , from clay minerals
to bacterial fragments , to facilitate
the formation of ice nuclei .
heterogeneous nucleation is customarily
formulated within the cnt framework in terms of geometric arguments .
specifically6where f( )
1 is the shape factor , a quantity that accounts for
the fact that three different interfacial free energies must be balanced : , , and .
for instance , considering a supercooled
liquid nucleating on top of an ideal planar surface offered by the
foreign phase , we obtain the so - called young s relationwhere is the contact angle , namely ,
a measure of the extent to which the crystalline nucleus wets the foreign surface .
thus , the contact angle determines whether
and how much it could be easier for a critical nucleus to form in
an heterogeneous fashion , as for 0 < ,
the volume - to - surface energy ratio is larger for
the spherical cap nucleating
on the foreign surface than for the sphere nucleating in the liquid .
this simple formulation is clearly only a rough approximation of what
happens in reality . at first
, the contact angle is basically a macroscopic
quantity , of which the microscopic equivalent is in most cases ill - defined
on the typical length scales involved in the heterogeneous nucleation
process .
in addition , in most cases ,
the nucleus will not be shaped like a spherical cap , and to make things
more complicated , many different nucleation sites with different morphologies
typically exist on the same impurity . finally , the kinetic prefactor , , becomes even more obscure in
heterogeneous
nucleation , as it is plausible that the foreign phase will affect
the dynamical properties of the supercooled liquid . moving toward strong
supercooling , several things can happen to the
supercooled liquid phase . whether one can avoid the glass transition
largely depends on the specific liquid under consideration and on
the cooling rate ( see , e.g. , ref ( 58 ) ) . assuming that the system can be cooled sufficiently
slowly , hence avoiding both the glass transition and crystal nucleation ,
one can , in principle , enter a supercooled regime in which the liquid
becomes unstable with respect to the crystalline phase .
this region
of the phase diagram is known as the spinodal region , where the tiniest perturbation , for example , of the local density
or the degree of ordering leads the system toward the crystalline
phase without paying anything in terms of free energy ( see figure 1 ) .
in fact , below
a certain critical temperature , , the free energy barrier for nucleation
is zero , and the liquid transforms spontaneously into the crystal
on very short time scales .
the same picture holds for molecules in
solution , as nicely discussed by gebauer et al . , and it can not , by definition , be described by conventional
cnt , according to which a small value
persists even at the strongest supercoolings . although spinodal regimes have been observed
in a variety of scenarios , the existence
of a proper spinodal decomposition from the supercooled liquid to
the crystalline phase has been debated ( see , e.g. , ref ( 61 ) ) .
enhanced - sampling md
simulations , which we discuss in section 2.2 , have suggested
that barrierless crystal nucleation is possible at very strong supercooling ,
whereas other works claim that this is not the case ( see , e.g. , ref ( 63 ) ) .
here , we simply note
that , at strong supercooling not necessarily within the presumed
spinodal regime a number of assumptions on which cnt relies
become , if not erroneous , ill - defined .
the list is long , and in fact ,
a number of nucleation theories able
to at least take into account the emergence of a spinodal decomposition
exist , although they have mostly been formulated for condensation
problems . in any case
, the capillarity approximation is most likely
to fail at strong supercoolings , as the size of the critical nucleus
becomes exceedingly small , down to losing its meaning in the event
of a proper spinodal decomposition .
moreover , we shall see , for instance ,
in section 2.2 , that
the shape of the crystalline clusters is anything but spherical at
strong supercooling and , at the same time , the kinetic prefactor assumes
a role of great importance .
in fact , nucleation at strong supercooling
might very well be dominated by , as the mobility of the supercooled
liquid
is what really matters when the free energy barrier for nucleation
approaches vanishingly small values .
strong supercooling is important
because this is the regime in which most computational studies have
been performed .
large values of t imply high
nucleation rates and smaller critical nuclei , although as one moves
away from , most of the assumptions of cnt
are progressively
invalidated . at this point ,
given the substantial approximations
of cnt and especially its old age , the
reader might
be waiting for us to introduce the much more elegant , accurate , and
comprehensive theories that experiments and simulations surely embrace
today . sadly , this is not the case .
many of them , such as dynamical nucleation theory , mean - field kinetic nucleation theory , and coupled flux theory , are mainly limited to condensation
problems , and some others have only rarely been applied , for example ,
to crystallization in glasses , such as
diffuse interface theory .
several improvements
on cnt have been proposed , targeting specific aspects such as the
shape of the crystalline nuclei or the
finite size of the nonsharp crystal liquid interface .
nucleation theories largely unrelated to cnt
can also be found , such as classical density functional theory ( cdft ) ( classical , not to be confused with the celebrated
quantum mechanical framework of hohenberg and kohn ) .
a fairly complete inventory of nucleation theories , together
with an excellent review of nucleation in condensed matter , can be
found elsewhere . here
, we do not discuss
the details of any of these approaches , as indeed none of them has
been consistently used to model crystal nucleation in liquids .
this
is because cnt , despite having many shortcomings , is a simple yet
powerful theory that is able to capture at least qualitatively the
thermodynamics and kinetics of nucleation for very different systems ,
from liquid metals to organic crystals .
it has been extended to include
heterogeneous nucleation , and it is fairly easy to modify it to take
into consideration multicomponent systems such as binary mixtures
as well .
several different
experimental approaches have been employed to understand the thermodynamics
and kinetics of crystal nucleation in liquids .
although this review
discusses theory and simulations almost exclusively , we present in
this section a concise overview of the state - of - the - art experimental
techniques to highlight their capabilities as well as their limitations .
a schematic synopsis focusing on both spatial and temporal resolutions
is sketched in figure 4 , and an inventory of notable applications is reported in table 1 . as already stated ,
nucleation is a dynamical process usually occurring on very small
time and length scales ( nanoseconds and nanometers , respectively ) .
thus , obtaining the necessary spatial and temporal resolutions is
a tough technical challenge .
overview of some of the experimental methods
that have been applied
to characterize nucleation .
ranges of the spatial and temporal resolutions
typical of each approach are reported on the x and y axes , respectively .
for instance , colloids offer a playground where
simple microscopy can image the particles involved in the nucleation
events , which occur on such long time scales ( seconds ) that a full
characterization in time of the process has been achieved .
specifically , confocal microscopy has led to three - dimensional imaging
of colloidal systems , unraveling invaluable information about the
critical nucleus size , for example . in a
similar fashion ,
sleutel et al . achieved molecular resolution
of the formation of two - dimensional glucose isomerase crystals by
means of atomic force microscopy .
this
particular investigation featured actual movies showing both crystal
growth and the dissolution of precritical clusters , as well as providing
information about the influence of the substrate .
in addition , cryo - tem
techniques have recently provided two - dimensional snapshots of nucleation
events at very low temperatures . in selected cases , where the time
scales involved are again on the order of seconds , dynamical details
have been obtained , as in the cases of caco3 , metal phosphate , and magnetite .
however , more often than not , crystal
nucleation in liquids takes
place within time windows too small ( nanoseconds ) to allow for a sequence
of snapshots to be taken with high - spatial - resolution instruments .
in these cases ,
microscopic insights can not be obtained , and much
more macroscopic measurements have to be performed . in this
context ,
several experimental approaches aim at examining
a large number of independent nucleation events for a whole set of
rather small configurations of the system , basically performing an
ensemble average .
for example , in droplet experiments , nucleation
is characterized as a function of time or temperature .
freezing is
identified for each nucleation event within the ensemble of available
configurations by techniques such as femtosecond x - ray scattering , optical microscopy , and powder x - ray diffraction . from these data , the nucleation rate is often reconstructed by measuring
either metastable zone widths or induction times ( several examples are listed in , e.g. , refs ( 111115 ) ) , thus providing a solid connection to theoretical frameworks such
as cnt ( see section 1.1 ) . an essential technical detail within this class of measurements
is that the volume available for each nucleation event has to be as
small as possible to reduce the occurrence of multiple nucleation
events within the same configuration .
high - throughput devices such
as the lab - on - a - chip can significantly
improve the statistics of the nucleation events , thus enhancing the
capabilities of these approaches .
another line of action focuses
on the study of large , macroscopic
systems .
freezing is detected by techniques such as differential scanning
calorimetry , fourier transform infrared spectroscopy ( ftirs ) , and analytical ultracentrifugation or by some flavor of chamber experiments . in this case , the frozen fraction of the overall system and/or the
nucleation temperatures can be obtained , and in some cases , nucleation
rates have been extracted ( see table 1 ) .
finally , experimental methods that can detect
nucleation and the
formation of the crystal ( predominantly by means of optical microscopy )
but do not provide any microscopic detail have helped to shed light
on issues such as the role of the solvent or impurities .
this is usually
possible by examining the amount of crystalline phase obtained along
with its structure .
even though there are a large number of
powerful experimental techniques
and new ones emerging ( e.g. , ultrafast x - ray ) , it is still incredibly challenging to obtain microscopic - level
insight into nucleation from experiments .
as we shall see now , md
simulations provide a powerful complement to experiments .
when dealing
with crystal nucleation in liquids , atomistic simulations should provide
a detailed picture of the formation of the critical nucleus . the simplest
way to achieve
this is by so - called brute - force md simulations , which
involve cooling the system to below the freezing temperature and then
following its time evolution until nucleation is observed .
brute - force
simulations are the antagonist of enhanced - sampling simulations , where
specific computational techniques are used to alter the dynamics of
the system so as to observe nucleation on a much shorter time scale .
monte carlo ( mc ) techniques , although typically coupled with enhanced
sampling techniques , can be used to recover , but the calculation of requires
other methods , such as kinetic
monte carlo ( kmc ) .
the natural choice
to simulate nucleation events is instead md simulations , which directly
provide the temporal evolution of the system .
isobaric
ensemble ( npt ) , where p ( usually
ambient pressure ) and t < are kept constant by means of a barostat
and a thermostat , respectively . such computational tweaking is a double - edged
sword .
in fact , nucleation and most notably crystal growth are exothermic
processes , and within the length scale
probed by conventional atomistic simulations ( 110 nm ) , it is necessary to keep the system at constant temperature .
on the other hand , in this way , dynamical and structural effects in
both the liquid and the crystalline phases due to the heat developed
during the nucleation events are basically neglected . although the actual extent of these effects is not yet clear , forcing
the sampling of the canonical ensemble is expected to be especially
dangerous when dealing with very small systems affected by substantial
finite - size effects . more importantly
small coupling constants and clever approaches
( e.g. , stochastic thermostats ) can be
employed to limit the effects of the thermostats , but in general ,
care must be taken . the same reasoning applies for p and barostats as well .
a density change of the system is usually
associated with nucleation , the crystalline
phase being more ( or less , in the case of , e.g. , water ) dense than
the liquid parent phase .
three conditions must be fulfilled
to extract from brute - force
md simulations:(1)the system must be allowed to evolve
in time until spontaneous fluctuations lead to a nucleation event.(2)the system size must be
significantly
larger than the critical nucleus.(3)significant statistics of nucleation
events must be collected .
the system must be allowed to evolve
in time until spontaneous fluctuations lead to a nucleation event .
the most daunting obstacle is probably the first one because of the
so - called time - scale problem . in most cases ,
nucleation
is a rare event , meaning that it usually occurs on a very long time
scale ; precisely how long depends strongly on t .
a rough estimate of the number of simulation steps required to
observe a nucleation event within a molecular dynamics run is reported
in figure 5 . under
the fairly optimistic assumption that classical md simulations can
cope with up to 10 molecules on a time scale of
nano-/microseconds
, there is only a very narrow set of conditions
for which brute - force classical md simulations could be used to investigate
nucleation , usually only at strong supercooling .
time scales typical
of first - principles simulations , also reported in figure 5 assuming up to 10 molecules , indicate that unbiased ab initio simulations of
nucleation events are unfeasible .
nucleation rate as a
function of the simulation time needed
within an md simulation to observe a single nucleation event .
the
blue shaded region highlights the approximate simulation times currently
affordable by classical md simulations ; clearly , only very fast nucleation
processes can be simulated with brute - force md . for homogeneous ice
nucleation , and can typically be observed for t = 30 k and
t = 80 k , respectively .
in the derivations of classical and ab initio simulation times , 10 and 10 molecules , respectively ,
were considered ,
together with the number density of a generic supercooled liquid , = 0.01 molecules .
the number
of atoms ( or molecules ) in the system defines the time scale accessible
to the simulation and , thus , the severity of the time - scale problem .
the reason large simulation boxes , significantly larger than the size
of the critical nucleus , are needed is because periodic boundary conditions
will strongly affect nucleation ( and growth ) if even the precritical
nuclei are allowed to interact with themselves .
this issue worsens at mild
supercooling , where the critical nucleus size rapidly increases toward
dimensions not accessible by md simulations .
third , it is not
sufficient to collect information on just one
nucleation event .
nucleation is a stochastic event following a poisson
distribution ( at least ideally ; see section 1.1 ) , and so to obtain the nucleation rate ,
one needs to accumulate decent statistics . taking
these issues
into consideration , various approaches for
obtaining have emerged .
one approach , known as the
yasuoka matsumoto method , involves
simulating a very large system , so that different nucleation events
can be observed within a single run . in this case ,
large simulation
boxes are needed to collect sufficient statistics and to avoid spurious
interactions between different nuclei .
another family of methods involves
running many different simulations using much smaller systems , which
is usually computationally cheaper .
once a collection of nucleation
events has been obtained , several methods for extracting can be employed .
the simplest ones ( mean
lifetime and survival probability methods ) involve the fitting of the nucleation times to poisson
statistics .
a more in - depth technique , the so - called mean first - passage
method , allows for a detailed analysis
of the nucleus population but requires a probability distribution
in terms of nucleus size .
the literature offers a notable number
of works in which brute - force
md simulations have been successfully applied .
most of them rely on
one approach to circumvent the above - mentioned issues , particularly
the time - scale problem . as we shall see in section 2 , to simulate nucleation events , one almost
always has to either choose a very simple system or increase the level
of approximation sometimes dramatically , for instance , by coarse - graining
the interatomic potential used . in
the previous section
, we introduced the time - scale problem , the main
reason brute - force md simulations are generally not feasible when
studying crystal nucleation . enhanced sampling methods
alter how the
system explores its configurational space , so that nucleation events
can be observed within a reasonable amount of computational time .
broadly speaking
, one can distinguish between free - energy methods
and path - sampling methods , both of which have been extensively discussed
elsewhere ( see , e.g. , refs ( 156 and 162164 ) ) .
thus , only the briefest of introductions is needed here . of the many enhanced sampling methods , only a handful
this is because information
is needed about both the thermodynamics of the system ( the free energy
barrier for nucleation ) and
the kinetics of the nucleation process
( the kinetic prefactor ) .
when dealing with crystal nucleation
in supercooled liquids , free - energy - based methods are rather common ,
such as umbrella sampling ( us ) and metadynamics . in both cases , and indeed in almost all enhanced sampling methods
currently available , the free energy surface of the actual system
is coarse - grained by means of one or more order parameters or collective
variables .
the choice of the order parameter is not trivial and can
have dramatic consequences .
an external bias is then applied to the
system , leading to a modified sampling of the configurational space
that allows for the reconstruction of the free energy profile with
respect to the chosen order parameter and , thus , for the computation
of the free energy barrier .
however , there is a price to be paid : upon introduction
of an extra term into the system hamiltonian , the actual dynamics
of the system is to some extent hampered , and much of the insight
into the nucleation mechanism is lost .
one
needs complementary methods , usually
aimed at estimating the probability for the system on top of the nucleation
barrier in the space of the selected order parameter to
get back to the liquid phase or to evolve into the crystal .
most frequently ,
such methods are based on some flavor of transition state theory , such as the bennett chandler formulation , and require a massive set of md or kmc simulations to be performed . on the other hand , the ever - growing family of path - sampling methods
can provide direct access to the kinetics of the nucleation process .
these approaches again rely on the definition of an order parameter ,
but instead of applying an external bias potential , an importance
sampling is performed so as to enhance the naturally occurring fluctuations
of the system . within the majority of the path - sampling approaches
currently used , including transition interface sampling ( tis ) and forward flux sampling ( ffs ) , the
ensemble of paths connecting the liquid and the crystal is divided
into a series of interfaces according to different values of the order
parameter . by sampling the probability with which the system crosses
each of these interfaces , a cumulative probability directly related
to the nucleation rate can be extracted .
other path - sampling techniques
such as transition path sampling ( tps ) rely
instead on the sampling of the full ensemble of the reactive trajectories .
in both cases , by means of additional simulations involving , for example ,
committor analysis distribution and
thermodynamic integration , one can subsequently
extract the size of the critical nucleus and the free energy difference
between the solid and liquid phases , respectively .
many different
path - sampling methods are available , but to our knowledge , only tps ,
tis , and most prominently ffs have allowed for estimates of crystal
nucleation rates . under certain conditions , path - sampling methods
do not alter the dynamics of the system , allowing for invaluable insight
into the nucleation mechanism .
however , they are particularly sensitive
to the slow dynamics of strongly supercooled systems , which hinder
the sampling of the paths and makes them exceptionally expensive computationally .
although the past few decades have taught us that enhanced sampling
techniques are effective in tackling crystal nucleation of colloids
( see section 2.1 ) ,
lennard - jones melts ( see section 2.2 ) , and other atomic liquids ( see section 2.3 ) , only recently have these
techniques been applied to more complex systems .
one challenging
scenario for simulations of nucleation is provided
by the formation of crystals from solutions characterized by very
low solute concentration .
although this occurrence is often encountered
in real systems of practical interest , it is clearly extremely difficult
for md simulations , even if aided by conventional enhanced sampling
techniques , to deal with just a few solute molecules dissolved within
1010 solvent molecules . in these cases ,
the diffusion of the solute plays a role of great relevance , and the
interaction between solvent and solute can enter the nucleation mechanism
itself .
thus , obtaining information about the thermodynamics , let
alone the kinetics , of nucleation at very low solute concentrations
is presently a formidable task .
however , efforts have been devoted
to further our understanding of solute migration and solute - nuclei
association , for example , as demonstrated by the pioneering works
of gavezzotti and co - workers and more recently
by kawska and co - workers . in the latter work ,
the authors illustrate an approach that relies on the modeling of
the subsequent growth step , where solute particles ( often ions ) are
progressively added to the ( crystalline or not ) cluster . after each
of these growth steps , a structural optimization of the cluster and
the solvent by means of md simulations
although this
method can not provide quantitative results in terms of the thermodynamics
and/or the kinetics of nucleation , it can , in principle , provide valuable
insight into the very early stages of crystal nucleation when dealing
with solutions characterized by very low solute concentrations . on a final note , we mention seeded md simulations .
this technique
relies on simulations in which a crystalline nucleus of a certain
size is inserted into the system at the beginning of the simulation .
although useful information about critical nucleus size can be obtained
in this way , the method does not usually allow for a direct calculation of the
nucleation rate . however , seeded md simulations are one of the very
few methods by which it is currently possible to investigate solute
precipitate nucleation ( see , e.g. , knott et al . ) . in this case
, the exceedingly low attachment rate of
the solute often prevents both free - energy- and transition - path - sampling - enhanced
sampling methods from being applied effectively . as we shall
see in the next few sections , the daunting computational
costs , together with the delicate choice of order parameter and the
underlying framework of cnt ,
still make enhanced - sampling simulations
of crystal nucleation in liquids an intimidating challenge .
we have chosen to review
different classes of systems , which we
present in order of increasing complexity .
we start in sections 2.1 and 2.2 with colloids
and lennard - jones liquids , respectively .
these systems are described
by simple interatomic potentials that allow large - scale md simulations ,
and thus with them , many aspects of cnt can be investigated and nucleation
rates calculated . in some cases , the latter can can be directly compared
to experimental results . as such , colloids and
lennard - jones liquids
represent a sort of benchmark for md simulations of crystal nucleation
in liquids , although we shall see that our understanding of crystal
nucleation is far from satisfactory even within these relatively easy
playgrounds . in section 2.3 ,
we discuss selected atomic liquids of technological interest
such as liquid metals , supercooled liquid silicon , and phase - change
materials for which nucleation occurs on very small time scales . as
the first example of a molecular system ,
we review the body of computational
work devoted to unraveling both the homogeneous ( section 2.4.1 ) and heterogeneous ( section 2.4.2 ) formation
of ice , offering a historical perspective guiding the reader through
the many advances that have furthered our understanding of ice nucleation
in the past decades .
next , we present an overview of nucleation
from solution ( section 2.5 ) , where simulations
have to deal with solute and solvent .
we take into account systems
of great practical relevance such as urea molecular crystals , highlighting
the complexity of the nucleation mechanism , which is very different
from what cnt predicts .
finally , section 2.6 is devoted to the formation of gas hydrates . as a general rule ,
increasing the complexity of the system raises
more questions about the validity of the assumptions underpinning
cnt .
the reader will surely notice that simulations have revealed
many drawbacks of cnt along the way and that reaching decent agreement
for the nucleation rate between experiments
and simulations still
remains a formidable task .
one reason for this is
the simplicity of the interatomic potential customarily used to model
them : the only interaction a hard - sphere particle experiences comes
from elastic collisions with other particles . because there is no
attractive force between particles , a hard - sphere system is entirely
driven by entropy . as a consequence ,
the phase diagram is very simple
and can be entirely described with one single parameter , the volume
fraction . only two different phases are possible : a fluid
and a crystal . at volume fractions
< 0.494 , the system
is in its fluid state ; at 0.492 < < 0.545 , the system
will be a mixture of fluid and crystalline states ; and at
> 0.545 , the thermodynamically most stable phase is the crystal .
the
transformation from fluid to crystal occurs through a first - order
phase transition . despite their simplicity ,
colloids made of polymers are commonly used for this purpose , the
most prominent example being poly(methyl methacrylate ) ( pmma ) spheres
coated with a layer of poly(12-hydroxystearic acid ) .
after the spheres
have been synthesized , they are dissolved in a mixture of cis - decaline and tetraline , which enables the use of a wide
range of powerful optical techniques to investigate nucleation .
the possibility of using these large hard spheres in nucleation
experiments has two major advantages : first , a particle size larger
than the wavelength used in microscopy experiments makes it possible
to track the particle trajectories in real space . in additional , nucleation
occurs in a matter of seconds , which allows experimentalists to follow
the complete nucleation process in detail . compared to other systems
,
it is therefore possible to observe the critical nucleus directly ,
for example , by confocal microscopy ( see section 1.2 ) , which is of crucial importance for understanding
nucleation .
these qualities of hard - sphere systems make them ideal
candidates to advance our understanding of nucleation . as such ,
it
is not surprising that the freezing of hard spheres is better characterized
than any other nucleation scenario , and in fact , a number of excellent
reviews in this field already exist .
our aim here is thus not to give a detailed overview of the field
but to highlight some of the milestones and key discoveries and connect
them to other nucleation studies . to keep the discussion reasonably
brief , we limit the latter to neutral and perfectly spherical hard - sphere
systems . however , we note that a sizable amount of work has been devoted
to a diverse range of colloidal systems , such as nonspherical particles , charged particles , and mixtures of different colloidal particles , to name just a few .
readers interested in the state of the
art in about 2000 are referred to other reviews . in the
early 2000s , two major advances in the field were made , one
on the theoretical side and the other experimentally . in 2001 , auer
and frenkel computed absolute nucleation
rates of a hard - sphere system using kmc simulations .
they did so by
calculating pcrit , the probability of
forming a critical nucleus spontaneously , and , the
kinetic prefactor .
they found that the experimental and
theoretical nucleation rates disagreed by several orders of magnitude .
this was surprising , because simulations did really well in describing
all sorts of properties of hard spheres before .
it was worrisome because
only very few sound approximations were made by auer and frenkel to
obtain their nucleation rates .
the authors suggestion , that the problem
lay in experiments or , more precisely , in the interpretation of experiments ,
showed a possible way to resolve the discrepancy . in the same year ,
gasser et al . conducted ground - breaking
experiments , imaging the nucleation of a colloidal suspension in real
space using confocal microscopy .
four snapshots of their system containing
approximately 4000 particles are shown in figure 6 .
this was a significant step , because nucleation
had previously been investigated indirectly , using the structure factor
obtained from light - scattering experiments , for example . in their
study
, they were able to directly measure the size of a critical nucleus
for the first time .
achieving sufficient temporal and spatial resolution
at the same time is possible thus far only for colloidal systems ( for
more details about experimental techniques , see section 1.2 ) .
they found that the nucleus
was rather aspherical with a rough surface ; both of these effects
are completely neglected in cnt .
note that aspherical nuclei also
appear in lj systems , for example ( see section 2.2.1 ) .
in addition , a random hexagonal close - packed
( rhcp ) structure for the hard spheres was observed , in good agreement
with auer and frenkel .
this is interesting ,
because slightly different systems such as soft spheres and lennard - jones
particles seem to favor body - centered - cubic ( bcc ) stacking .
however ,
gasser et al.s study did not resolve the discrepancy between
experimental and simulated nucleation rates , as their results were
in agreement with earlier small - angle light - scattering experiments .
red ( large ) and blue ( small ) spheres show crystal- and
liquid - like particles , respectively .
the size of the observed volume
is 58 m by 55 m by 20 m , containing about 4000
particles .
after shear melting of the sample , snapshots were taken
after ( a ) 20 , ( b ) 43 , ( c ) 66 , and ( d ) 89 min .
much of the subsequent work focused
on trying to resolve this discrepancy
between experiments and simulation .
found experimental
evidence supporting a two - step crystallization process ( see section 1.1.2 ) in hard - sphere
systems .
other systems such as proteins and molecules in solution
( see section 2.5 )
were well - known at that time to crystallize through a more complex
mechanism than that assumed by cnt .
even for hard - sphere systems ,
two - step nucleation processes were reported before 2006 ; the occurrence of this mechanism was attributed to details of the
polydispersity of the hard spheres , however .
the new insight provided
by schpe et al . in 2006 and 2007 was that the two - step nucleation
process is general , and as such , it does not depend on either polydispersity
or volume fraction . in 2010 , simulations performed by schilling et
al . supported these experimental findings .
using unbiased mc simulations , schilling et al .
not
even the simplest model system seemed to follow the traditional picture
assumed in cnt .
could this two - step mechanism explain why the computational
rates disagreed with experiments ?
at
first , it seems like a tempting explanation , because auer and frenkel had to introduce order parameters to calculate
absolute nucleation rates .
such a conclusion , however , automatically
presupposes a reaction pathway , which might not necessarily match
the nucleation pathway taken in experiments .
showed in the same year , however , that very
different computational approaches [ brute - force md , us , and ffs , which
we described earlier ( see section 1.3.2 ) ] led to the same nucleation rates ,
all in agreement with auer and frenkel .
they therefore concluded that the discrepancy between simulations
and experiments did not lie in the computational approach employed
by auer and frenkel .
they offered two possible explanations , one being
that hydrodynamic effects , completely neglected in the simulations ,
might play a role and the other being possible difficulties in interpreting
the experiments .
schilling et al . tried
to address one of the key issues when comparing experiments with simulations :
uncertainties and error estimation . whereas the determination of the
most characteristic quantity in hard - sphere systems , the volume fractions ,
is straightforward for simulations ,
experimentalists are confronted
with a more difficult task in this case . the typical error in determining
the volume fraction experimentally is about 0.004 , which translates
into an uncertainty in the nucleation rate of about an order of magnitude .
upon taking these considerations into account ,
the authors concluded
that the discrepancy can be explained by statistical errors and uncertainties .
does this mean that the past 10 years of research tried to explain
a discrepancy that is actually not there ?
rightfully pointed out that , whereas the rates
between experiments and simulations coincide at high volume fraction ,
they still clearly disagree in the low - volume - fraction regime .
no
simple rescaling justified by statistical uncertainty could possibly
resolve that discrepancy . in their article
, they also addressed a
different issue . in a computational study in 2010 , kawasaki and tanaka obtained , by means of brownian dynamics , nucleation rates in good agreement with experiments ,
contrary to the nucleation rates computed by auer and frenkel using
brute - force md .
it should be noted that
kawasaki and tanaka did not use a pure hard - sphere potential , but
used a weeks chandler andersen potential instead .
was
the approximation of a hard - sphere system , something that can never
be fully realized in experiments , the problem all the time ?
what filion
et al . showed is that different computational approaches ( brute - force
md , us , and fss ) all lead to the same nucleation rates , all of them
in disagreement with what kawasaki and tanaka found . through a detailed
evaluation of their approach and
that of kawasaki and tanaka , they
concluded that their rates are more reliable .
the discrepancy was
back on the table , where it still remains and is as large as ever . for a detailed comparison between experimental and computational
rates ,
the message we want to convey here is that
the disagreement between simulations and experiments in the simplest
system still persists today .
it is worth mentioning that this fundamental
disagreement between simulations and experiments is not unique to
colloids .
other systems such as water ( sections 2.4.1 and 2.4.2 ) and
molecules in solution ( section 2.5 ) also show discrepancies of several orders of magnitude
in nucleation rates .
this long - standing debate is of great relevance
to all investigations dealing with systems modeled using any flavor
of hard - sphere potential .
a notable example in this context is the
crystallization of proteins , which are usually treated as hard spheres .
despite basically neglecting most of the complexity of these systems ,
this substantial approximation
has allowed for a number of computational
studies that , although outside the scope of this review , certainly contributed
to furthering our understanding of the self - assembly of biological
particles . beyond hard
spheres ,
the lennard - jones liquid is
a widely studied model system that does just that .
it can be seen
as the natural extension of the hard - sphere model , to which it becomes
equivalent when the strength of the attractive interactions goes to
zero .
lj liquids were first introduced in 1924 , and since then , they have been the subject of countless
computational studies .
lj potentials allow for exceedingly fast md
simulations , and a wide range of thermodynamic information is available
for them , such as the phase diagram and the interfacial free energy .
the stable structure of the lj system up to is a face - centered - cubic ( fcc )
crystal ;
slightly less stable in free energy is a hexagonal - close - packed ( hcp )
structure , which , in turn , is significantly more stable then a third
body - centered - cubic ( bcc ) phase . with his
study of liquid argon in 1964 , rahman reported what is probably the
first lj md simulation .
his findings
showed good agreement with experimental data for the pair distribution
function and the self - diffusion coefficient , thus demonstrating that
lj potentials can properly describe noble elements in their liquid
form at ambient pressure .
to
the best of our knowledge , nucleation of lj liquids was investigated
for the first time in 1969 by de wette et al . and
in 1976 by mandell et al . for two - dimensional and three - dimensional systems , respectively .
early simulations investigating the condensation of lj vapors into a liquid already
indicated a substantial discrepancy with cnt rates .
it is worth noticing
that the order parameter for crystal - like particles presented by ten
wolde et al .
fostered a considerable
amount of later work devoted to improving the order parameters customarily
used to describe crystal nucleation from the liquid phase ( see , e.g. ,
ref ( 254 ) ) .
in 2008 ,
kalikmanov et al . compared cnt and cdft
( see section 1.1 )
simulations with condensation data for argon .
they found that cnt
spectacularly failed to reproduce experimental condensation rates ,
underestimating them by up to 26 orders of magnitude .
this disagreement
triggered a number of computational studies aimed at clarifying the
assumption of the sphericity of the critical nucleus within the freezing
of lj liquids . by embedding pre - existing spherical clusters into supercooled
lj liquids , bai and
li found values of the
critical nucleus size in excellent agreement with cnt within a broad
range of temperatures .
however , these results have been disputed by
the umbrella sampling simulations of wang et al .
, for example , as well as the path - sampling investigation
of moroni et al . in both cases
in addition , moroni et al . pointed out that the critical nucleus
size is determined by a nontrivial interplay between the shape , the
size , and the degree of crystallinity of the cluster .
such a scenario
is clearly much more complex than the usual cnt picture , as it violates
the capillarity approximation ( see 1.1.1 ) .
nonspherical nuclei were also observed by trudu et al . , who extended the conventional cnt formula to
account for ellipsoidal nuclei .
such a tweak gave much better estimations
of both the critical nucleus size and the nucleation barrier .
recall
that the shape of the critical nuclei can be observed experimentally
in very few cases ( see sections 1.2 and 2.1 ) .
however , at
very strong supercooling , things fell apart because of the emergence
of spinodal effects ( see section 1.1 ) .
note that cnt fails at strong supercooling even
without the occurrence of spinodal effects , as the time lag ( transient
time ) needed for structural relaxation into the steady - state regime
results in a time - dependent nucleation rate .
for instance , huitema et al . showed
that incorporating the time dependence into the kinetic prefactor
yields an improved estimate of nucleation rates .
in fact , by embedding
extensions to the original cnt framework , one can , in some cases ,
recover a reasonable agreement between simulations and experiments
even at strong supercooling .
as an example , peng et al . also showed that including enthalpy - based terms
in the formulation of the temperature dependence of substantially improves
the outcomes of
cnt .
another aspect that
has been thoroughly addressed within the crystal nucleation of lj
liquids is the structure of the crystalline clusters involved .
the
mean - field theory approach of klein and leyvraz suggests a decrease of the nucleus density as well as an
increase of the bcc character when moving toward the spinodal region .
these findings were confirmed by the umbrella sampling approach of
ten wolde et al . , who reported a bcc shell surrounding fcc cores .
furthermore , wang
et al . showed that the distinction between
the crystalline clusters and the surrounding liquid phase falls off
as a function of t .
in fact , the free energy
barrier for nucleation , computed by means of umbrella sampling simulations
( see section 1.3.2 ) , was found to be on the order of kbt at t = 52% .
in addition ,
the nuclei undergo substantial structural changes toward nonsymmetric
shapes , a finding validated by the metadynamics simulations of trudu
et al .
the same authors investigated
the nucleation mechanism close to the critical temperature for spinodal
decomposition , ( see section 1.1.4 ) , where the free energy basin corresponding
to the liquid phase turned out to be ill - defined , that is , already
overlapping with the free energy basin of the crystal .
such a finding
suggested that , below , there is no free energy barrier for nucleation ,
indicating that the liquid is unstable rather than metastable and
that the crystallization mechanism has changed from nucleation toward
the more collective process of spinodal decomposition ( see section 1.1.4 and figure 1 ) .
insights
into the interplay between nucleation and polymorphism have been provided
by the simulations of ten wolde et al .
, among others , suggesting that ,
within the early stages of the nucleation process , the crystalline
clusters are bcc - like , later turning into fcc crystalline kernels
surrounded by bcc shells .
performed
a cdft study to determine the difference between the free energy barrier
for nucleation required for the creation of an fcc or bcc critical
nucleus .
in addition , the difficulty for nucleation of the three different
crystal orientations for fcc was ranked ( 100 ) > ( 110 ) > ( 111 ) .
these
studies confirm the presence of a two - step mechanism ( see section 1.1.2 ) and the
validity of ostwald s step rule for the lj model . as we will see later ( e.g. , homogeneous ice nucleation , section 2.4.1 ) , nucleation
through metastable phases has also been observed for more complicated
liquids .
important contributions regarding polymorph control during
crystallization were made by desgranges and delhommelle , who investigated nucleation
under different thermodynamic conditions . by keeping the temperature
constant and altering the pressure , they were able to influence the
amount of bcc particles .
this reached up to a point where the nucleus
was almost purely bcc - like .
calculation of the bcc liquid line
in the phase diagram showed that these nucleation events occurred
in the bcc existence domain .
additionally , the transformation from
fcc to hcp during crystal growth , well after the critical nucleus
size has been reached , was studied by changing the temperature at
constant pressure . as depicted in figure 7 , at t = 10% , a small
number of hcp atoms were observed surrounding the fcc core , whereas
at t = 22% , much larger hcp domains formed
within the crystallite , suggesting that the conversion from hcp to
fcc is hindered at higher temperatures . on a final note ,
we emphasize
that many findings related to polymorphism are often quite dependent
on the choice of the order parameters employed .
this issue is not
limited to lj systems , and it is especially important when dealing
with similarly dense liquid and crystalline phases ( e.g. , metallic
liquids ) , where order parameters usually struggle to properly distinguish
the different crystalline phases from the liquid . in particular , it remains to be seen whether the fractional
bcc , fcc , and hcp contents of the lj nuclei that we have discussed
will stand the test of the last generation of order parameters .
cross section
of postcritical crystalline clusters of 5000 lj particles
for t = ( a ) 10% and ( b ) 22% .
fcc- , hcp- , and
bcc - like particles are depicted in gray , yellow , and red , respectively .
at t
= 22% substantial hcp domains form within
the crystallite , whereas at t = 10% , hcp particles
can be found almost exclusively on the surface of the fcc core . reprinted
with permission from ref ( 247 ) .
heterogeneous
crystal nucleation has also been investigated for a variety of lj
systems .
used
umbrella - sampling simulations ( see section 1.3.2 ) to calculate the free energy barrier
for heterogeneous nucleation of an lj liquid on top of an ideal impurity ,
represented by a single fcc ( 111 ) layer of lj particles . by explicitly
varying the lattice spacing of the substrate , asub
, they calculated as a
function of asub aequi , where aequi is the lattice
spacing of the equilibrium
crystalline phase .
aequi = 0 , whereas
for large values of asub aequi , nucleation proceeds within the bulk of
the supercooled liquid phase .
these findings support the early argument
of the zero lattice mismatch introduced by turnbull and vonnegut to justify the striking effectiveness of agi
crystals in promoting heterogeneous ice nucleation .
in fact , in several
situations , one can define a disregistry or lattice mismatch
as7values of close to or even
equal to
zero have often been celebrated as the main ingredient that makes
a crystalline impurity particularly effective in promoting heterogeneous
nucleation .
however , the universality of this concept has been severely
questioned in the past few decades , as we shall see in section 2.4.2 for heterogeneous
ice nucleation .
nonetheless , it seems that the argument regarding
zero lattice mismatch can hold for certain simple cases , as demonstrated
by mithen and sear , who studied heterogeneous
nucleation of lj liquids on the ( 111 ) and ( 100 ) faces of an fcc crystal
by means of ffs simulations ( see section 1.3.2 ) .
they reported a maximum in the heterogeneous
nucleation rate for a small , albeit nonzero , value of ( see figure 8) . the difference
between their study and that of wang et al . is simply that many more values of were taken into account
by mithen and sear , thus allowing the
maximum of to be determined
more precisely . on a different
note ,
dellago et al . performed tis simulations
( see section 1.3.2 ) to investigate heterogeneous crystal nucleation of lj supercooled
liquids on very small crystalline impurities .
they found that even
tiny crystalline clusters of just 10 lj particles can actively
promote nucleation and that the morphology of the substrate can play
a role as well .
specifically , whereas fcc - like clusters were rather
effective in enhancing nucleation rates , no substantial promotion
was observed for icosahedrally ordered seeds .
nucleation rates computed
with the ffs method for a rigid hexagonal
surface of lj atoms in contact with a lj liquid .
potentials 1 and
2 describe the interaction between substrate and liquid and differ
only slightly by the value of they use .
these results show that the maximum
in the nucleation rate occurs at nonzero values of the lattice mismatch
. reprinted with permission from ref ( 271 ) .
mc simulations performed by page
and sear have demonstrated that confinement
effects can be of great relevance
as well .
they computed heterogeneous nucleation rates for a lj liquid
walled inbetween two flat crystalline planes characterized by a certain
angle sub .
a maximum of was
found for a specific value of sub , boosting the
nucleation rate by several orders of magnitude
with respect to the promoting effect of a flat crystalline surface .
in addition , different values of sub led to the
formation of different crystalline polymorphs .
recently probed
the influence of structured and structureless lj potential walls or
nucleation rates .
both types of wall were found to increase the temperature
at which nucleation occurs .
we shall see in section 2.4.2 that the interplay between the morphology
of the substrate and the strength of the liquid
md simulations
of lj liquids are computationally cheap , making them the perfect candidates
to examine how finite - size effects impact crystal nucleation .
the
seminal work of honeycutt and andersen took into account up to 1300 lj particles at , which turned out to be too
few particles
to completely rule out the effects of periodic boundary conditions .
in fact , the authors suggested that extra care had to be taken because
of the diffuseness of the interface between the supercooled liquid
phase and the crystalline nucleus , which can induce an artificial
long - range order in the system , leading to a nonphysically high nucleation
rate .
these findings are particularly relevant , as the critical nucleus
size at this t value is on the order of just
a few tens of particles , representing a tiny fraction of the whole
system .
only a few years later , swope and andersen investigated the same effects by taking into account up
to 10 lj particles subjected to the same strong supercooling
as probed by honeycutt and andersen . according to their large - scale md simulations ,
. this outcome must be
carefully pondered , as currently , the vast majority of simulations
dealing with crystallization of realistic systems can not afford to
take into account system sizes 3 orders of magnitude larger than the
size of the critical nucleus .
examined the nucleation of an lj liquid in a wide range of temperatures
( 70140 k ) .
although nonphysical instantaneous crystallization
was observed for systems on the order of 500 particles , simulation
boxes containing about 10000 particles seemed to be free from finite - size
effects .
recently described a novel class of finite - size
effects unrelated to periodic boundary conditions .
in fact , they showed
that the equilibrium density of critical nuclei , , can effectively
influence the absolute value of nucleation rates .
specifically , at
very strong supercooling , the critical nuclei will on average form
very shortly after the transient time , whereas at mild t , the stochastic nature of nucleation will lead to a consistent
scatter of the nucleation times .
in other words , in the latter scenario ,
either exceedingly large systems must be taken into account , or a
sizable number of independent simulations must be performed to deal
with the long tails of the distribution of nucleation times .
examples
include the sutton chen potentials for several metals and the tosi fumi potential for molten salts such as nacl .
terms accounting
for the directionality of covalent bonds have been included , for example ,
in the stillinger
weber potential for si ; the bond order potentials of tersoff for si , gaas , and ge ; and the reactive potential of brenner for carbon - based systems .
another class of
interatomic potential is based on the concept of local electronic
density and includes , for instance , the finnis sinclair potentials for metallic systems , the whole family of the embedded - atom - method
( eam ) potentials , and the glue potential for au and al .
many of these potentials are still incredibly
cheap in terms of computer time , thus allowing for large - scale , unbiased
md simulations .
recently , massively parallel md runs succeeded in
nucleating supercooled liquid al and
fe using an eam potential and a finnis
as up to 10 atoms were taken
into account , actual grain boundaries were observed , providing unprecedented
insight in to the crystal growth process .
the nucleation of bcc fe
crystallites and the evolution of the resulting grain boundaries at
different temperatures can be appreciated in figure 9a .
the sizable dimension of the simulation
boxes ( 50 nm ) allowed nucleation events to be observed within
hundreds of picoseconds , and grain coarsening ( i.e. , the process by
which small crystallites end up incorporated into larger ones ) is
also clearly visible .
mere visual inspection of the nucleation trajectories
depicted in figure 9a suggests different nucleation regimes as a function of temperature .
in fact , the same authors calculated a temperature profile for the
nucleation rate , shown in figure 9b , that demonstrates the emergence of a maximum of value characteristic
of diffusion - limited
nucleation ( see section 1.1.1 ) .
crystal nucleation of supercooled fe by means of large - scale
md
simulations .
yellow circles highlight
small crystalline grains doomed to be incorporated into the larger
ones later on because of grain coarsening .
( b ) nucleation rate as
a function of temperature . reprinted with permission from ref ( 290 ) .
a field that has greatly
benefited from md simulations is the crystallization
of metal clusters , as nicely reviewed by aguado and jarrold .
for instance , it is possible to probe the interplay
between the size of the clusters and the cooling rate upon crystal
nucleation and growth . in this context , shibuta reported three different outcomes for supercooled liquid
mo nanoparticles modeled by means of a finnis sinclair potential ,
namely , the formation of a bcc single crystal , a glassy state , or
a polycrystalline phase . in some cases , nucleation rates obtained
from simulations were consistent with cnt , as in the case of ni nanodroplets , for which nucleation events were again observed
by means of brute - force md simulations using the sutton chen
potential .
the influence of the redox potential on the nucleation
process has also been investigated .
milek and zahn employed an enhanced flavor of the eam potential to study
the nucleation of ag nanoparticles from solution .
they established
that the outcome of nucleation events is strongly influenced by the
strength of the redox potential , able to foster either a rather regular
fcc phase or a multitwinned polycrystal .
similar to what was done
for lj liquids , the effects of confinement were assessed for au nanodomains
modeled using the glue potential by pan and shou . according to their findings ,
l and chen instead investigated surface - layering - induced crystallization of
ni si nanodroplets using a modified eam potential .
it seems
that , for this particular system , atoms proximal to the free surface
of the droplet assume a crystalline - like ordering on very short time
scales , thus triggering crystallization in the inner regions of the
system .
no such effect has been reported in the case of surface - induced
crystallization in supercooled tetrahedral liquids such as si and
ge , as investigated by li et al . through
ffs simulations employing both tersoff and stillinger
the presence of the free surface facilitates crystal nucleation
for this class of systems as well , but surface layering was not observed .
instead
, the authors claimed that the surface reduces the free energy
barrier for nucleation as it introduces a pressure - dependent term
in the volume free energy change expected for the formation of the
crystalline clusters .
the situation is quite different for surface - induced
ice nucleation , at least according to the coarse - grained mw model
of molinero and moore .
in fact , haji - akbari
et al . recently investigated ice nucleation
in free - standing films of supercooled mw water using both ffs and
us , finding that , in these systems , crystallization is inhibited in
the proximity of the vapor
very recently ,
gianetti et al . extended the investigation
of haji - akbari et al . to the crystallization
of a whole family of modified stillinger
weber liquids with
different degrees of tetrahedrality , locating a crossover
from surface - enhanced to bulk - dominated crystallization in free - standing
films as a function of . another seminal study by li et al .
, again using ffs , focused on homogeneous ice
nucleation within supercooled mw water nanodroplets , where nucleation
rates turned out to be strongly size dependent and in general consistently
smaller ( by several orders of magnitude ) than the bulk case .
ffs was
also applied by li et al . to examine
homogeneous nucleation of supercooled si .
ffs has also been successful
in predicting homogeneous crystal nucleation rates in molten nacl ,
modeled using a tosi fumi potential by valeriani et al .
large discrepancies between their results and
experimental nucleation rates can be appreciated when cnt is used
to extrapolate the calculations to the milder supercooling probed
by the actual measurements .
given that the authors obtained consistent
results using two different enhanced sampling methods , this study
hints again at the many pitfalls of cnt .
a unique
example of a class of materials for which nucleation can be effectively
addressed by brute - force md simulations is given by so - called phase - change
materials .
these systems are of great technological
interest as they are widely employed in optical memories ( e.g. , dvd - rw )
and in a promising class of nonvolatile memories known as phase - change
memory , based on the fast and reversible
transition from the amorphous to the crystalline phase .
although crystal
nucleation in amorphous systems , especially metallic and covalent
glasses , is beyond the scope of this review , we refer the reader to
the excellent work of kelton and greer for a detailed introduction . here
we just note that in phase change
memories the amorphous phase is often heated above the glass transition
temperature , so that crystal nucleation occurs within the supercooled
liquid phase .
phase - change materials used in optical and electronic
devices are typically tellurium - based chalcogenide alloys ( see ref ( 305 ) ) . the family of the pseudobinary
compounds ( gete)x(sb2te3)y represents a prototypical system .
although both the structure and dynamics of these systems are far
from trivial , nucleation from the melt takes place on the nanosecond
time scale for a wide range of supercooling .
thus , with phase - change materials , we have a great opportunity to
investigate nucleation in a complex system by means of brute - force
md simulations .
we note that the crystallization of these systems
has been extensively characterized by different experimental techniques
[ particularly tem and afm ( see section 1.2 ) ; the crystallization kinetics has also
been recently investigated by means of ultrafast - heating calorimetry and ultrafast x - ray imagining ] , but because of the exceptionally high nucleation rates ,
it is difficult to extract information about the early stages of the
nucleation process .
unfortunately , phase - change materials require ab
initio methods or sophisticated interatomic potentials with first - principles
accuracy .
in fact , several attempts have been made to study nucleation
in phase - change materials by ab initio md in very small systems .
although these studies provided useful insights into the nucleation
mechanism , severe finite - size effects prevented the full characterization
of the crystallization process .
the limited length and time scales
typical of first - principles calculations were recently outstripped
in the case of the prototypical phase - change material gete by the
capabilities of a neural network interatomic potential .
such potentials allow for a computational speedup
of several orders of magnitude compared to conventional ab initio
methods while retaining an accuracy close to that of the latter .
although nucleation rates have not yet been
calculated , detailed investigations of homogeneous and heterogeneous
nucleation have already been reported .
for instance ,
as shown in figure 10 , a single - crystalline nucleus formed in a 4000-atom model of supercooled
liquid gete in the 625675 k temperature regime within a few
hundred picoseconds . on the same timescale ,
several nuclei appeared
below 600 k , suggesting that the free energy barrier for nucleation
is vanishingly small for this class of materials just above the glass
transition temperature .
this is because of the fragility of the supercooled liquid , which displays a
substantial atomic mobility even at large supercoolings .
thus , in this particular case , the kinetic
prefactor ( see eq 5 ) is not hindered that much by the strong
supercooling ,
whereas the free energy difference between the liquid and the crystal ( see eq 1 ) skyrockets as expected , leading to the exceedingly
high nucleation rates characteristic of these materials . fast crystallization
of supercooled gete by means of md simulations
with neural - network - derived potentials .
the number of crystalline
nuclei larger than 29 atoms at different temperatures in the supercooled
liquid phase is reported as a function of time ( notice the exceedingly
small time scale at strong supercooling ) .
two snapshots at the highest
and lowest temperatures showing only the crystalline atoms are also
reported .
at high temperature , a single nucleus is present , whereas
several nuclei ( each one depicted in a different color ) appear at
low temperature .
copyright 2013 american
chemical society . in conclusion , whereas
md simulations have by no means exhausted
the field of crystal nucleation of atomic liquids , they have certainly
provided insight into a number of interesting systems and paved the
way for the study of more complex systems , as we shall see in the
following sections .
ice
nucleation impacts many different areas , ranging from aviation to biological cells and earth s
climate .
it is therefore not surprising
that a considerable body of work has been carried out to understand
this fundamental process .
we can not cover it all here ; instead , we
give a general overview of the field , starting with a discussion of
nucleation rates .
this allows us to directly compare experiments and
simulations and to identify strengths and weaknesses of different
approaches .
experimental nucleation
rates have been measured over a broad range of temperatures , most
often with micrometer - sized water droplets so as to avoid heterogeneous
nucleation . in figure 11 , we bring together nucleation rates obtained from various experiments ,
along with computed nucleation rates . compilation of homogeneous
nucleation rates for water , obtained
by experiments and simulations .
the x axis shows
the supercooling with respect to the melting point of different water
models or 273.15 k for experiment .
the y axis shows
the logarithm of the nucleation rate in m s. rates obtained with computational approaches are
shown as solid symbols ; experimental rates are shown as crossed symbols .
for each computational study , the computational approach and the water
force field used
is not included in this graph , because their
study was conducted at a small supercooling ( 20 k ) , which resulted
in a very low estimated nucleation rate far outside this plot ( it
would correspond to 83 on the y axis ) .
taborek performed measurements with different setups ,
namely , using sorbitan tristearate ( sts ) and sorbitan trioleate ( sto )
as surfactants .
data for the graph were taken from refs ( 124 , 299 , 301 , and 322335 ) . accessing nucleation rates from
md simulations became feasible
only in the past few years as a result of advances in force fields
( such as the coarse - grained mw potential )
and enhanced sampling techniques described earlier ( see section 1.3.2 ) .
these
methods have therefore been widely used for studies of not only homogeneous
but also heterogeneous nucleation ( see section 2.4.2 ) . from the comparison of experimental
and computational nucleation rates reported in figure 11 ,
first ,
nucleation rates vary hugely with supercooling , by a factor of more
than 10 .
second , nucleation rates differ substantially
( approximately 10 orders of magnitude ) between simulations ( solid
symbols ) and experiments ( crossed symbols ) at relatively small supercoolings
( 3050 k ) . at larger supercoolings , the agreement appears
to be slightly better , even though very few simulations have been
reported at very strong supercooling .
the third striking feature is
that , whereas the experimental results agree well with each other
( within 12 orders of magnitude ) , the computational rates differ
from each other by a factor of approximately 10 . what is the cause of disagreement between different computational
approaches ?
part of the reason is certainly that different water models
lead to different rates ; see , for example , espinosa et al . yet , even if the same water model is employed ,
the rates do not agree with each other very well .
an early
study by moore and molinero succeeded
in calculating the avrami exponent for the crystallization
kinetics of ice from brute - force md simulations at very strong supercooling ,
obtaining results remarkably similar to experiment . however , mw nucleation rates turned out to be far less encouraging .
in fact , li et al . and reinhardt and
doye both performed simulations using
the mw model , obtaining nucleation rates that differed by about 5
orders of magnitude .
the only major difference was the enhanced sampling
technique employed , ffs by li et al . and us by reinhardt and doye .
the statistical uncertainties of the two approaches ( 12 orders
of magnitude ) are much smaller than the 5-orders - of - magnitude discrepancy
between the two studies .
it was also shown that the two methods agree
very well with each other for colloids , for example ( see section 2.1 ) .
the use of different computational approaches therefore
also seems to be unlikely as the source of the disagreement .
what
the cause is remains elusive . because we can not cover all of
the work shown in figure 11 in detail here , we now discuss
just two studies
first , that of sanz et al . , which agrees best with the experimental rates .
the authors used
the tip4p/2005 and tip4p / ice water models in combination with seeded
md simulations ( see section 1.3.2 . for more details ,
seeding involves considerably
more assumptions than , for example , us or ffs . in particular
, the
approach assumes a cnt - like free energy profile , although it does
not usually employ the macroscopic interfacial free energy .
furthermore ,
the temperature dependence of key quantities such as and ( see section 1.1.1 ) is approximated .
nevertheless , the
agreement between their nucleation rates and experiment seemingly
outperformed other approaches . in a more recent work , espinosa et
al .
however , it should be noted that the
good agreement between the nucleation rates reported in refs ( 51 and 326 ) and the experimental data could originate from error cancellation .
in fact , whereas the rather conservative definition of crystalline
nucleus adopted in these works will lead to small nucleation barriers
( and thus to higher nucleation rates ) , the tip4p family of water models
is characterized by small thermodynamic driving forces to nucleation , which , in turn , results in smaller nucleation
rates .
the second work we briefly discuss here is the very recent
study
( 2015 ) of haji - akbari and debenedetti .
the authors directly calculated the nucleation rate at 230 k of
an all - atom model of water ( tip4p / ice ) using a novel ffs sampling
approach .
this was a tour de force ,
but strikingly , their rates differed from experiment by about 11 orders
of magnitude .
the authors noted that this might be as close as one
can actually get to experiment with current classical water models .
this is because of the extreme sensitivity of nucleation rates to
thermodynamic properties such as and , which , according to cnt , enter exponentially
( section 1.1.1 )
in the definition of .
for instance ,
an uncertainty of only 67%
for at 235 k leads to an
error of about 9 orders
of magnitude in .
experimental
estimates for range from 25 to 35 mn / m ; computational estimates range from about 20 to 35 mn / m . as
another example , haji - akbari and debenedetti explicitly quantified the extent to which the tip4p / ice model underestimates
the free energy difference between the crystalline and liquid phases
and found that the mismatch between and alone
leads to an overestimation of the
free energy barrier for nucleation of about 60% , which translates
into nucleation rates up to 9 orders of magnitude larger .
in fact ,
taking into account such a discrepancy brings the results of haji - akbari
and debenedetti within the confidence interval of the experimental
data .
thus , it is clear that we simply do not know some key quantities
accurately enough to expect perfect agreement between simulations
and experiments .
in addition to issues of modeling water / ice
accurately , finite - size
effects can be expected to also play a role [ as they do with lennard - jones
systems ( section 2.2 ) and molecules in solution ( section 2.5 ) ] . only recently was this issue addressed
explicitly for ice nucleation by english and tse in unbiased simulations with the mw model .
they were able
to simulate systems containing nearly 10 million water molecules on
a microsecond time scale and found that larger systems favor the formation
of crystallization precursors compared to smaller ones .
interestingly ,
lifetimes of the precursors were found to be less sensitive to system
size .
a quantitative understanding of finite - size effects on nucleation
rates remains elusive nevertheless . in summary , it can be said
that , in terms of accurate nucleation
rates , experiments are still clearly superior to simulations .
however ,
the advantage of simulations is that the nucleation mechanism can
also be obtained , which , at present , is not possible with experiments ,
although femtosecond x - ray laser spectroscopy might be able to partially
overcome this limitation in the near future . in 2002
were the first to report a nucleation event
in an unbiased simulation based on an all - atom model of water ( tip4p ) .
their landmark work opened the doors to the study of ice nucleation
at an atomistic level .
they found that nucleation took place once
a sufficient number of long - lived hydrogen bonds were formed with
a nucleus of ice .
recent evidence suggests that , most likely , their
nucleation trajectory was driven by finite - size effects .
together with the simulations of vrbka and jungwirth , also affected by severe finite - size effects , the work of matsumoto et al . remains , to date ,
the only seemingly unbiased md simulation observing homogeneous ice
nucleation with an all - atom force field .
what really enabled
the community to investigate ice formation at a molecular level was
the development of the coarse - grained mw potential for water in the early 2010s . using unbiased md simulations
based on the mw force field , moore and molinero in 2011
provided evidence that , in the supercooled
regime around the homogenous nucleation temperature , th , the fraction of 4-fold - coordinated water molecules
increases sharply prior to a nucleation event . in a separate work ,
the same authors suggested that , at
very strong supercooling , the critical nucleus is mostly made of cubic
ice , which subsequently evolves into a mixture of stacking - disordered
cubic and hexagonal ice layers . in the same year , li et al . identified another structural motif that might
play a role in ice nucleation .
they consistently observed a topological
defect structure in growing ice nuclei in their ffs simulations based
on the mw representation of water .
this defect , depicted in figure 12a , can be described
as a twin boundary with 5-fold symmetry , and it has also been observed in nucleation simulations of tetrahedral liquids
simulated with the stillinger weber potential , on which the
mw coarse - grained model was built . ( a ) formation of a topological defect
with 5-fold symmetry during
homogeneous ice nucleation .
the snapshots ( i iv ) show the time
evolution of the defect structure , indicated by black dashed lines .
reprinted with permission from ref ( 322 ) ( copyright 2011 royal
society of chemistry ) , in which li et al
( b ) nucleation
of an ice cluster forming homogeneously from i0-rich precritical
nuclei .
water molecules belonging to ic , ih ,
a clathrate - like phase , and i0 are depicted in yellow ,
green , orange , and magenta , respectively .
( iii ) the crystalline cluster
evolves in a postcritical nucleus , formed by an ic - rich
core surrounded by an i0-rich shell .
( iv ) the same postcritical
nucleus as depicted in iii , but only particles with 12 or more connections
( among ice - like particles ) are shown .
the color map refers to the
order parameter q12 specified in ref ( 325 ) , from which this image
was reprinted with permission ( copyright 2014 nature publishing group ) .
the unbiased md simulations on which the analysis is based feature
10000 mw molecules . in 2012 ,
another significant
leap in understanding the nucleation
mechanism of ice from a structural point of view was made by combining
experimental and computational techniques .
specifically , malkin et al . showed that ice forming homogeneously
is stacking - disordered ( the corresponding ice structure was called
isd ) , meaning that it is made out of cubic and hexagonal
ice layers stacked in a random fashion . in 2014 , two studies
substantiated the potential relevance of precursor
structures prior to ice formation .
liquid transition in supercooled water in a molecular
model of water ( st2 ) . in their study
,
the authors sampled the energy landscape of supercooled water and
found two metastable liquid basins corresponding to low - density ( ldl )
and high - density ( hdl ) water .
the appealing idea behind the transition
from hdl to ldl prior to ice nucleation is that ldl is structurally
closer to ice than hdl .
note that the existence of two metastable
liquid basins was not a general finding : the mw model does not have
a basin for ldl , for example .
indeed ,
the presence of this liquid liquid phase transition is a highly
debated issue .
another conceptually similar
idea is ice formation through ice
0 ( i0 ) , proposed by russo et al . instead of a liquid
liquid phase transition that transforms
water into another liquid state prior to nucleation , the authors proposed
a new ice polymorph ( i0 ) to bridge the gap between supercooled
water and ice .
i0 is a metastable ice polymorph and is
structurally similar to the supercooled liquid .
it has a low interfacial
energy with both liquid water and ice ic / ih .
russo et al . therefore proposed i0 to bridge liquid water
to crystalline ic / ih .
indeed , the authors found
i0 at the surface of growing ice nuclei in md simulations ;
we show part of a nucleation trajectory in figure 12b .
furthermore , they showed that the shape
of the nucleation barrier is much better described by a core shell - like
model ( ic / ih core surrounded by i0 ) compared to the classical nucleation model .
this is important ,
because it suggests that models that are based solely on cnt assumptions
might not be appropriate for describing homogeneous ice nucleation .
however , the emergence of i0 has not yet been reported
by any other nucleation study , including the recent work of haji - akbari
and debenedetti that we previously mentioned
in the context of nucleation rates . in that work
, the authors performed a topological analysis of the nuclei ,
validated by the substantial statistics provided by the ffs simulations .
as depicted in figure 13 , the majority of nuclei that reached the critical nucleus size contained
a large amount of double - diamond cages ( ddcs , the building blocks
of ic ) , whereas nuclei rich in hexagonal cages ( hcs , the
building blocks of ih ) had a very low probability to overcome
the free energy barrier for nucleation .
in addition , even postcritical
nuclei had a high content of ddcs , whereas hcs did not show any preference
to appear within the core of the postcritical nuclei .
this evidence
is consistent with the findings reported in ref ( 323 ) and in contrast with
the widely invoked scenario in which a kernel of thermodynamically
stable polymorph ( in this case , ih ) is surrounded by a
shell of a less stable crystalline structure ( in this case , ic ) .
( left ) a typical double - diamond cage ( ddc , blue ) and a
hexagonal
cage ( hc , red ) , the building blocks of ic and ih , respectively .
( right ) temporal evolution of an ice nucleus from
( i , ii ) the early stages of nucleations up to ( v , vi ) postcritical dimensions ,
as observed in the ffs simulations of haji - akbari and debenedetti .
about 4000 water molecules , modeled with the
tip4p / ice potential , were considered
in the npt ensemble at t
40 k. one can clearly notice the abundance of ddcs throughout the
whole temporal evolution .
in contrast , hc - rich nuclei have only a
marginal probability to cross the nucleation barrier ( see text ) . reprinted
with permission from ref ( 327 ) .
copyright 2015 national academy of sciences . in the past few years , the understanding of homogeneous
ice nucleation
has improved dramatically .
we now have a good understanding of the
structure of ice that forms through homogeneous nucleation , stacking - disordered
ice .
furthermore , there is very good agreement ( within 2 orders of
magnitude ) between experimental nucleation rates in a certain temperature
range .
computational methods face the problem of being very sensitive
to some key thermodynamic properties ; the nucleation rates they predict
are therefore less accurate . on the other hand ,
they allow us to study
conditions that are very challenging to probe experimentally , and
they also provide insight into the molecular mechanisms involved in
the crystallization process .
as
mentioned in the previous section , homogeneous ice nucleation becomes
extremely slow at moderate supercooling .
we do not , for example , have to wait for
temperatures to reach 30 c before we have to use a deicer
on our car windows .
in fact , the formation of ice in nature occurs
almost exclusively heterogeneously , thanks to the presence of foreign
particles .
these ice - nucleating agents facilitate the formation of
ice by lowering the free energy barrier for nucleation ( see figure 1 ) . indeed , the work
of sanz et al . , in which homogeneous
ice nucleation was studied using seeded md ( see section 1.3.1 ) , found rates so low
at temperatures above t = 20 k that they concluded
that all ice nucleation above this temperature must occur heterogeneously .
homogeneous nucleation is still of great importance in atmospheric
processes and climate modeling , as under certain conditions , both
heterogeneous and homogeneous nucleation are feasible routes toward
the formation of ice in clouds , as reported in ref ( 354 ) , for example . in
addition to the challenges
( both computational and experimental ) faced
when investigating homogeneous ice nucleation , one also has to consider
the structure of the water surface interface and how this impacts
the nucleation rate .
generally , the experimental data for the rates
and characterization of the interfacial structure come from two different
communities : climate scientists have provided much information on
how various particles , often dust particles or biological matter such
as pollen , affect ice nucleation ( as depicted in figure 14 ) , whereas surface scientists
have invested a great deal of effort in trying to understand , at the
molecular level , how water interacts with and assembles itself at
surfaces ( see , e.g. , ref ( 355 ) ) .
this means that there is a huge gap in our understanding ,
as the surfaces of the particles used to obtain rates are often not
characterized , whereas surface science experiments are generally carried
out at pristine , often metallic , surfaces under ultrahigh - vacuum conditions .
we will see in this section that computational studies have gone some
way toward bridging this gap , although there is still much work to
be done should we wish to quantitatively predict a material s
ice - nucleating efficacy .
potential immersion - mode ice nucleus concentrations , nice , a measure of the efficiency of a given
substance
to boost heterogeneous ice nucleation , as a function of temperature
for a range of atmospheric aerosol species .
note the wide range of
nucleating capability for materials as diverse as soot and bacterial
fragments over a very broad range of temperatures .
copyright 2012 royal society of chemistry . from a computational
perspective , it is the surface science experiments that lend themselves
most readily to modeling .
in fact , even relatively expensive computational
methods such as density functional theory ( dft ) , which have not featured
much in this article , have proven indispensable in furthering our
understanding of how water behaves at surfaces , especially when used
in conjunction with experiments ( see , e.g. , refs ( 355 and 357 ) for an overview ) . as such , early
computational studies focused on understanding how the surface affected
the first few layers of water , especially with respect to the concept
of lattice mismatch ( see section 2.2 ) , where a surface that has a structure commensurate
with ice acts as a template for the crystal .
nutt and co - workers investigated the adsorption structures of water at a model hexagonal
surface and at baf2(111 ) using interaction potentials derived
from ab initio calculations .
although the surfaces under investigation
had structures that matched the basal face of ice well , they found
disordered structures of water to be more favorable than ice - like
overlayers . using dft , hu and michaelides investigated the adsorption
of water on the ( 001 ) face of the clay mineral kaolinite , a known ice - nucleating agent in the atmosphere .
the ( 001 ) surface
of kaolinite exposes a pseudohexagonal arrangement of oh groups that
were proposed to be the cause of its good ice - nucleating ability .
although they found that a stable ice - like
layer could form at the surface , the amphoteric nature of the kaolinite
surface , depicted in figure 15 , meant that all of water molecules could participate in four
hydrogen bonds , making further growth on top of the ice - like layer
unfavorable .
investigated adsorption
of water on kaolinite using the clayff and spc / e potentials and grand canonical monte carlo ( gcmc ) .
although some hexagonal
patches of water were seen in the contact layer , the overall structure
was mostly disordered , and the hexagonal structures that did form
were strained relative to those found in ice . also using gcmc , cox
et al .
they found that , for atomically flat surfaces ,
a nominally zero lattice mismatch produced disordered contact layers
comprising smaller - sized rings ( i.e. , pentagons and squares ) and observed
hexagonal ice - like layers only for surfaces with larger lattice constants .
the
amphoteric nature of kaolinite is important to its ice - nucleating
ability .
( left ) ice - like contact layers at the kaolinite surface ,
with the ( a , c ) basal and ( b , d ) prism faces of ice adsorbed on kaolinite ,
as viewed from the ( a , b ) side and ( c , d ) top .
( right ) adsorption energy
of ice on kaolinite when bound through either its basal face ( red
data ) or its prism face ( blue data ) for varying numbers of layers
of ice .
( open and solid symbols indicate data obtained with a classical
force field and with dft , respectively . )
when only the contact layer
is present , the basal face structure is more stable than the prism
face structure , but as soon as more layers are present , the prism
face structure becomes more stable .
this can be understood by the
ability of the prism face to donate hydrogen bonds to the surface ,
and to the water molecules above , through the dangling
hydrogen bonds seen in b and d. reprinted with permission from ref ( 371 ) .
2010 , the above types of study were the state
of the
art for simulations of heterogeneous ice nucleation .
although they
provided evidence that properties such as lattice match alone are
insufficient to explain a material s ice - nucleating ability ,
because ice nucleation itself was not directly observed , only inferences
could be drawn about how certain properties might actually affect
ice nucleation .
yan and patey investigated
the effects of electric fields on ice nucleation using brute - force
molecular dynamics ( the electric fields were externally applied and
were not due to an explicit surface ) .
they found that the electric
field needed to act over only a small range ( e.g. , 10 ) and
that the ice that formed near the surface
was ferroelectric
cubic ice , although the rest of the ice that formed above was not .
cox et al . performed simulations of heterogeneous ice nucleation in which the atomistic natures of both the
water and the surface were simulated explicitly , using tip4p/2005 water and clayff to describe kaolinite . despite the fact that
the simulations were affected by finite - size effects
, the simulations
revealed that the amphoteric nature of the kaolinite is important to ice nucleation . in the liquid
, a strongly bound
contact layer was observed , and for ice nucleation to occur , significant
rearrangement in the above water layers was required .
it was found
that ice nucleated with its prism face , rather than its basal face ,
bound to the kaolinite , which was unexpected based on the theory that
the pseudohexagonal arrangement of oh groups at the surface was responsible
for templating the basal face .
cox et al . rationalized the formation
of the prism of ice at the kaolinite as being due to its ability to
donate hydrogen bonds both to the surface and to the water molecules
above ( see figure 15 ) , whereas the basal face maximizes hydrogen bonding to the surface
only .
more recent simulation studies , employing
rigid and constrained models of kaolinite , have also found the amphoteric
nature of the kaolinite surface to be important .
however , the heterogeneous nucleation mechanism of water
on clays is yet to be validated by unconstrained simulations unaffected
by substantial finite - size effects . as in the case
of simulations of homogeneous ice nucleation
, the use of the coarse - grained
mw potential has seen the emergence
of computational studies that actually quantify the ice - nucleating
efficiencies of different surfaces .
recently , lupi et al . investigated ice nucleation at carbonaceous
surfaces ( both smooth graphitic and rough amorphous surfaces ) using
cooling ramps to measure nonequilibrium freezing temperatures tf
tf tfhomo , where tf is the temperature at which
ice nucleates in the presence of a surface and tfhomo = 201
1 k is the temperature at which homogeneous ice nucleation occurs .
it was found that the rough amorphous surface did not enhance ice
nucleation ( tf = 0 k ) , whereas
the smooth graphitic surfaces promoted ice nucleation ( tf = 1113 k ) .
this was attributed to
the fact that the smooth graphitic surface induced a layering in the density profile of water above the surface , whereas the rough
amorphous surface did not .
lupi and molinero quantified the extent
of layering as where (z ) is the density
of water at a height z above the surface and 0 (zbulk ) , where zbulk is a height where the density profile is
bulk - like . in a subsequent work using the same methodology , lupi and
molinero investigated how the hydrophilicity
of graphitic surfaces affected ice nucleation .
the hydrophilicity
of the surface was modified in two different ways : first , by uniformly
modifying the water surface interaction strength and , second ,
by introducing hydrophilic species at the surface .
it was found that
the two ways produced qualitatively different results : uniformly modifying
the interaction potential led to enhanced ice nucleation , whereas
increasing the density of hydrophilic species was detrimental to ice
nucleation ( although the surfaces still enhanced nucleation relative
to homogeneous nucleation ) . it was concluded that hydrophilicity is
not a good indicator of the ice - nucleating ability of graphitic surfaces .
as for the difference between increasing the hydrophilicity by uniformly
modifying of the interaction potential and by introducing hydrophilic
species , lupi and molinero again saw that the extent of layering in
water s density profile above the surface correlated well with
the ice - nucleating efficacy .
the general applicability of the layering
mechanism , however , was left as an open question .
cox et al . addressed the question of the general applicability of the layering
mechanism by investigating ice nucleation rates over a wider range
of hydrophilicities ( by uniformly changing the interaction strength )
on two surfaces with different morphologies : ( i ) the ( 111 ) surface
of a face - centered - cubic lj crystal ( fcc-111 ) that provided distinct
adsorption sites for the water molecules and ( ii ) a graphitic surface ,
similar to that of lupi et al .
although
it was found that the layering mechanism ( albeit with a slight modification
to the definition used by lupi et al . ) could describe the ice - nucleating
behavior of the graphitic surface , at the fcc-111 surface , no beneficial
effects of layering were observed .
this was attributed to fact that
the fcc-111 surface also affected the structure of the water molecules
in the second layer above the surface , in a manner detrimental to
ice nucleation .
it was concluded that layering of water above the
surface can be beneficial to ice nucleation , but only if the surface
presents a relatively smooth potential energy surface to the water
molecules .
the studies at the carbonaceous and fcc-111 surfaces discussed above hinted that the heterogeneous nucleation mechanism
could be very different at different types of surfaces .
although there
is experimental evidence that , for example , different carbon nanomaterials
are capable of boosting ice nucleation ( see , e.g. , ref ( 378 ) ) , most experiments can
only quantify the ice - nucleating ability of the substrates ( see section 1.2 ) .
however ,
the structure of the water substrate interface and any insight
into the morphology of the nuclei are typically not available , making
simulations essential to complement the experimental picture . in this
respect , zhang et al . assessed that
the ( regular ) pattering of a generic crystalline surface at the nanoscale
can strongly affect ice formation .
more generally , the interplay between
hydrophobicity and surface morphology was recently elucidated by fitzner
et al .
brute - force md simulations of
heterogeneous ice nucleation were performed for the mw water model
on top of several crystalline faces of a generic fcc crystal , taking
into account different values of the water surface interaction
strength , as well as different values of the lattice parameter .
the
latter is involved in the rather dated concept of zero lattice mismatch , which we introduced in section 2.2 ( see eq 7 ) and which has been often
quoted as the main requirement of an effective ice - nucleating agent .
however , a surprisingly nontrivial interplay between hydrophobicity
and morphology was observed , as depicted in figure 16 .
clearly , neither the layering nor the
lattice mismatch alone are sufficient to explain such a diverse scenario .
in fact , the authors proposed three additional microscopic factors
that can effectively aid heterogeneous ice nucleation on crystalline
surfaces : ( i ) an in - plane templating of the first water overlayer
on top of the crystalline surface ; ( ii ) a first overlayer buckled
in an ice - like fashion ; and ( iii ) enhanced nucleation in regions of
the liquid beyond the first two overlayers , possibly aided by dynamical
effects and/or structural templating effects of the substrate extending
past the surface water interface .
in addition , it turned out that
different lattice parameters can lead to the nucleation and growth
of up to three different faces of ice [ basal , prismatic , and secondary
prismatic ( { 1120 } ) ] on top of the very same surface ,
adding a layer of complexity to the nucleation scenario
. insights
into the interplay between hydrophobicity and morphology were also
very recently obtained by bi et al . , who investigated heterogeneous ice nucleation on top of graphitic
surfaces by means of ffs simulations using the mw model .
among their
findings , the authors suggested that the efficiency of ice - nucleating
agents can be a function not only of surface chemistry and surface
crystallinity but of the elasticity of the substrate as well .
( a ) heat maps representing
the values of ice nucleation rates on top of four different fcc surfaces
[ ( 111 ) , ( 100 ) , ( 110 ) , ( 211 ) ] , plotted as a function of the adsorption
energy , eads , and the lattice parameter , afcc .
the lattice mismatch with respect
to ice on ( 111 ) is indicated below the corresponding graph in panel
a. the values of the nucleation rate , , are
reported as log10(j / j0 ) , where j0 refers to the
homogeneous nucleation rate at the same
temperature .
( b ) sketches of the different regions ( white areas ) in
( eads , afcc ) space in which a significant enhancement of the nucleation rate
is observed .
each region is labeled according to the face of ih nucleating and growing on top of the surface [ basal , prismatic ,
or ( 11/200 ) , together with an indication of what
it is that enhances the nucleation , where temp , buck ,
and highe refer to the in - plane template
of the first overlayer , the ice - like buckling of the contact layer ,
and the nucleation for high adsorption energies on compact surfaces ,
respectively .
reinhardt and doye used umbrella sampling
with the mw model to investigate nucleation at a smooth planar interface
and at an ice - like surface .
they found that the flat planar interface
did not help nucleate ice and that homogeneous nucleation was the
preferred pathway .
one explanation given for this finding was that ,
as the density of liquid water is higher than that of ice , an attractive
surface favors the liquid phase .
it was also noted that the mw potential
imposes an energy penalty for nontetrahedral triplets , that removing
neighbors at the surface decreases this energetic penalty , and that
this reduction in tetrahedrality favors the liquid phase .
cabriolu
and li recently studied ice nucleation at graphitic surfaces using
forward flux sampling , again with the
mw model . under the assumptions that depends linearly on t and
that does not depend on t ,
cabriolu and li also extracted the values of the contact
angle
at different temperatures , which , along with the free energy barrier ,
turned out to be consistent with cnt for heterogeneous nucleation
( see section 1.1.3 ) .
although intriguing , the generality of this finding to surfaces
that include strong and localized chemical interactions remains an
open question .
we have seen that , for both homogeneous and heterogeneous
nucleation , using the coarse - grained mw model has greatly enhanced
our ability to perform quantitative , systematic simulation studies
of ice nucleation .
we must face the fact , however , that this approach
will further our understanding of heterogeneous ice nucleation only
so far . as discussed for kaolinite ,
an explicit treatment
of the hydrogen bonds is essential in describing heterogeneous ice
nucleation .
in addition , the mw model ( as well as the majority of
fully atomistic water models ) can not take into account surface - charge
effects .
surfaces can polarize water molecules in the proximity of
the substrate , alter their protonation state , and even play a role
in determining the equilibrium structure of the liquid at the interface .
in light of recent studies
, it seems that these
effects can heavily affect nucleation rates of many different systems .
as discussed , enhanced
sampling techniques such as umbrella sampling and forward flux sampling have been applied to heterogeneous ice nucleation with the mw model ,
and we have seen the latter applied successfully to homogeneous nucleation
with an all - atom model of water ; the
computational cost , however , was huge .
although the presence of an
ice - nucleating agent should help reduce this cost , the parameter space
that we wish to study is large , and systematically studying how the
various properties of a surface affect ice nucleation requires the
investigation of many different surfaces .
simulating heterogeneous ice nucleation under realistic conditions
does not mean just mild supercooling ; we also need realistic models
of the surfaces that we wish to study !
most studies of kaolinite have
considered only the planar interface , even though , in nature , kaolinite
crystals have many step edges and defects .
ice nucleation at agi was
also recently studied , although bulk truncated
structures for the exposed crystal faces were used . in the case of
agi(0001 ) , this is problematic , as the wurtzite structure of the crystal
means that this basal face is polar and likely to undergo reconstruction .
furthermore , agi is photosensitive , and it
has been shown experimentally that exposure to light enhances its
ice - nucleating efficacy , suggesting
that structural motifs at the surface very different from those expected
from the bulk crystal structure are important .
the development of
computational techniques to determine surface structures , along with
accurate force fields to describe the interaction with water , will
be essential if we are to fully understand heterogeneous ice nucleation .
understanding
crystal nucleation from solution is a problem of great practical interest ,
influencing , for instance , pharmaceutical , chemical , and food processing
companies .
being able to obtain a microscopic description of nucleation
and growth would allow the selection of specific crystalline polymorphs ,
which , in turn , can have an enormous impact on the final product .
an ( in)famous case illustrating the importance
of this issue is the drug ritonavir , originally
marketed as solid capsules to treat hiv .
this compound has at least
two polymorphs : the marketed and thoroughly tested polymorph ( pi ) and a second more stable crystalline phase pii that appeared after pi went to market .
pii is basically nonactive as a drug because of a much lower solubility
than pi . as such and , most importantly , because of the
fact that pii had never been properly tested , ritonavir
was withdrawn from the market in favor of a much safer alternative
in the form of gel capsules .
many other examples could be listed , as various environmental factors ( such
as the temperature , the degree of supersaturation , the type of solvent ,
and the presence of impurities ) can play a role in determining the
final polymorph of many classes of molecular crystals .
thus , it is
highly desirable to pinpoint a priori the conditions leading to the
formation of a specific polymorph possessing the optimal physical / chemical
properties for the application of interest .
the term nucleation from solution encompasses a whole range of systems ,
from small molecules in aqueous or organic solvents to proteins , peptides ,
and other macromolecular systems in their natural environment .
these
systems are very diverse , and a universal nucleation framework is
probably not applicable to all of these cases .
the review by dadey
et al . discusses the role of the solvent
in determining the final crystal .
many aspects of the nucleation of
solute precipitates from solution were recently reviewed by agarwal
and peters . in this section ,
a central issue
with md simulations of nucleation from solution
is the choice of order parameters able to distinguish different polymorphs .
many of these collective variables have been used in enhanced - sampling
simulations ( see section 1.3.2 ) .
md simulations of nucleation from solution are particularly challenging
because of finite - size effects due to the nature of the solute / solvent
system . in the nvt and npt ensembles , where md simulations of nucleation are usually
performed
however ,
the ratio between the numbers of solute molecules in the crystalline
phase and in the solution varies during the nucleation events , leading
to a change in the chemical potential of the system .
this occurrence
has negligible effects in the thermodynamic limit , but it can substantially affect the outcomes of , for example ,
free - energy - based enhanced - sampling simulations .
simulations of models
containing a large number ( 1010 ) of
molecules can alleviate the problem , although this is not always the case .
an analytic correction to the
free energy for npt simulations of nucleation of
molecules from solution was proposed in refs ( 394 and 404 ) on the basis of a number of previous works ( see , e.g. , refs ( 152 , 400 , and 405 ) ) and applied
later in ref ( 406 ) as
well .
alternative approaches include seeded md simulations ( see section 1.3.1 ) and simulations mimicking the grand canonical ensemble ( vt ) , where the number of constituents
is not a constant and the number of molecules in in this case
it is worth noticing that nucleation
of molecules in solution is a challenging playground for experiments
as well .
for instance , quantitative data about nucleation of ionic
solutions are amazingly hard to find within the current literature .
this is in stark contrast with the vast amount of data covering , for
example , ice nucleation ( as illustrated in section 2.4 ) . among the countless
organic compounds ,
urea molecules can be regarded as a benchmark for
md simulation of nucleation from solution .
this is because urea is
a system of great practical importance that ( i ) displays fast nucleation
kinetics and ( ii ) has only one experimentally characterized polymorph .
early studies by piana and co - workers focused on
the growth rate of urea crystals , which turned out to be consistent
with experimental results .
years later , the inhibition of urea crystal
growth by additives was investigated by salvalaglio et al .
the investigation of the early stages of nucleation was tackled
only recently by salvalaglio et al . for
urea molecules in aqueous and organic ( ethanol , methanol , and acetonitrile )
solvents . in these studies ,
the resulting free energies , modified for finite - size effects related
to the solvent , suggested that different
solvents lead to different nucleation mechanisms . whereas a single - step
nucleation process is favored in methanol and ethanol , a two - step
mechanism ( see section 1.1.2 )
emerges for urea molecules in acetonitrile and water , as
depicted in figure 17 . in this case , the initial formation of an amorphous albeit
dense
note that , according to the free energy surface reported in figure 17a , the amorphous
clusters ( configurations 2 and 3 in figure 17a , b ) are unstable with respect to the liquid
phase ; that is , they are not metastable states having their own free
energy bases , but rather , they originate from fluctuations within
the liquid phase .
this evidence , together with the fact that the transition
state ( configuration 4 in figure 17a , b ) displays a fully crystalline core , prompts the
following , long - standing question : if the critical nucleus is mostly
crystalline and the amorphous precursors are unstable with respect
to the liquid phase , can we truly talk about a two - step mechanism ?
reference ( 394 ) suggests
the terms ripening regime two - step nucleation when
dealing with stable amorphous precursors and crystallization - limited
two - step nucleation when the amorphous clusters are unstable
and the limiting step is the formation of a crystalline core within
the clusters .
salvalaglio et al . also
observed two polymorphs ( pi and pii ) in the
early stages of the nucleation process .
pi corresponds
to the experimental crystal structure and is the most stable structure
in the limit of an infinite crystal .
pii , however , is more stable for small crystalline clusters .
in agreement with the ostwald rule ( see section 2.2 ) , the small crystalline clusters that
initially form in solution are of the pii type , and the
subsequent conversion from pii to pi seems to
be an almost - barrierless process .
( a ) free - energy surface ( fes ) associated
with the early stages
of nucleation of urea in aqueous solution , as obtained by salvalaglio
et al . from a well - tempered metadynamics
simulation of 300 urea molecules and 3173 water molecules , within
an isothermal isobaric ensemble at p = 1 bar
and t = 300 k ( simulation s2 in ref ( 406 ) with a correction term
to
the free - energy included to represent the case of a constant supersaturation
of 2.5 ) .
the contour plot of the fes is reported as a function of
the number of molecules belonging to the largest connected cluster
( n , along the ordinate ) and the number of molecules
in a crystal - like configuration within the largest cluster ( no , along the abscissa ) .
note that n no by definition and that cnt
would prescribe that the evolution of the largest cluster in the simulation
box is such that n = no ( i.e. , only the diagonal of the contour plot is populated ) .
the
presence of an off - diagonal basin provides evidence of a two - step
nucleation of urea crystals from aqueous solutions .
this is further
supported by the representative states sampled during the nucleation
process , shown in panel b. urea molecules are represented as blue
spheres , and red connections are drawn between urea molecules falling
within a cutoff distance of 0.6 nm of each other .
an approach similar to that employed in ref ( 413 ) was used to investigate
crystal nucleation of 1,3,5-tris(4-bromophenyl)benzene molecules in
water and methanol .
these simulations showed the emergence of prenucleation
clusters , consistent with recent experimental results based on single - molecule real - time transmission
electron microscopy ( smrt - tem ; see section 1.2 ) .
the formation of prenucleation clusters
in the early stages of nucleation from solution has been observed
in several other cases . this is of great relevance , as cnt is not able to account for two-
( or multi- ) step nucleation .
md simulations have been of help in several
cases , validating or supporting a particular mechanism .
for instance ,
md simulations provided evidence for two - step nucleation in aqueous
solutions of -glycine and n - octane ( or n - octanol ) solutions of d-/l - norleucine . sodium chloride
( nacl )
nucleation from supersaturated brines represents an interesting
challenge for simulations , as the system is relatively easy to model
and experimental nucleation rates are available .
the first simulations
of nacl nucleation date back to the early 1990s , when ohtaki and fukushima performed brute - force md simulations using
very small systems ( 448 molecules including water molecules and ions )
and exceedingly short simulation times ( 10 ps ) .
thus , the
formation of small crystalline clusters that they observed was most
likely a consequence of finite - size effects .
more recently , the tps
simulations of zahn suggested that the
centers of stability for nacl aggregates consist of nonhydrated na ions octahedrally coordinated with cl ions ,
although the results were related to very small simulations boxes
( containing 310 molecules in total ) .
tentative insight into
the structure of the crystalline clusters
came with the work of nahtigal et al .
, featuring simulations of 4132 molecules ( 4000 water molecules and
132 ions ) in the 6731073 k range for supercritical water at
different densities ( 0.170.34 g / cm ) .
they reported
a strong dependence of the crystalline cluster size distribution on
the system density , with larger clusters formed at lower densities .
the emergence of
amorphous precursors was also reported in the work of chakraborty
and patey , who performed large - scale md
simulations featuring 56000 water molecules and 4000 ion pairs in
the npt ensemble .
the spc / e model was used for water , and the ion parameters were those used
in the opls force field .
their findings
provided strong evidence for a two - step mechanism of nucleation , where
a dense but unstructured nacl nucleus is formed first , followed by
a rearrangement into the rock salt structure , as depicted in figure 18a . on a similar
note , metadynamics simulations performed by giberti et al . using the gromos force field for the ions and the spc / e model for water suggested the emergence of a wurtzite - like polymorph
in the early stages of nucleation .
this precursor could be an intermediate
state along the path from brine to the nacl crystal .
however , alejandre
and hansen pointed out a strong sensitivity
of the nucleation mechanism on the choice of the force field . ( a ) snapshots
from an md simulation of crystal nucleation of nacl
from aqueous solution . the simulations , carried out by chakraborty
and patey , involved 56000 water molecules
and 4000 ion pairs ( concentration of 3.97 m ) in the npt ensemble .
all na ( black ) and cl ( yellow ) ions within 2 nm of a reference na ion ( larger
and blue ) are shown , together with water molecules ( oxygen and hydrogen
atoms in red and white , respectively ) within 0.4 nm from each ion .
from the relatively homogeneous solution ( 3 ns ) ,
this fluctuation in the concentration of the
ions leads to a subsequent ordering of the disordered cluster ( 10
ns ) in a crystalline fashion ( 30 ns ) , consistently with a two - step
nucleation mechanism .
( b ) comparison of nacl nucleation rates , , as a function
of the driving force for
nucleation , reported as 1/(/kbt ) .
red points and blue and gray ( continuous )
lines were estimated by three different approaches in the simulations
of zimmermann et al .
experimental data
obtained employing an electrodynamic levitator trap ( na et al . ) , an efflorescence chamber ( gao et al . ) , and microcapillaries ( desarnaud et al . )
are also reported , together with a tentative
fit ( fitexp , dotted line ) .
note the substantial ( up to about 30 orders of magnitude )
discrepancy between experiments and simulations .
in fact , very recent simulations by zimmermann et al . demonstrated that the gromos force field overestimates
the stability of the wurtzite - like polymorph .
the authors employed
a seeding approach within an nvt setup for which
the absence of depletion effects was explicitly verified .
the force fields used were those developed
by joung and cheatham for na and cl and spc / e for water , which provide reliable solubilities and accurate chemical
potential driving force . using a methodology
introduced in ref ( 193 ) ,
a thorough investigation of
the latter demonstrated that the limiting factor for n , which , in turn , strongly affects the kinetics of
nucleation ( see section 1.1.1 ) , is not the diffusion of the ions within the solution
but is instead the desolvation process needed for the ions to get
rid of the solvent and join the crystalline clusters .
moreover , zimmermann
et al . evaluated the nucleation free
energy barrier as well as the nucleation rate as a function of supersaturation ,
providing three estimates using different approaches .
the results
are compared with experiments in figure 18b , showing a substantial discrepancy as
large as 30 orders of magnitude .
interestingly , experimental nucleation
rates are much smaller than what is observed in simulations , contrary
to what has been observed for colloids , for example ( see section 2.1 ) .
we stress
that the work of zimmermann et al . employed state - of - the - art computational
techniques and explored nacl nucleation under different conditions
using a variety of approaches .
the fact that these tour de force simulations
yielded nucleation rates that differed significantly from experiments
casts yet another doubt on the possibility of effectively comparing
experiments and simulations .
however , it must be noted that zimmermann
et al . assumed a value of about 5.0
molnacl / kgh2o for the nacl solubility
in water , as proposed in ref ( 432 ) .
( 3.64 molnacl / kgh2o ) and more recently by mester
and panagiotopoulos ( 3.71 molnacl / kgh2o ) .
, once again demonstrating the severe sensitivity of nucleation rates
to any of the ingredients involved in their calculations . on
a final note ,
we stress that many other examples of molecular
dynamics simulations looking at specific aspects of crystal nucleation
from solution exist in the literature . for instance , a recent study
by anwar et al .
describes secondary
crystal nucleation , where crystalline seeds are already present within
the solution .
the authors suggest , for a generic solution represented
by lennard - jones particles , a ( secondary ) nucleation mechanism enhanced
by the existence of pncs ( see section 1.1.2 ) .
kawska et al . stressed instead the importance of proton transfer within
the early stages of nucleation of zinc oxide nanoclusters from an
ethanol solution .
the emergence of similar ripening processes , selecting
specific crystalline polymorphs , for example , according to the effect
of different solvents is still fairly unexplored but bound to be of
great relevance in the future .
finally , several computational studies
have dealt with the crystallization of calcium carbonate , which was
recently reviewed extensively in ref ( 18 ) and thus , together with the broad topic of crystal
nucleation of biominerals , is not discussed in here .
natural gas
hydrates are crystalline compounds in which small gas molecules are
caged ( or enclathrated ) in a host framework of water
molecules . as natural gas molecules ( e.g. , methane , ethane , propane )
are hydrophobic , gas hydrates are favored by conditions of high pressure
and low temperature , and are found to occur naturally in the ocean
bed and in permafrost regions . with
exceptionally high gas storage capabilities and the fact
that it is
believed that gas hydrates exceed conventional gas reserves by at
least an order of magnitude , there is
interest in trying to exploit gas hydrates as a future energy resource .
although gas hydrates might potentially play a positive role in the
energy industry s future , they are currently considered a hindrance :
if mixed phases of water and natural gas are allowed to cool in an
oil pipeline , then a hydrate can form and block the line , causing
production to stall .
understanding the mechanism(s ) by which gas hydrates
nucleate is likely to play an important role in the rational design
of more effective hydrate inhibitors .
there are two
main types of natural gas hydrates : structure i ( si ) , which has a
cubic structure ( space group pm3n ) , and structure ii ( sii ) , which also has a cubic structure ( space
group fd3m ) .
( there is also
a third , less common type , sh , which has a hexagonal crystal structure ,
but we do not discuss this structure any further here . ) structurally ,
the water frameworks of both si and sii hydrates are similar to that
of ice ih , with each water molecule finding itself in an
approximately tetrahedral environment with its nearest neighbors .
unlike ice ih , however , the water framework consists of
cages , with cavities large enough to accommodate a gas molecule . between the si and sii hydrates , there exist three types of cages ,
which are denoted 56 depending on the numbers of five- and six - sided faces that
make up the cage .
for example , common to both the si and sii hydrates
is the 5 cage , where the water molecules sit on the vertices
of a pentagonal dodecahedron .
along with 5 cages , the
si hydrate also consists of a 56 cages , which
have two six - sided faces and 12 five - sided faces : there are two 5 cages and six 56 cages in the unit
cell .
the sii hydrate , on the other hand , has a unit cell made up
of 16 5 cages and eight 56 cages .
because of the larger size of the 56 cage ,
the sii structure forms in the presence of larger guest molecules
such as propane , whereas small guest molecules such as methane favor
the si hydrate .
( this is not to say that small guest molecules are
not present in sii , just that the presence of larger guest molecules
is necessary to stabilize the larger cavities . )
the si , sii , and sh
crystals structures are shown in figure 19 , along with the individual cage structures .
further details regarding the crystal structures of natural gas hydrates
can be found in ref ( 439 ) .
crystal structures of the si , sii and sh gas hydrates , along with
the corresponding cage structures .
first , sloan and co - workers proposed the labile cluster hypothesis ( lch ) , which essentially describes
the nucleation process as the formation of isolated hydrate cages
that then agglomerate to form a critical hydrate nucleus .
second ,
the local structure hypothesis ( lsh ) was proposed
after umbrella sampling simulations by radhakrishnan and trout suggested that the guest molecules first arrange
themselves in a structure similar to the hydrate phase , which is accompanied
by a perturbation ( relative to the bulk mixture ) of the water molecules
around the locally ordered guest molecules . for the same reasons as
already outlined elsewhere ( see section 1.2 )
, it is experimentally challenging the
verify which , if either , of these two nucleation mechanisms is correct .
what we will see in this section is how computer simulations of gas
hydrate nucleation have been used to help shed light on this process .
although not the first computer simulation study of natural gas
hydrate formation ( see , e.g. , refs ( 444447 ) ) , one the most influential simulation works on gas hydrate formation
is that of walsh et al . , in which methane
hydrate formation was directly simulated under conditions of 250 k
and 500 bar .
it was found that nucleation proceeded through the cooperative
organization of two methane and five water molecules into a stable
structure , with the methane molecules adsorbed on opposite sides of
a pentagonal ring of water molecules .
this initial structure allowed
the growth of more water faces and adsorbed methane , until a 5 cage formed .
after persisting for 30 ns , this 5 cage opened when two new water molecules were inserted into the
only face without an adsorbed methane molecule , on the side opposite
to that where several new full cages were completed .
this opening
of the original 5 cage was then followed by the relatively
fast growth of methane hydrate .
after 240 ns , the original 5 cage transformed
into a 56 cage , a structure not found in
any equilibrium hydrate structure .
walsh et al . also found that 5 cages dominated , in terms of abundance , during the early
stages of nucleation .
56 cages ( which along
with the 5 cages comprise the si hydrate ) were the second
most abundant , although their formation occurred approximately 100
ns after that of the initial 5 cages .
a significant amount
of the larger 56 cages that are found in
the sii hydrate was also observed , which was rationalized by the large
number of face - sharing 5 cages providing an appropriate
pattern .
the 56 cages were also observed
in an abundance close to that of the 56 cages .
the final structure can be summarized as a mixture of si and sii motifs ,
linked by 56 cages .
a similar structure had
previously been reported as a result of hydrate growth simulations .
( a c ) a pair of methane molecules is
adsorbed on either side of a single pentagonal face of water molecules .
partial cages form around this pair , near the eventual central violet
methane molecule , only to dissociate over several nanoseconds .
( d , e )
a small cage forms around the violet methane , and other methane molecules
adsorb at 11 of the 12 pentagonal faces of the cage , creating the
bowl - like pattern shown .
( f , g ) the initial central cage opens on the
end opposite to the formation of a network of face - sharing cages ,
and rapid hydrate growth follows .
( h ) a snapshot of the system after
hydrate growth shows the fates of those methane molecules that made
up the initial bowl - like structure ( other cages not shown ) .
. provided useful insight
into the hydrate nucleation mechanism , the
conclusions were based on only two independent nucleation trajectories .
soon after the publication by walsh et al .
water
model based on mw water under conditions
of 210 k and 500 atm ( the melting point of the model is approximately
300 k ) .
owing to the reduced computational cost of the coarse - grained
model , they were also able to study a much larger system size than
walsh et al .
( 8000 water and 1153 guest molecules vs 2944 water and 512 guest molecules ) . in agreement with walsh
, the initial stages of
the nucleation mechanism were also dominated by 5 cages ,
and a mixture of si and sii motifs connected by 56 cages was observed .
it was also observed that solvent - separated
pairs of guest molecules were stabilized by greater numbers of guest
molecules in the cluster . as gas hydrates
are composed of solvent - separated
pairs of guest molecules as opposed to contact pairs , this suggests
a resemblance to the lsh , where the local ordering of guest molecules
drives the nucleation of the hydrate .
, however , also
found a likeness to the lch : clusters of guest molecules and their
surrounding water molecules formed long - lived blobs that slowly diffused
in solution .
these blobs could be considered large analogues of the
labile clusters proposed in the lch . through analysis of their simulation
data ,
jacobsen et al . concluded that the blob is a guest - rich precursor
in the nucleation pathway of gas hydrates with small guest molecules
( such as methane ) .
note that the distinction between blobs and the
amorphous clathrate is that the water molecules have yet to be locked
into the clathrate hydrate cages in the former .
sketch of the nucleation mechanism of methane hydrates
proposed
in ref ( 451 ) .
clusters
of guest molecules aggregate in blobs , which transform into amorphous
clathrates as soon as the water molecules arrange themselves in the
cages characteristic of crystalline clathrate , which eventually form
upon the reordering of the guest molecules and thus of the
cages in a crystalline fashion .
note that the difference between
the blob and the amorphous clathrate is that the water molecules have
yet to be locked into clathrate hydrate cages in the former .
copyright 2010 american chemical society . both the work of walsh et al . and that of jacobson
et al . suggest
that amorphous hydrate structures are involved in the nucleation mechanism ,
although both studies were carried out under high driving forces .
in ref ( 453 )
, jacobsen
and molinero addressed the following two questions raised by the above
studies : how could amorphous nuclei grow into a crystalline form ?
are amorphous nuclei precursors intermediates for clathrate hydrates
under less forcing conditions ? by considering the size - dependent melting
temperature of spherical particles using the gibbs
thomson
equation , jacobson and molinero found for all temperatures that the
size of the crystalline critical nucleus was always smaller than that
of the amorphous critical nucleus , with the two becoming virtually
indistinguishable in terms of stability for very small nuclei of 15
guest molecules ( i.e. , under very forcing conditions ) . from a thermodynamic
perspective , this would suggest that nucleation would always proceed
through a crystalline nucleus .
the observation of amorphous nuclei , even at temperatures as high
as 20% supercooling , hints that their formation might be favored for
kinetic reasons . employing the cnt expression for the free energy
barrier suggested that the amorphous nuclei could be kinetically favored
up to 17% supercooling if a/x =
0.5 , where a and x are the surface
tensions of the liquid - amorphous and liquid - crystal structures , respectively .
jacobson and molinero estimated x 36 mj / m and 16 < a < 32 mj / m ,
so it is certainly plausible that amorphous precursors are intermediates
for clathrate hydrates under certain conditions .
the growth of clathrate
hydrates from amorphous and crystalline seeds was also studied , where
it was found that crystalline clathrate can grow from amorphous nuclei .
as the simulation led to fast mass transport
, the growth of postcritical
nuclei was relatively quick , and the amorphous seed became encapsulated
by a ( poly)crystalline shell . under conditions where an amorphous
nucleus forms first because of a smaller free energy barrier but diffusion
of the guest species becomes a limiting factor , it is likely that
small nuclei would have long enough to anneal to structures of greater
crystallinity before growing to the macroscopic crystal phase .
it thus appears that gas hydrates might exhibit a multistep nucleation
process involving amorphous precursors for reasonably forcing conditions ,
but for temperatures close to coexistence , it seems that nucleation
should proceed through a single crystalline nucleus . by assuming a
cnt expression for the free energy ( as well as the total rate ) , knott
et al . used the seeding technique
( see section 1.3.1 ) to compute
the nucleation rate for si methane hydrate with relatively mild supersaturation
of methane , in a manner similar to that of espinosa et al . for homogeneous ice nucleation as discussed
in section 2.4.1 .
they found vanishingly small homogeneous nucleation rates of 10 nuclei cm s , meaning that , even with all of earth s ocean waters , the
induction time to form one crystal nucleus homogeneously would be
10 years !
knott et al . therefore concluded that ,
under mild conditions , hydrate nucleation must occur heterogeneously .
compared
to homogeneous nucleation , the heterogeneous nucleation of gas hydrates
has been little studied .
liang et al . investigated the steady - state growth of a h2s hydrate
crystal in the presence of silica surfaces , finding that the crystal
preferentially grew in the bulk solution rather than at the interface
with the solid .
they also observed that , in one simulation , local
gas density fluctuations of the dissolved guest led to the spontaneous
formation of a gas bubble from solution , which was located at the
silica interface .
this had two effects on the observed growth : ( i )
the bubble depleted most of the gas from solution , leading to an overall
decrease of the crystal growth rate , and ( ii ) because of the location
of the guest bubble , the silica surface effectively acted like a source
of gas , promoting growth of the crystal closer to the interface relative
to the bulk .
investigated the heterogeneous nucleation
of co2 hydrate in the presence of a fully hydroxylated
silica surface , first in a two - phase system where the water and co2 were well - mixed and then in
a three - phase system where the co2 and water were initially
phase - separated .
for the two - phase system ,
the authors reported the formation of an ice - like layer at the silica
surface , above which a layer composed of semi-5 cage - like
structures mediated the structural mismatch between the ice - like contact
layer and the si hydrate structure above .
in the three - phase system ,
nucleation was observed at the three - phase contact line , along which
the crystal nucleus also grew .
this was attributed to the stabilizing
effect of the silica on the hydrate cages , plus the requirement for
the availability of both water and co2 . in a later work ,
bai et al . investigated the effects
of surface hydrophilicity ( by decreasing the percentage of surface
hydroxyl groups ) and crystallinity on the nucleation of co2 hydrate .
they found that , in the case of decreased hydrophilicity ,
the ice - like layer at the crystalline surface vanished , replaced instead
by a single liquid - like layer upon which the hydrate directly nucleated .
whereas shorter induction times to nucleation at the less hydrophilic
surfaces were reported ,
although certainly an interesting observation ,
as only a single trajectory was performed for each system , studies
in which multiple trajectories are used to obtain a distribution of
induction times would be desirable , and as the hydrate actually appears
to form away from the surface in all cases , a full comparison of the
heterogeneous and homogeneous rates would also be a worthwhile pursuit .
there have also been a number of studies investigating the potential
role of ice in the nucleation of gas hydrates .
pirzadeh and kusalik performed md simulations of methane hydrate
nucleation in the presence of ice surfaces and reported that an increased
density of methane at the interface induced structural defects ( coupled
58 rings ) in the ice that facilitated the formation of hydrate
cages .
nguyen et al . used md simulations
to directly investigate the interface between a gas hydrate and ice
and found the existence of an interfacial transition layer ( itl ) between the two crystal structures .
the water molecules in
the itl , which was found to be disordered and two to three layers
of water in thickness , had a tetrahedrality and potential energy intermediate
between those of either of the crystal structures and liquid water .
the authors suggested that the itl could assist the heterogeneous
nucleation of gas hydrates from ice by providing a lower surface free
energy than either of the ice liquid and hydrate liquid
interfaces .
differential scanning calorimetry experiments by zhang
et al . found ice and hydrate formation
to occur simultaneously ( on the experimental time scale ) , which was
attributed to the heterogeneous nucleation of ice , which , in turn ,
facilitated hydrate formation .
poon and peters provide a possible explanation for ice acting as a heterogeneous
nucleating agent for gas hydrates , aside from the structural considerations
of refs ( 460 and 462 ) : at a growing
ice front , the local supersaturation of methane can be dramatically
increased , to the extent that induction times to nucleation are reduced
by as much as a factor 10 .
computer simulations
of hydrate nucleation have certainly contributed
to our understanding of the underlying mechanisms , especially in the
case of homogeneous nucleation .
one fairly consistent observation
across many simulation studies ( e.g. , refs ( 444 , 445 , 447 , 448 , 451 , 453 , and 464 ) ) suggests that some type of ordering of dissolved guest molecules
precedes the formation of hydrate cages .
another is that amorphous
nuclei , consisting of structural elements of both si and sii hydrates
form when conditions are forcing enough .
nevertheless , open questions
still remain . in particular , the prediction that homogeneous nucleation
rates are vanishingly small under mild conditions
emphasizes the need to better understand heterogeneous
nucleation . to this end , enhanced sampling techniques such as ffs ,
which was recently applied to methane hydrate nucleation at 220 k
and 500 bar , are likely to be useful ,
although directly simulating nucleation under mild conditions is still
likely to be a daunting task .
another complicating factor is that ,
aside from the presence of solid particles , the conditions from which
natural gas hydrates form are often highly complex ; for example , in
an oil or gas line , there is fluid flow , and understanding how this
effects the methane distribution in water is likely to be an important
factor in determining how fast gas hydrates form . in this respect ,
we have described only a fraction of the many
computer simulation
studies of crystal nucleation in supercooled liquids and solutions .
still , we have learned that md simulations have dramatically improved
our fundamental understanding of nucleation .
for instance , several
studies on colloidal particles ( see section 2.1 ) provided evidence for two - step nucleation
mechanisms , and the investigation of lj liquids yielded valuable insights
into the effects of confinement ( see section 2.2 ) .
in addition , the investigation of more
realistic systems has provided outcomes directly related to problems
of great relevance .
for example , the influence of different solvents
on the early stages of urea crystallization ( see section 2.5 ) has important consequences
in fine chemistry and in the fertilizer industry , and the molecular
details of clathrate nucleation ( see section 2.5 ) could help to rationalize and prevent
hydrate formation in oil or natural gas pipelines .
thus , it is fair
to say that md simulations have been and will remain a powerful complement
to experiments .
however , simulations are presently affected
by several shortcomings ,
which hinder a reliable comparison with experimental nucleation rates
and limit nucleation studies to systems and/or conditions often far
from those investigated experimentally .
these weaknesses can be classified
in two main categories : ( i ) limitations related to the accuracy of
the computational model used to represent the system and ( ii ) shortcomings
due to the computational techniques employed to simulate nucleation
events.(i)in
an ideal world , ab initio calculations
would be the tool of the trade . unfortunately , in all but a handful
of cases such as the phase - change materials presented in section 2.3 , the time - scale
problem makes ab initio simulations of crystal nucleation unfeasible
( see figure 5 ) .
as
this will be the status quo for the next few decades , we are forced
to focus our efforts on improving the current classical force fields
and on developing novel classical interatomic potentials .
this is
a fundamental issue that affects computer simulations of materials
as a whole . although this is not really an issue for nucleation of
simple systems such as colloids ( section 2.1 ) , things start to fall apart when dealing
with more realistic systems ( see , e.g. , sections 2.5 and 2.6 ) and become
even worse in the case of heterogeneous nucleation ( see , e.g. , section 2.4.2 ) , as the
description of the interface requires extremely transferable and reliable
force fields .
machine learning techniques such as neural network potentials ( see section 2.3 and refs ( 467 and 468 ) ) are emerging
as possible candidates to allow for classical md simulations with
an accuracy closer to first - principles calculations , but the field
is constantly looking for other options that are capable of bringing
simulations closer to reality.(ii)the limitations of the computational
techniques currently employed to study crystal nucleation are those
characteristic of rare - events sampling .
brute - force md simulations
( see section 1.3.1 ) allow for an unbiased investigation of nucleation events , but the
time - scale problem limits this approach to very few systems , typically
very distant from realistic materials ( see , e.g. , sections 2.1 and 2.2)although notable exceptions exist ( see section 2.3 ) .
it is also
worth noticing that , whereas brute - force md is not able to provide
a full characterization of the nucleation process , useful insight
can still be gained , for example , into prenucleation events .
enhanced sampling techniques ( see section 1.3.2 ) are rapidly evolving and have the potential
to take the field to the next level .
however , free energy methods
as they are do not give access to nucleation kinetics and , in the
case of complex systems ( see , e.g. , sections 2.4.1 and 2.5 ) , are
strongly dependent on the choice of the order parameter . on the other
hand , in light of the body of work reviewed , it seems that path - sampling
methods can provide a more comprehensive picture of crystal nucleation .
however , at the moment , these techniques are computationally expensive ,
and a general implementation is not available yet , although consistent
efforts have recently been put in place .
we believe that the development
of efficient enhanced sampling methods specific to crystal nucleation
is one of the crucial challenges ahead . in
an ideal world , ab initio calculations
would be the tool of the trade .
unfortunately , in all but a handful
of cases such as the phase - change materials presented in section 2.3 , the time - scale
problem makes ab initio simulations of crystal nucleation unfeasible
( see figure 5 ) .
as
this will be the status quo for the next few decades , we are forced
to focus our efforts on improving the current classical force fields
and on developing novel classical interatomic potentials .
this is
a fundamental issue that affects computer simulations of materials
as a whole .
although this is not really an issue for nucleation of
simple systems such as colloids ( section 2.1 ) , things start to fall apart when dealing
with more realistic systems ( see , e.g. , sections 2.5 and 2.6 ) and become
even worse in the case of heterogeneous nucleation ( see , e.g. , section 2.4.2 ) , as the
description of the interface requires extremely transferable and reliable
force fields .
machine learning techniques such as neural network potentials ( see section 2.3 and refs ( 467 and 468 ) ) are emerging
as possible candidates to allow for classical md simulations with
an accuracy closer to first - principles calculations , but the field
is constantly looking for other options that are capable of bringing
simulations closer to reality .
the limitations of the computational
techniques currently employed to study crystal nucleation are those
characteristic of rare - events sampling .
brute - force md simulations
( see section 1.3.1 ) allow for an unbiased investigation of nucleation events , but the
time - scale problem limits this approach to very few systems , typically
very distant from realistic materials ( see , e.g. , sections 2.1 and 2.2)although notable exceptions exist ( see section 2.3 ) .
it is also
worth noticing that , whereas brute - force md is not able to provide
a full characterization of the nucleation process , useful insight
can still be gained , for example , into prenucleation events .
enhanced sampling techniques ( see section 1.3.2 ) are rapidly evolving and have the potential
to take the field to the next level .
however , free energy methods
as they are do not give access to nucleation kinetics and , in the
case of complex systems ( see , e.g. , sections 2.4.1 and 2.5 ) , are
strongly dependent on the choice of the order parameter . on the other
hand , in light of the body of work reviewed , it seems that path - sampling
methods can provide a more comprehensive picture of crystal nucleation .
however , at the moment , these techniques are computationally expensive ,
and a general implementation is not available yet , although consistent
efforts have recently been put in place .
we believe that the development
of efficient enhanced sampling methods specific to crystal nucleation
is one of the crucial challenges ahead . at the moment
, simulations of crystal nucleation of complex liquids
are restricted to small systems ( 1010 particles ) , most often under idealized conditions .
for instance ,
it is presently very difficult to take into account impurities or ,
in the case of heterogeneous nucleation , defects of the substrate .
indeed , defects seem to be ubiquitous in many different systems , such
as ice , hard - sphere crystals , lj crystals , and organic crystals as
well .
defects are also often associated with polymorphism , but possibly
because of the inherent difficulties in modeling them ( or in characterizing
them experimentally ) , they are under - represented in the current literature .
these are important aspects that almost always impact experimental
measurements and that should thus be included in simulations as well
.
in general , simulations of nucleation should allow us not only to
provide microscopic insight but also to make useful predictions and/or
to provide a general understanding to be applied to a variety of systems .
these two ambitious goals are particularly challenging for simulations
of heterogeneous nucleation . in light of the literature we have reviewed
in this work ,
we believe that much of the effort in the future has
to be devoted to ( i ) enabling atomistic simulations of heterogeneous
nucleation dealing with increasingly realistic interfaces and ( ii )
obtaining general , maybe non - material - specific trends able to point
the community into the right direction , even at the cost of sacrificing
accuracy to a certain extent .
on the other hand , we hope that the
body of work reviewed here will inspire future experiments targeting
cleaner , well - defined systems by means of novel techniques , possibly
characterized by better temporal and spatial resolution .
improving
on the current limitations of the computational models and techniques
would enable simulations of much larger systems over much longer time
scales , with a degree of accuracy that would allow a fruitful comparison
with experiments .
we think this should be the long - term objective
for the field . up to now
, the only way to connect simulations and
experiments has been through the comparison of crystal nucleation
rates , which even now still exhibit substantial discrepancies for
every single class of systems we have reviewed .
this is true not only
for complex liquids such as water ( see section 2.4.1 ) but even for model systems such as
colloids ( section 2.1 ) .
this , together with the fact that , in some cases , even experimental
data are scattered across several orders of magnitude , suggests that
we are dealing with crystal nucleation in liquids within a flawed
theoretical framework .
it
is thus no wonder that every
aspect of this battered theory has been criticized at some point .
for instance , the emergence of two - step ( or even multistep ) mechanisms
for nucleation has been reported for many different systems ( see sections 2.1 , 2.2 , 2.5 , and 2.6 ) and can not be easily embedded in cnt as it is , although
several improvements on the original cnt formulation have appeared
within the past decade ( see section 1.1.2 ) . nonetheless , cnt is basically the
only theory invoked by both experiments and simulations when dealing
with crystal nucleation from the liquid phase .
cnt is widely used
because it offers a simple and unified picture for nucleation and
it is often very useful .
however , as demonstrated by both experiments
and simulations , even the basic rules governing the formation of the
critical nucleus can change dramatically from one system to another .
thus , we believe that any sort of theoretical universal approach ,
a brand new cnt , so to say , will be unlikely to significantly further
the field . indeed , we fear that the same reasoning will hold for the
computational methods required .
we can not think of a single enhanced
sampling technique capable of tackling the complexity of crystal nucleation
as a whole .
the interesting but uncomfortable truth is that each class
of supercooled liquids often exhibits unique behavior , which , in turn ,
results in specific features ruling the crystal nucleation process .
thus , it is very much possible that different systems under different
conditions could require different , ad hoc flavors of cnt .
although
the latter have been evolving for decades , we believe that a sizable
fraction of the new developments in the field should aim at producing
particular flavors of cnt , specifically tailored to the problem at
hand . in conclusion , it is clear that md simulations have proven
themselves
to be of the utmost importance in unraveling the microscopic details
of crystal nucleation in liquids . we have reviewed important advances
that have provided valuable insights into fundamental issues and diverse
nucleation scenarios , complementing experiments and furthering our
understanding of nucleation as a whole .
we feel that the ultimate
goal for simulations should be to get substantially closer to the
reality probed by experiments and that , to do so , we have to sharpen
our computational and possibly theoretical tools . in particular , we
believe that the community should invest in improving the classical
interatomic potentials available as well as the enhanced sampling
techniques currently used , enabling accurate simulations of crystal
nucleation for systems of practical relevance .
Output:
| the nucleation of
crystals in liquids is one of nature s
most ubiquitous phenomena , playing an important role in areas such
as climate change and the production of drugs .
as the early stages
of nucleation involve exceedingly small time and length scales , atomistic
computer simulations can provide unique insights into the microscopic
aspects of crystallization . in this review , we take stock of the numerous
molecular dynamics simulations that , in the past few decades , have
unraveled crucial aspects of crystal nucleation in liquids .
we put
into context the theoretical framework of classical nucleation theory
and the state - of - the - art computational methods by reviewing simulations
of such processes as ice nucleation and the crystallization of molecules
in solutions .
we shall see that molecular dynamics simulations have
provided key insights into diverse nucleation scenarios , ranging from
colloidal particles to natural gas hydrates , and that , as a result ,
the general applicability of classical nucleation theory has been
repeatedly called into question .
we have attempted to identify the
most pressing open questions in the field .
we believe that , by improving
( i ) existing interatomic potentials and ( ii ) currently available enhanced
sampling methods , the community can move toward accurate investigations
of realistic systems of practical interest , thus bringing simulations
a step closer to experiments . |
PubmedSumm4872 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the prevalence varies between 0.6% and 1.3% in various series.1)2 ) anomalous origin of a coronary artery from the opposite sinus of valsalva represents small fraction of these anomalies.3 ) although most instances of anomalous origin of the coronary artery are unlikely to have any clinical sequelae , a few are potentially significant and trigger sudden death and myocardial ischemia4)5 ) because position or orientation may lead to coronary flow compromise.5 ) we report an uncommon case of anomalous origin of the right coronary artery ( rca ) originating from the left sinus of valsalva with paroxysmal supraventricular tachycardia ( psvt ) and myocardial ischemia .
a 58-year - old man presented with chest pain and palpitation for 2 hours at rest .
his blood pressure was 130/90 mm hg , pulse rate 196 beats per minute , respiratory rate 20 per minute and body temperature 36.6. the electrocardiogram showed psvt with pulse rate 190 bpm ( fig .
follow - up electrocardiography displayed st change and t inversion in leads ii , iii , avf and v 4 - 6 ( fig .
cardiac enzyme showed transient increase ; creatine kinase - mb 5.8 ng / ml ( normal < 5 ng / ml ) , myoglobin 154 ng / ml ( normal < 110 ng / ml ) , troponin t 0.3 ng / ml ( normal < 0.1 ng / ml ) .
after the acute episode terminated , he was treated with aspirin , lipid lowering agent , angiotension ii receptor blocker and intravenous heparin .
coronary ct angiography revealed that the rca arose from the left sinus of valsalva with acute angle of the ostium and course between the right ventricular outflow tract and the aorta ( figs . 2 and 3 ) .
the treadmill test was done with good exercise performance and the result showed st depression in leads iii , avf .
24 hours holter monitoring showed one episode of non - sustained ventricular tachycardia for 0.8 seconds .
we continued medical treatment including atii receptor blocker , bisoprolol and aspirin and recommended life style modification .
coronary artery anomalies , after hypertrophic cardiomyopathy , are the second most common cause of exercise - related sudden cardiac deaths . these anomalies have been associated with myocardial ischemia , arrhythmia and sudden death during exercise.6)7 ) the prevalence of coronary artery anomalies has been reported between 0.6 to 1.3% in angiographic series and 0.3% in autopsy series.1 - 4)7 ) anomalous origin of the rca from the left sinus of valsalva represents a small fraction less than 3% of total coronary anomalies.5 ) mechanisms of the restricted coronary blood flow suggest that the acute angle of ostium , slit - like orifice limit the flow of coronary artery.5)8 ) also , possible mechanisms are compression of the intramural segment by the aortic valve commissure and compression between the aorta and pulmonary artery.8 ) in case of interarterial course between aorta and pulmonary artery , luminal compression of the coronary artery is related to the pressure of the aorta because the pressure of the pulmonary artery was much lower than that of the aorta.8 ) on that account , anomalous coronary artery stemming from opposite sinus of valsalva can trigger syncope , myocardial ischemia and sudden death in the absence of critically fixed stenosis.5 ) the methods for evaluation of anomalous origin of coronary artery include angiography , intravascular ultrasound , transthoracic and transesophageal echocardiogram , coronary ct angiography , and mri.8 ) coronary angiography is limited for evaluation of coronary anomalies since it is sometimes difficult to cannulate the orifice and the complex three dimensional structure of the arteries is displayed in a two dimensional plane.8 ) coronary ct angiography is a non - invasive diagnostic modality which provides much higher spatial resolution and three dimensional images.8)9 ) understanding ischemic mechanisms in anomalous origin of the rca is attributed to excellent information about the origin and the course of the anomalous coronary artery from multidetector ct images.10 ) in the case of our patient , the axial image showed an acute - angled take off of the rca from the ascending aorta and a small orifice of the rca which was thought to be one of the mechanisms for the ischemia .
recent recommendations have favored surgical management of all symptomatic patients.11 - 13 ) nevertheless , there is concern about risk of surgical procedure.12 ) we believed that sudden arrhythmias such as psvt are brought about by hemodynamic changes , widening of aortic root and coronary artery luminal compression between the aorta and the pulmonary artery limiting the coronary artery flow .
st change in ekg and elevated troponin t could be explained as a response to pacing induced stress as well as a response to myocardial ishemia.14 ) in our patient , myocardial ischemia induced by the coronary anomaly is more likely because of mild hypokinesia of septum and anterior wall of lv , and ischemic change of treadmill test was confirmed .
it is a limitation of this case report that the cause of psvt , whether atrio - ventricular nodal reentry or accessory pathway , was not evaluated by cardiac electrophysiologic study .
the electrophysiologic study could help to clarify the relation between coronary anomaly and psvt . in our patient ,
coronary ct angiography showed that the anomalous rca with inter - arterial pathway and the whole coronary tree was free of any stenotic lesion .
Output:
| anomalous origin of a coronary artery is rare and does not generally lead to myocardial infarction and paroxysmal supraventricular tachycardia ( psvt ) .
we report an uncommon case of anomalous origin of the right coronary artery ( rca ) originating from the left sinus of valsalva with psvt and myocardial ischemia . a 58-year - old man presented with psvt .
after arrhythmia subsided , electrocardiogram showed st and t wave abnormalities , and transient cardiac enzymes were found to be elevated .
coronary ct angiography confirmed that there was anomalous origin of the rca originating from the left sinus of valsalva and no intracoronary stenotic lesion .
he was managed with conservative treatment , having no symptoms on clinical follow - up for 4 years . |
PubmedSumm4873 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: postural control is essential in performance of independent activities of daily living in
stroke patients1 .
postural control is
defined as the ability to maintain the center of mass ( com ) within the base of support with
minimal postural sway , and the sensory systems ( visual , somatosensory , and vestibular
systems ) , cognitive processing , and movement strategies are needed for maintenance of
postural control2 . in general , postural
control can be classified according to static and dynamic postural control3
. therefore , evaluation of postural control
should be considered for both aspects of static and dynamic postural control . in the clinic
or hospital
setting , the berg balance scale ( bbs ) and timed up and go test ( tug ) are used
mainly for evaluation of dynamic postural control4 ,
5 , and measurement of postural sway
using a force platform is commonly used for evaluation of static postural control6 .
. a force platform system can provide quantifying data for
postural control of subjects by measuring the postural sway7 .
in addition , lajoie et
al.9 reported an association of
increased postural sway with reduction of dynamic balance ability . on the other hand
, some
studies reported that an increase in postural sway is not necessarily an indication of poor
dynamic balance ability but simply indicates static balance ability10 , 11 .
thus , the
question of whether or not postural sway is associated with dynamic balance is still
debatable .
the purpose of the current study was to gain a more comprehensive understanding
of the relationship between postural sway and dynamic balance in post stroke patients .
thirty - one stroke patients were recruited on a
voluntary basis from an inpatient hospital .
subjects were included if ( 1 ) they had a
diagnosis of stroke ( cerebral cortex lesion : ischemic brain injury or intracerebral
hemorrhage ) based on magnetic resonance imaging or computed tomography , ( 2 ) they were able
to understand and follow simple verbal instructions ( korean version of the mini - mental state
examination score > 24 ) , ( 3 ) they had no known musculoskeletal conditions that would
affect the ability to stand safely ; and ( 4 ) they had no serious visual impairment or hearing
disorder .
the exclusion criteria were ( 1 ) participation in another study or rehabilitation
program , ( 2 ) severe heart disease or uncontrolled hypertension and pain , and ( 3 ) any
neurologic or orthopedic disease that might interfere with the study .
all subjects
participated in conventional rehabilitation programs consisting of physical and occupational
therapy during hospitalization .
three of the 34 potential subjects were excluded because
they met the exclusion criteria ( participation in another study or uncontrolled
hypertension ) . ultimately
, 31 subjects ( 20 men and 11 women ; age 64.25 years ; stroke
duration 12.70 months ; mmse - k score 26.35 ) were included in this study .
the subjects were
briefed on the experimental procedure , and written consent forms were collected from all
subjects prior to conduct of the experiment ; the subjects voluntarily signed informed
consent forms .
human subject ethical approval was obtained from the relevant committee of
the sahmyook university institutional review board prior to conduct of the experiment . a good balance system ( good balance system , metitur , oy ,
jyvaskyla , finland ) was used for measurement of postural sway velocity and velocity moment
of subjects in the standing posture . according to a previous study , the good balance
system has adequate reliability for research and clinical use
in stroke patients11 . on the basis of the
coordinate values for x and y ,
the following parameters were calculated : ( 1 ) mean speed of
movement of the center of pressure ( cop ) in the anteroposterior ( ap ) direction ( mm / s ) ; ( 2 )
mean speed of movement of the cop in the mediolateral ( ml ) direction ( mm / s ) , and ( 3 ) mean
velocity moment ( mm / s ) .
postural sway velocity moment is defined as the average
horizontal area covered by movement of the center ( ap and ml direction ) of force per second .
the force platform , which was an equilateral triangle ( 800 mm ) , was connected to a
three - channel dc amplifier .
signals from the amplifier were converted into digital form
using a 12-byte converter ( sampling frequency=50 hz ) and stored on the hard disk of a
personal computer . for measurement of postural sway under the stable surface condition
,
subjects stood on the force plate with their legs spread at shoulder width and then looked
at a number on a monitor three times for 30 seconds . for measurement of postural sway under
the unstable surface condition
, a subject stood on the force plate , which was covered with
foam , with their legs spread at shoulder width and then looked at a number on a monitor
three times for 30 seconds11 .
three
repeats of each measurement were performed , and the average was used in the statistical
analysis .
the following
instruction was communicated to the subjects in order to ask them to move their bodies as
little as possible : please try your best to stand without swaying .
the berg balance scale ( bbs ) and timed up and go test ( tug ) were used for measurement of
dynamic balance ability .
the bbs is a valid and reliable instrument for measurement of both
the static and dynamic aspects of balance in elderly people after a stroke4 .
the tug is measured as the time ( seconds )
required for performance of the following : stand up from a chair , walk 3 m at a normal
walking speed , turn around , walk back to the chair , and sit back down on the chair .
all measurements , including postural sway and dynamic balance ( bbs
and tug ) , were performed while the patients were in a rehabilitation ward , and the assessor
was blinded . the spss ver .
correlations between postural sway
under stable and unstable conditions and dynamic balance abilities ( bbs and tug ) were
assessed using pearson s correlational coefficient .
general characteristics and data concerning postural sway and dynamic balance ability of
the subjects are summarized in table
1table 1.general characteristics and dependent variables of the subjects ( n=31)variablesmsd ( % ) gendermale / female ( % ) 20/11 ( 64.5/35.5)paretic sideright / left ( % ) 25/6 ( 80.6/19.4)etiologyinfarction / hemorrhage ( % ) 18/13 ( 58.1/41.9)age ( years)64.24.8height ( cm)165.36.2mass ( kg)63.57.5post stroke duration ( months)12.72.5mmse - k ( score)26.32.2stable conditionap - psv(eo ) ( mm / s)7.12.4ml - psv(eo ) ( mm / s)10.83.4psvm(eo ) ( mm)33.024.8ap - psv(ec ) ( mm / s)9.25.1ml - psv(ec ) ( mm / s)17.08.6psvm(ec ) ( mm)58.664.1unstable conditionap - psv(eo ) ( mm / s)11.54.6ml - psv(eo ) ( mm / s)16.56.6psvm(eo ) ( mm)71.838.2ap - psv(ec ) ( mm / s)20.611.8ml - psv(ec ) ( mm / s)41.243.6psvm(ec ) ( mm)222.6173.7dynamic balancebbs ( score)41.45.2tug ( sec)21.74.1values are expressed as numbers ( % ) or meanssd.mmse-k : korean version of the mini mental state examination .
eo , eyes open ; ec , eyes
closed ; ap - psv , anteroposterior postural sway velocity ; ml - psv , mediolateral postural
sway velocity ; psvm , postural sway velocity moment ; bbs , berg balance scale ; tug ,
timed up and go test .. values are expressed as numbers ( % ) or meanssd .
eo , eyes open ; ec , eyes
closed ; ap - psv , anteroposterior postural sway velocity ; ml - psv , mediolateral postural
sway velocity ; psvm , postural sway velocity moment ; bbs , berg balance scale ; tug ,
timed up and go test . the correlations between postural sway and dynamic balance in the stable and unstable
conditions are summarized in table 2table 2.correlation between postural sway and dynamic balance ( n=31)ap - psv ( eo)mm / sml - psv ( eo)mm / spsvm ( eo)mmap - psv ( ec)mm / sml - psv ( ec)mm / spsvm ( ec)mmstable conditionbbs ( score)0.240.100.200.140.110.07tug ( sec)0.100.010.210.060.070.24unstable conditionbbs ( score)0.46**0.060.200.42*0.230.50**tug ( sec)0.330.080.080.160.050.32psvm , postural sway velocity moment ; ap - psv , anteroposterior postural sway velocity ;
ml - psv , mediolateral postural sway velocity ; bbs , berg balance scale ; tug : timed up
and go test ; eo , eyes open ; ec , eyes closed .
no significant correlation was observed
between postural sway and dynamic balance except for the bbs score and anteroposterior
postural sway velocity in the eyes open condition ( r=0.46 , p<0.01 ) ,
anteroposterior postural sway velocity in the eyes closed condition
( r=0.42 , p<0.05 ) , and postural sway velocity moment
( r=0.50 , p<0.01 ) .
however , in the stable condition , no significant
correlation was observed between postural sway and dynamic balance .
psvm , postural sway velocity moment ; ap - psv , anteroposterior postural sway velocity ;
ml - psv , mediolateral postural sway velocity ; bbs , berg balance scale ; tug : timed up
and go test ; eo , eyes open ; ec , eyes closed .
the current study was conducted in order to investigate the relationship between postural
sway and dynamic balance in post stroke patients . according to our main findings , no
significant correlation was observed between postural sway and dynamic balance except
between the bbs score and anteroposterior postural sway velocity in the eyes open condition ,
anteroposterior postural sway velocity in the eyes closed condition , and postural sway
velocity moment on the unstable surface ( foam ) .
in addition , in the stable condition , no
significant correlation was observed between postural sway and dynamic balance .
postural control is defined as a complex skill involving interaction with sensory and motor
systems , and postural control is essential and inevitable to maintenance of independent
activities of daily living in stroke patients12 ,
13 .
humans are swayed in several
directions for maintenance of standing balance within the base of support , and a force
platform is commonly used in assessment of postural sway14 , 15 . through many previous
studies3 , 16 ,
17 , increases in postural sway
have
been shown to be associated with a reduction in balnace ability and weight trasfer and to
lead to an increased incidence of falls .
chisholm et al.18 reported an association of decreases in postural sway with
functional movement .
in addition , niam et al.19 reported negative correlation of postural sway with dynamic balance
( bbs ) in stroke patients .
in contrast , our findings showed no significant correlation between postural sway and
dynamic balance . according to previous studies investigating dynamic balance and postural
sway10 , 20
increases in
postural sway may not be associated with maintenance of dynamic postural stability . in
stroke patients with damage to the central nervous system ,
body movements are made as they
attempt to control their posture in the standing position and as they try to maintain their
center of mass21 .
thus , the results of
our study indicate that a decrease in postural sway does not necessarily reflect improvement
of dynamic balance ability .
we believe that this finding may be useful in balance
rehabilitation for prevention of falls after stroke .
, many factors
can affect postural sway including the vestibular , somatosensory , and visual systems .
in
particular , postural control can be affected through fatigue in the musculature surrounding
the ankles , knees , and hip24 , 25 .
thus , conduct of additional studies will be needed in order to fully understand the
relation between postural sway and dynamic balance ability .
Output:
| [ purpose ] the purpose of the current study was to investigate the relationship between
postural sway and dynamic balance in post stroke patients . [ subjects ] thirty - one stroke
patients ( 20 men and 11 women ; age 64.25 years ; stroke duration 12.70 months ; mmse - k score
26.35 ) participated in this study .
[ methods ] this study applied a cross - sectional design .
a good balance system was used for measurement of the postural sway velocity
( anteroposterior and mediolateral ) and velocity moment of subjects under the eyes open and
eyes closed conditions in a standing posture .
the postural sway of subjects was measured
under two surface conditions ( stable and unstable surfaces ) .
[ results ] on the unstable
surface ( foam ) , no significant correlation was observed between postural sway and dynamic
balance except for the berg balance scale ( bbs ) score and anteroposterior postural sway
velocity under the eyes open condition , anteroposterior postural sway velocity under the
eyes closed condition , and postural sway velocity moment .
in addition , in the stable
condition , no significant correlation was observed between postural sway and dynamic
balance .
[ conclusion ] our results indicate that a decrease in postural sway does not
necessarily reflect improvement of dynamic balance ability .
we believe that this finding
may be useful in balance rehabilitation for prevention of falls after a stroke . |
PubmedSumm4874 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: bone involvement in epithelial ovarian cancer is very unusual , with several series noting an incidence of < 2% [ 1 , 2 ] .
a recently encountered ovarian cancer patient who was found to have significant bone involvement at the time of disease recurrence , after an extended treatment - free interval , emphasizes the potential risk of metastatic disease in such sites and suggests possible unique features associated with this event .
a 60-year - old female with a history of epithelial ovarian cancer was seen for a second opinion concerning management .
she had originally been diagnosed with , and treated for , this malignancy in 1998 . following initial
surgery and chemotherapy , the patient remained without evidence of disease until 2007 when documented recurrence within the peritoneal cavity led to an attempt at secondary surgical cytoreduction .
the patient experienced considerable bone marrow suppression from this regimen , presumably due ( at least in part ) to the residual effects of her prior chemotherapy .
the patient subsequently remained well until the fall of 2010 when she developed both lower pelvic and back pain .
a pelvic pet / ct scan revealed a pre - sacral mass with definite erosion of the cancer into the sacrum .
the mass was felt to be unresectable and a decision was made to initially treat her with a platinum - based combination chemotherapy program ( carboplatin plus pegylated liposomal doxorubicin ) , and to then consider surgery or local radiation therapy ( depending on the impact of the response to the cytotoxic therapeutic regimen ) .
one of the remarkable features of epithelial ovarian cancer is its localization in most patients to the peritoneal cavity during the majority of its natural history , despite potentially quite large tumor volumes contained within this region of the body .
it has been hypothesized that successful spread of the malignancy requires a variety of essential specific growth factors and nutrients found within the peritoneal cavity and peritoneal fluid .
however , it is also well recognized that women with advanced ovarian cancer who experience more prolonged survival have a greater likelihood of experiencing metastatic spread to additional locations , such as the central nervous system [ 1 , 2 ] .
it is possible that late - developing malignant clones have lost the essential requirement for external growth factor support in order to become established in distant sites .
it is also reasonable to hypothesize that these cancers have been present , but quiescent , in these regions of the body for long periods before they become clinically evident .
the patient presented in this report was known to have had epithelial ovarian cancer for 12 years prior to the documentation of metastatic spread to the bone , an observation consistent with other reports of the development of bone involvement as a late metastatic event in the natural history of the malignancy [ 1 , 2 , 4 , 5 , 6 ] .
it is relevant for clinicians caring for ovarian cancer patients to appreciate that although bone is a most unusual initial site of metastatic spread in this setting , bony involvement may become a more common feature in the increasing proportion of patients with this malignancy who are expected to experience extended survival ( > 45 years ) but who , unfortunately , are not expected to be cured of the disease process .
Output:
| bone involvement is uncommon in epithelial ovarian cancer . in this report , a case of bone metastases from ovarian cancer
is described and the potential risk factors for such a rare occurrence are discussed .
it is possible that such an event will become more common in the future as patients with advanced ovarian cancer experience prolonged survival but the cancer is not eliminated . |
PubmedSumm4875 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the original investigations showed that ced-3 and ced-4 genes play essential roles in either the initiation or execution of the cell death program during the development of the model organism nematode caenorhabditis elegans ( c. elegans ) .
further study proposed that ced-3 acts as a cysteine protease in controlling the onset of programmed cell death in c. elegans , and the ced-3 protein in c. elegans is similar to human interleukin-1 ( il-1 ) converting enzyme ( ice ) gene , a cysteine protease that can cleave the 31 kd inactive precursor of il-1 to generate the active form of cytokine .
overexpression of ice ( currently named caspase-1 ) is sufficient to induce programmed cell death of mammalian cells , suggesting that members of the ced-3/ice gene family might function in programmed cell death in vertebrates . with this encouragement , so far fourteen members of mammalian caspase family have been identified .
in general , caspase presents within the cell as inactive zymogen that consists of an n - terminal prodomain of variable length , a large subunit ( p20 ) , a short linker motif , and a small subunit ( p10 ) . in response to apoptotic stimuli
, the zymogens are activated through proteolytic processing at specific asparagine residues located within the prodomain , resulting in the generation of active caspases in the form of ( p20)2(p10)2 heterotetramer .
active caspases subsequently initiate apoptosis or inflammatory responses by the cleavage of specific substrates [ 2 , 3 ] .
based on the structure and function , the caspase family can be divided into three categories .
the caspases bearing larger prodomains are inflammatory caspases ( caspase-1 , -4 , -5 , -11 , -12 , -13 , and -14 ) and initiator / apical / upstream of apoptosis caspases ( caspase-2 , -8 , -9 , and -10 ) , while caspases with shorter prodomains are effector / executioner / downstream caspases ( caspase-3 , -6 , and -7 ) .
the effector caspases perform the actual destruction of the cell and are proteolytically activated by the apical caspases that initiate the caspase cascade .
caspase zymogen can be activated by the so - called extrinsic pathway through the death receptor signaling complex for procaspases-8 and -10 , and the intrinsic mitochondria - mediated pathway through the apoptosome as activating complex for procaspase-9 .
in addition , caspases can also be activated by the granzyme b - mediated and endoplasmic reticulum ( er ) stress - mediated pathways [ 24 ] .
the executioner caspases and initiator caspases possess distinct mechanisms of activation - cleavage for the executioners and cleavage - independent dimerization for the initiators .
the executioner caspases exist constitutively within the cell as inactive dimers and require cleavage within their interdomain linker for activation .
in contrast , the zymogens of the initiator caspases exist as inactive monomers and require dimerization to get activated . of note
, this activation is independent of cleavage , which is different from the common mechanism shared by the executioner caspases and most other protease zymogens . upon activation ,
the effector caspases carry out the death signal through cleavage of their specific substrates that leads to activation of other destructive enzymes such as dnases or degradation of structural and signalling proteins within the cell . as specific cysteine proteases ,
caspases typically recognize xxxd , a four - amino - acid motif with an asparagine as the c - terminal residue and cleaving site .
thus far , more than 390 caspase substrates have been identified , including a number of leukemia - specific proteins that will be discussed later [ 58 ] .
the human caspase-3 gene , a homology to c. elegans ced-3 gene , encodes a 32 kda protein and was first cloned from human jurkat t - lymphocytes in 1994 .
extensive studies have identified caspase-3 as the primary effector caspase in most mammalian cells including leukemia cells .
recently , caspase-3 has been demonstrated to play an important role in determining the cellular sensitivity to diverse apoptotic stimuli , including doxorubicin , etoposide , and cisplatin .
in addition , caspase-3 is involved in a number of nonapoptotic events including proliferation of forebrain cells , keratinocytes and b - cells , mhc ii expression and dendritic cell maturation , differentiation of neural stem cells , myoblasts , osteoblasts , platelets , erythroblasts , and lens epithelial cells [ 1322 ] .
for example , caspase-3-deficient 129x1/svj mice are prenatal lethal and exhibit significant neural precursor cell expansion and exencephaly .
in contrast , caspase-3-deficient c57bl/6 mice are viable , fertile and display no apparent brain pathology [ 23 , 24 ] .
caspase-7 was independently cloned as ice - lap3 , mch3 , and cmh-1 in three different laboratories . due to the high similarity in structure ( 58% ) and
substrates specificity with caspase-3 , caspase-7 has been considered functionally redundant with caspase-3 . indeed ,
similar to caspase-3 , caspase-7-deficient mice on a c57bl/6 background have a normal lifespan and display little discernable apoptotic phenotype .
however , mice deficient for both caspase-3 and -7 in the same strain die shortly after birth , supporting the functional redundancy of these two caspases during embryogenesis [ 24 , 26 ] . more intriguingly
, several studies using cell - free extracts system or caspase-7-deficient mice revealed that caspase-7 also performs distinct , specialized roles in typical apoptosis , er stress pathway , and inflammatory responses [ 25 , 2729 ] .
for instance , walsh et al . screened 20 different purified substrates and found that 12 of them including bid , x - linked iap ( xiap ) , gelsolin , and caspase-6 were preferentially cleaved by caspase-3 , whereas one ( cochaperone p23 ) was more susceptible to proteolytic processing by caspase-7 .
caspase-6 is not as broadly studied as caspases-3 and -7 , but is considered as an effector caspase based on its short prodomain and interdomain cleavage activation mechanism .
caspase-6 substrates include a wide range of proteins involved in cell cycle , survival , or development such as satb1 , p27kip1 , notch1 , ap-2 , lamin a , akt , and 5-lipoxygenase [ 3037 ] .
caspase-6-deficient mice develop normally and are only mildly resisted to anti - fas - induced apoptosis .
interestingly , caspase-6 has been demonstrated to play critical roles in nonapoptotic procedures including b - cell activation and differentiation , axonal degeneration , and human gastric and colorectal carcinomas development [ 37 , 39 , 40 ] .
since nowell and hungerford discovered philadelphia chromosome originated from t(9;22 ) in chronic myeloid leukemia ( cml ) in 1960 , chromosomal aberrations have attracted much attention in the field of cancer cytogenetics , particularly in hematologic malignancies [ 41 , 42 ] . to date , more than 500 recurrent chromosomal aberrations have been identified in leukemia , a frequency much higher as compared to solid tumors .
chromosomal translocations are the most commonly happened and well characterized among all the chromosome disturbances .
for instance , the runx1 gene , located in chromosome 21q22 and a pivotal regulator of definitive hematopoiesis , has been identified in 17 translocations at the molecular level .
the occurrence of subtype - specific chromosomal translocations in leukemia strongly suggests that these aberrations play important roles in the process of carcinogenesis .
moreover , chromosomal translocations are also used as diagnostic and therapeutic markers for leukemia [ 45 , 46 ] .
based on the important role of these fusion proteins in the initiation and development of specific leukemia , drug - triggered fusion protein inhibition or degradation has been proven to be a successful strategy in the treatment of leukemia . of great interests , other than ubiquitination , several prevalent fusion proteins have been demonstrated to be degraded as caspase-3 substrates , including pml - rar , aml1-eto , bcr - abl , and taf15-ciz
more importantly , rather than merely a by - stander apoptotic effect , the proteolysis of these fusion proteins by caspase is mostly involved in nonapoptotic events such as cell differentiation and proliferation .
this provides a new mechanism and potential that might help to develop novel strategy to cure fusion protein - associated leukemia .
the chromosome translocation t(15;17)(q22;q21 ) is seen in 98% acute promyelocytic leukemia ( apl ) patients , characterized by a terminal differentiation block of myeloid cell development [ 45 , 50 , 51 ] .
this translocation juxtaposes the promyelocytic leukemia ( pml ) gene on chromosome 15 with the retinoic acid receptor ( rar ) gene on chromosome 17 and results in the expression of the pml - rar fusion protein in hematopoietic myeloid cells .
this frequently occurred fusion protein initiates apl by acting as a transcriptional repressor that interferes with genes involved in cell differentiation , apoptosis , and self - renewal [ 50 , 52 , 53 ] .
two therapeutic agents in clinical use for apl , all - transretinoic acid ( atra ) , and arsenic trioxide ( as2o3 ) can target pml - rar and induce pml - rar degradation through ubiquitin - proteasome pathway , resulting in a complete remission with the differentiation and apoptosis of leukemic cells [ 5456 ] .
earlier , nervi et al . found that pml - rar is cleaved by a caspase-3-like activity induced by atra treatment and identified aspartate 522 within the -helix region of the pml component as a caspase-3 cleavage site .
interestingly , inhibition of caspase activity could prevent retinoic acid- ( ra- ) induced pml - rar degradation without impairing ra - induced differentiation , suggesting that apl cells may undergo differentiation in the presence of pml - rar expression .
these findings are in agreement with recent data indicating that other than degrade pml - rar , atra is able to induce a switch in pml - rar activity from a repressor to an activator of myeloid differentiation , possibly by triggering its transcriptional activator function on specific ra - target genes [ 5759 ] .
as proposed by the authors , another potential contribution of the degradation of pml - rar by caspase-3 is to leave the rar component intact and mediate ra - dependent transcription since the major caspase cleavage site locates within the pml component of the fusion protein . taken together , the role of cleavage of pml - rar by caspase-3 might play a critical role in atra - induced apl differentiation .
it is one of the most frequently occurred genetic abnormalities in acute myeloid leukemia ( aml ) , identified in 1520% of aml patients and over 40% cases of aml - m2 subtype and rare cases of m0 , m1 , and m4 subtypes of the french - american - british classification [ 60 , 61 ] .
this translocation leads to expression of the aml1-eto fusion transcription factor which is composed of the first 177 amino acids of aml1/runx1 and almost the entire eto ( also known as runx1t1 or mtg8 ) protein .
this fusion protein displays dichotomous function since it not only blocks differentiation but also induces growth arrest and apoptotic susceptibility of leukemic cells [ 6264 ] .
similar to pml - rar , both apoptosis - independent and -dependent degradation of aml1-eto have been reported [ 48 , 56 , 6568 ] , but the precise mechanism and biological significance of aml1-eto degradation remain obscure .
recently , we found that aml1-eto endows leukemic cells with susceptibility to both extrinsic and intrinsic apoptosis and provided direct evidence showing aml1-eto as a caspase-3 substrate .
site - directed mutagenesis analyses mapped two aspartates ( tmpd and llld ) within eto component as caspase-3-targeted sites in the aml1-eto sequence . more intriguingly , proteolytic cleavage of aml1-eto is essential for the apoptosis - enhancing effect of aml1-eto protein because double mutation of aspartates at 188 and 368 abrogated the apoptosis - amplified action of aml1-eto completely , while expression of the caspase-3-cleaved aml1-eto c - terminal fragment is sufficient to enhance apoptotic sensitivity .
sole expression of aml1-eto failed to generate leukemia in various murine transgenic models , suggesting that additional genetic events might be necessary for aml1-eto - positive cells to adopt leukemogenic behavior . because the effect of full - length aml1-eto on apoptosis does not favor leukemogenesis , we proposed that mutation of caspase-3-targeted sites that would result in the abrogation of apoptosis - enhancing effect might exist in t(8;21)-positive aml patients .
in fact , a previously unknown spliced variant transcript of aml1-eto ( aml1-eto9a ) in aml patients encoding a c - terminally truncated aml1-eto protein , which could induce rapid development of leukemia in murine retroviral transduction - transplantation model , has been identified in a number of aml patients .
the philadelphia chromosome , resulting from a reciprocal translocation between chromosomes 9q34 and 22q11 , generates a 190- or 210-kda fusion protein bcr - abl identified in more than 95% of chronic myeloid leukemia ( cml ) and half of patients with adult - onset acute lymphoblastic leukemia ( all ) [ 41 , 7173 ] .
the bcr - abl oncoprotein is a constitutively active tyrosine kinase that endows the leukemic cells with growth advantage .
in addition , leukemic blasts expressing bcr - abl display resistance to apoptosis , lack of cell adhesion , and arrested differentiation [ 7376 ] . similar to pml - rar ,
downregulation of bcr - abl has been observed during differentiation of leukemic cells , but the mechanism is still largely unknown [ 77 , 78 ] .
recently , using a k562 cell line transfected with a temperature - sensitive mutant of p53 , cotter group demonstrated that p53-induced erythroid differentiation in k562 cells required caspase activity , which resulted in the cleavage of c - abl and bcr - abl tyrosine kinases in the absence of apoptosis . in vitro experiment showed that c - abl and bcr - abl proteins are targets for caspase-3 and -7 but not for caspase-6 and -8 .
interestingly , although c - abl and bcr - abl proteins can be detected in both nucleus and cytoplasm / cytoskeleton , the nuclear pool of bcr - abl and c - abl proteins is preferentially cleaved by caspase(s ) following p53 expression in k562 cells , suggesting that only proteins present in a particular location are targeted for degradation .
the central role of bcr - abl kinase in leukemogenesis promotes it as an ideal target for drug screens to treat cml with the attempts to decrease the amount of the bcr - abl transcripts and/or to inhibit its tyrosine kinase activity .
imatinib mesylate ( gleevec , sti-571 ) , which blocks the binding of atp to the activated tyrosine kinase and allows the leukemic cells to differentiate and undergo apoptosis , has revolutionized the treatment of cml .
however , development of resistance towards imatinib has been a major limitation particularly in the treatment of advanced - stage cml .
mechanisms underlying drug resistance include overexpression of bcr - abl and amplification of the bcr - abl gene , acquired additional genomic alterations , and point mutations within the abl kinase domain that interfere with imatinib binding [ 80 , 81 ] .
more recently , bcr - abl alternative splicing has been described in a significant number of cml patients and recognized as a common mechanism for drug resistance [ 8284 ] .
ma et al . described several novel mutations that result in bcr - abl truncations of various lengths within the kinase domain , leading to mutants missing the abl c - terminal nuclear localization signal ( nls ) , dna- and actin - binding ( db and ab ) domains , respectively .
how did these truncations occur and their contributions to the drug resistance deserve further investigation .
of note , cleavage at the sequence dtad , one of the caspase-3-targeted sites within bcr - abl sequence , would release a 52-kda fragment , leaving the kinase domain intact .
these newly identified kinase domain truncations may provide a novel mechanism associated with drug resistance that is caused by executioner caspase activity .
taf15 belongs to a dna- and rna - binding protein family , known as the fet ( also named tet ) family that comprises tls / fus ( translocated in liposarcoma ) , ewsr1 ( ewing sarcoma ) , and taf15 . members of the fet family are implicated in transcriptional activation , mrna / microrna processing , and maintenance of genomic integrity [ 8 , 85 , 86 ] .
more intriguingly , the fusion of fet proteins to various transcription factors ( i.e. , erg , atfi , chop , fli - i ) has been found in multiple human malignancies including leukemia and solid tumors .
recently , a chromosomal translocation at t(12;17)(p13;q11 ) or its variant t(12;22)(p13;q12 ) resulting in the rearrangement of the ewsr1 or taf15 with the transcription factor ciz / nmp4 ( cas - interacting zinc finger protein / nuclear matrix protein 4 ) was identified in aml .
furthermore , taf15-ciz fusion proteins and wild - type taf15 are demonstrated to be cleaved by caspases-3 and -7 both ex vivo and in vitro .
the cleavage site recognized by these two caspases is dqpd / y . due to the lack of understanding of taf15-ciz fusion protein
it is interesting that v - src kinase could phosphorylate taf15 and taf15-ciz at a region containing the caspase cleavage site leading to the block of cleavage .
therefore , it is postulated that increased resistance to proteolysis caused by phosphorylation of taf15-ciz might be advantageous for cancer cells that lead to leukemogenesis [ 8 , 88 ] .
as the key effector of cellular death , caspase-3 expression / activity has been implicated as a predictor of survival in aml and all [ 89 , 90 ] .
however , the results thus far are controversial , and the clinical significance of caspase level in leukemia is still obscure . using quantitative western blot analysis , estrov et al . measured the level of nonactivated caspase-2 , -3 and activated ( cleaved ) caspase-3 in peripheral blood of 185 patients with newly diagnosed aml .
they reported that high levels of procaspase-2 and procaspase-3 denoted poor survival , whereas the high level of cleaved caspase-3 correlated with a favorable prognosis , although with merely a marginal significance . in contrast , most other studies yielded negative data in regards to the association between the level of caspase-3 and survival .
for example , campos et al . observed no relationship between procaspase-2 or procaspase-3 and clinical response of aml patients to therapy as assessed by flow cytometry .
svingen et al . also reported level of procaspase-2 or procaspase-3 from bone marrow samples failed to correlate with response of aml patients to chemotherapy .
detected caspase-3 activity in peripheral blood of children with leukemia prior to , and following , the onset of chemotherapy .
they found no association with clinical response but a significant correlation between the caspase-3 activity over the first 24 hours following chemotherapy and activities at hours 6 and 24 .
a hallmark feature of leukemia and other cancer cells is the ability to escape apoptosis that correlates with chemotherapy resistance .
therefore , there have been enormous efforts in developing new molecules that could reactivate the apoptotic program in tumor cells . up to now , a number of compounds / peptides / antibodies targeting a diverse range of apoptosis - related molecules are being explored at the preclinical and clinical levels . for instance , small molecules / antisenses / oligonucleotides that target bcl-2 , xiap , and survivin and antibodies that target death receptors have been approved by us fda in clinical trials [ 4 , 94 ] .
one potential strategy involves the modulation of natural cellular caspase inhibitors such as xiap , surviving , c - flip , and smac [ 9597 ] .
for example , xiap , a member of iap ( inhibitor of apoptosis ) family , is a natural caspase inhibitor that can specifically bind to the active sites of caspase-3 and -7 or the dimer interface of caspase-9 .
antisense oligonucleotide of xiap with a releasing caspase-3 activity effect has entered the phase i clinical trial in cancer treatment [ 4 , 94 , 98 ] .
another promising strategy is to design or discover small molecules / compounds that directly activate effector caspases . because the activation of effector caspases , particularly caspase-3 , is ultimately involved in most apoptotic events , molecules that directly target the effector caspases would be ideal drug candidates .
however , it would be extremely difficult considering their specific physiologic activation mechanism which requires cleavage by apical caspases .
intriguingly , after screening approximately 20,500 compounds , putt et al . identified pac-1 ( procaspase - activating compound-1 ) , a small molecule that can directly activate procaspase-3 in vitro and induce apoptosis of primary colon cancer cells .
although whether pac-1 activates caspase-3 through direct mechanism is still of dispute [ 100 , 101 ] , it provides a potential strategy in treating the many cancers including leukemia that express an elevated level of caspase-3 .
the pivotal role of effector caspases in multiple cancers including leukemia has been extensively investigated and recognized .
the close connection of effector caspases with leukemia - associated proteins promotes them as ideal target for treatment .
however , due to the dynamic state and specific activation mechanism of caspase , development of compounds of therapeutic value that directly target caspase is far from satisfactory . a better understanding of caspases activation mechanism and newly developed approaches such as chemical biology will help to generate new lead compounds for cancer treatment
. moreover , drug combination including caspases regulators and drugs that target cross talk signaling pathways may be promising and find their way into the clinic .
Output:
| caspases , a family of aspartate - specific cysteine proteases , play a major role in apoptosis and a variety of physiological and pathological processes .
fourteen mammalian caspases have been identified and can be divided into two groups : inflammatory caspases and apoptotic caspases . based on the structure and function ,
the apoptotic caspases are further grouped into initiator / apical caspases ( caspase-2 , -8 , -9 , and -10 ) and effector / executioner caspases ( caspase-3 , -6 , and -7 ) . in this paper
, we discuss what we have learned about the role of individual effector caspase in mediating both apoptotic and nonapoptotic events , with special emphasis on leukemia - specific oncoproteins in relation to effector caspases . |
PubmedSumm4876 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: trypanosomiasis has been endemic in zambia for a long time . the great african rinderpest pandemic which wiped out most of the ungulate population in the late 1880s contributed to the decline of the wildlife and tsetse distribution in zambia [ 1 , 2 ] . as a result , eastern zambia was largely free of tsetse making cattle rearing virtually possible in the luangwa valley towards the end of the 19th century . however , the quick repopulation of wildlife enhanced the increase of the tsetse population density in the luangwa valley .
this lead to wild game , mainly elephants , and tsetse to expand southward and eastward onto the plateau areas resulting into new outbreaks of bovine trypanosomiasis after the rinderpest epizootic [ 4 , 5 ] .
government attributed this expansion to occurrence of trypanosomiasis outbreaks in cattle and decided to establish the department of game and tsetse control in 1942 whose main task was to eliminate wildlife hosts of tsetse as a control strategy .
this resulted in public opposition and was abolished in 1960 . in the 1950s game fences were introduced to prevent the expansion of the wildlife population followed by the subsequent reinvasion of tsetse in the reclaimed tsetse - free areas [ 8 , 9 ] . by 1968 , spraying using endosulfan was introduced while odor - baited targets were introduced in 1970 to reduce tsetse infested areas [ 8 , 9 ] .
put together , game fences , bush burning , aerial spraying , and use of odor - baited targets were used to reduce the expansion of tsetse further away from the luangwa and zambezi valley ecosystem .
these practices were confined to communal areas unlike the national parks ( np ) in the valleys where wildlife and tsetse are allowed to interact freely . in the 1940s ownership of wildlife changed hands from tradition control to state control .
this led to creation of wildlife estates which restricted traditional hunting and access to protected areas by local people . as a result
, the luangwa valley was turned into game reserves in 1938 which put in place regulations forbidding illegal hunting of wildlife .
this led to increase in the wildlife population in the area despite continued poaching from local tribes that were dependent on wildlife as a source of revenue . by 1970 ,
the luangwa valley had over 100,000 elephants ( loxodonta africana ) , while the black rhinoceros was in the order of 4,00012,000 .
as law enforcement began to collapse , illegal hunting increased leading to drastic reduction of some species that led to annihilation of the black rhinoceros ( diceros bi cornis ) and significant reduction of the elephant population in subsequent years . by 1972 , the government turned the game reserves into national parks ( np ) with the view to reduce illegal hunting and improve conservation strategies in order to regain the lost wildlife population in the area .
although species like warthogs ( phacochoerus aethiopicus ) are still high , the overall wildlife population has been reduced due to poaching that has continued to persist in the area . despite some species decreasing
, the conservation strategy of preserving wildlife in state protected areas has significantly contributed to sustenance of tsetse rendering the luangwa and zambezi valley ecosystems , which lay in the common tsetse fly belt , to have the highest tsetse population density in southern africa .
this area provides a unique ecological niche that allows for a favorable interplay between wildlife reservoir hosts and vector tsetse flies .
this niche is supported by a favorable climate and vegetation that sustains a large biomass of wildlife . in 1978 ,
the zambian government turned all areas surrounding the nps into game management areas ( gmas ) allowing for coexistence of wildlife and human habitation in the interface areas . ultimately , this led to the collision of the expanding tsetse fly belt with the expanding human population making trypanoomiasis to be a threat to livestock and humans in the interface areas .
this paper reviews the ecological factors linked to the epidemiology of trypanosomiasis in the luangwa and zambezi valley ecosystems supported by the interplay between wildlife reservoir hosts , vector tsetse flies , and humans living in the interface areas using existing data and previous studies carried out in the area .
luangwa valley ecosystem is made of the luangwa valley which stretches for a distance of 700 km with an average width of 200 km .
the valley covers a total area of 63,000 km being part of the southern end of the great rift valley that cuts across eastern africa .
it is covered by a biomass that sustains a vast range of wildlife and glossina species . as shown in figure 1 , it is bordered by the muchinga escapement , mafinga mountains , and nyika plateau .
the banks of the riverine are made of thick miombo forests while the adjacent slopes are composed of mopane woodlands .
the valley floor is comprised of four nps and six gmas , namely , north luangwa ( 4,636 km ) , south luangwa ( 9,050 km ) , luambe ( 247 km ) , and lukusuzi ( 2,729 km ) ( figure 2 ) .
game management areas ( gmas ) are buffer zones used for wildlife utilization mainly hunting unlike the nps in which hunting is prohibited . in addition
the area has mean annual rainfall of 800 mm and an altitude of 500 m to 600 m. daily ambient temperatures range from 32c to 36c , with mean minimum daily temperatures of 16c to 23c , respectively .
[ 16 , 17 ] , that miombo and associated woodlands are the habitat of the tsetse fly , glossina morsitans , the presence of which has a profound effect on the ecology and utilization of woodlands . when there is wildlife in miombo , tsetse flies survive in large numbers .
hence , the combination of wildlife / miombo / tsetse fly is a natural ecosystem that sustains the persistence of trypanosomiasis for a long time .
as shown in figure 2 , the luangwa valley lies in an ecosystem that overlays nps and gmas with tsetse distribution being part of the famous common fly belt having the high tsetse infestation density that covers an estimated area of 322,000 km involving malawi , mozambique , zimbabwe , and zambia .
robinson et al . noted that in this common fly belt the highest tsetse densities are centered on the drainage systems of the luangwa and zambezi rivers .
the most common species of tsetse in the area are glossina morsitans morsitans westwood and glossina pallidipes austen . given the relative abundance of a diverse wildlife population and a high population density of glossina species , this area renders the best ecological niche for trypanosomiasis transmission between tsetse and wild game .
it encompasses the lower zambezi np and the luano , chiawa , and rufunsa gmas .
the np covers an area of 4092 km and total gma is estimated at 10361 km .
similar to the luangwa valley , the lower zambezi np lays in a tsetse - infested area ( figure 2 ) .
the lower zambezi np was established in 1983 which constitutes the valley floor bordered by the zambezi river on the east .
the riverine is covered by a thick forest which opens into the mopane and acacia woodlands .
it is surrounded by the zambezi escapement which makes the furthest end of the great rift valley in the south .
the mean annual rainfall is estimated at 700 m , while the mean maximum daily temperature varies between 32c and 38c .
the valley altitude varies from 350 m to 550 m. the common tsetse species found in the area are glossina morsitans morsitans westwood and glossina pallidipes austen .
it is also located in the common fly belt with highest tsetse density being in the drainage systems of the zambezi river .
the relative abundance of wild game has a significant influence on the survival of tsetse .
some host species are widely distributed with lesser restrictive habitat requirements , attracting lesser poaching , less trophy hunting and having a much higher breeding potential , while some species are highly restrictive in their habitat requirements , highly poached , and attracting lucrative trophy hunting prices leading to large numbers being hunted every year .
this makes some species to be ubiquitously distributed , while others are limited to selected ecological habitats best suited for their survival . for example , the warthog is a ubiquitously distributed species in the luangwa and zambezi valleys serving as one of the major sources of blood meals for tsetse while semiaquatic species like crocodiles and hippo are highly restrictive in their habitat requirements and as such are not commonly associated with trypanosomiasis .
this would account for the reason why okiwelu reported high proportion of warthog blood meal ( 62% ) in a survey involving several species in the luangwa valley .
species such as the rhinoceros which have become extinct are no more a source of blood meal for tsetse and have been replaced by others .
hence the relative abundance of wild game makes a wide choice of blood meals for tsetse .
current conservation strategies aimed at reducing poaching in order to increase the wildlife population in these areas favor enrichment of the wildlife / miombo / tsetse ecosystems that sustains the persistence of trypanosomiasis . given the wide host range of nocturnal species , the luangwa and zambezi valley ecosystems are likely to sustain trypanosomiasis for a long time .
differences in food sources among wild bovids tend to influence their contact with tsetse subsequently leading to varying degrees of exposure to trypanosomiasis infection .
observed that waterbuck , bushbuck , eland , and kudu were the most heavily infected species among the bovids at nawalia in the luangwa valley ( table 1 ) .
they correlated their findings to the fact that these animals were usually found in thick cover from which they seldom emerged and as such they were more constantly exposed to tsetse bites than puku and wildebeest which were usually found in open country for the greater part of the day .
these findings were supported by keymer dillman and townsend , and rottcher who observed a similar trend in the luangwa valley after several decades ( table 1 ) . in a more recent study , anderson et al . showed that waterbuck had the highest risk of trypanosomiasis infection followed by busbbuck and greater kudu .
hence , among the ruminants , browsers that mainly feed on tree leaves found in thickets where tsetse are mostly found are more prone to infection than the grazers found in open country , while semibrowsers that depend on both tree leaves and grazing are moderately susceptible .
anderson et al . observed that habitat had a significant for species like the bushbuck that were sedentary in thickets and pointed out that such species had a higher risk of infection than nonsedentary species that moved widely covering large areas .
although this observation might be true for some habitats , studies have also shown that bulk grazers like the african buffalo that are lesser browsers are also prone to heavy infections .
okiwelu showed that a close relationship between the feeding behavior of wild game and tsetse tends to influence disease transmission .
newberry et al . observed a similar trend in the luangwa valley that the daily feeding pattern of glossina morsitans morsitans was highly correlated with host behavior . at two selected study areas near mfuwe ( figure 1 ) elephants ,
rhinoceros , and hippopotamus entered the study areas at night and very early in the morning .
trypanosomes were highly detected from blood meals collected from these hosts in the morning collections only , while animals that were present throughout the day had trypanosomes in blood meals collected in the morning and evenings reflecting the diurnal feeding pattern of glossina spp .
okiwelu observed that warthogs were among the most preferred hosts being active in the morning and late afternoon correlating with the glossina flight activity which also had its peak early in the morning and late afternoon .
these findings reflect that diurnal species are more vulnerable to tsetse infestation , while the nocturnal species are lesser favorable hosts .
examined 142 wild rats , 15 mice , one wild rabbit , one squirrel , one galago , and two genet all being nocturnal species and were found negative of trypanosomiasis .
although okiwelu detected trypanosomes from blood meals of an aardvark which only feeds at night , studies carried out thus far indicate that nocturnal species are less favored hosts of tsetse subsequently being less infected by trypanosomes . seasonal variations in the movement of wild hosts has been reported to significantly influence the ecological behavior of glossina species . during the rain season
, wild bovids are widely dispersed covering large areas within the park with water supplies being widely distributed in the park . however , during the dry season as the water sources dry up , animals move to areas close to the river with tsetse densities increasing in area around the riverine .
this trend of seasonal movement has a significant influence on the distribution of tsetse flies rendering the riverine area to be the most densely populated with tsetse populations .
robinson pointed out that the principal factors that influence tsetse populations are host availability , climate , and vegetation .
host distribution and seasonal movement have a significant influence on the distribution of tsetse within an ecological habitat [ 29 , 30 ] .
rainfall has been known to indirectly affect infection rates by significantly altering the relative abundance of wild game . in the rain season
most bovids and suids are evenly distributed as watering points are widely distributed due to retention of water in various water reservoirs . as these watering points dry out in the dry season , wild game depend on the main rivers for water . similarly the seasonal distribution of tsetse varies in correlation with the relative distribution of the wild hosts in each ecological zone . in the dry season , the riverine vegetation which serves as the main source of green leaves for browsing species such as the kudu , waterbuck , and bushbuck also serves as the main resting places for tsetse as they keep away from the effect of excess heat .
hence seasonal movement of wild game influences local dispersal of tsetse within an ecological zone . temperature has a significant influence on the reproductive behavior and feeding habits of tsetse .
okiwelu observed that favorable conditions increase the longevity of individual flies , enabling many flies to become infected and infection to mature .
significant correlations have been established between the mean monthly trypanosome infection rate and mean monthly temperature [ 25 , 31 ] .
studies carried out in the luangwa valley have shown that age structure of tsetse populations is largely dependent on temperature and relative humidity [ 26 , 3235 ] .
tsetse birth rate is generally low in the cold season when the pupal and interlaval periods are at their maximum [ 31 , 35 , 36 ] .
kinghorn carried out comparative studies to determine the impact of temperature on the life cycle of tsetse by comparing the hatchability at nawalia in the luangwa valley to that of the upland areas at high altitude .
they observed that high altitude areas had long periods of low temperatures leading to the majority of the flies failing to emerge from puparia and many of those that did were malformed and quickly died .
the hatchability in the valley was high and they attributed this to the short periods of low temperatures unlike the high altitude areas that had longer periods of low temperatures .
most flies caught from the luangwa valley were infective by having infectious trypanosomes while those from the upland areas were less infective .
they also compared the infectivity of flies caught from the upland plateau areas and those of the luangwa valley during the hot season .
they observed that flies from the luangwa valley were three times more infective than the ones caught from the upland plateau implying that the ecosystem in the valley was more favorable to the breeding of tsetse than the plateau .
this accounts for reasons why the disease has persisted in the luangwa valley for over a century , mainly because of the favorable climatic conditions that favor the survival of tsetse flies and wildlife reservoirs .
the nocturnal resting and feeding behavior of tsetse flies has been reported by robinson in the luangwa valley and by r. d. pilson and b. m. pilson in the zambezi valley , while the diurnal feeding pattern in other places outside the luangwa and zambezi valley ecosystems has been reported by other scientist [ 25 , 38 ] .
r. d. pilson and b. m. pilson observed that feeding was confined to temperatures between 18c and 32c with a median of 25c in the zambezi valley .
studies have shown that the feeding activity in the luangwa and zambezi valleys follow a diurnal pattern with glossina species feeding more in the morning when ambient temperature rises above 18c declining as the temperatures increase in the late part of the morning .
this behavior befits the resting behavior and feeding pattern of most bovids and suids that make the large source of food for tsetse suggesting that the feeding and resting behavior of both vector and hosts species has been synchronized to render an optimal transmission pattern of trypanosomes in the zambezi and luangwa valleys .
generally long periods of low temperatures tend to depress feeding rendering the cold season and extreme hot season not conducive for the survival of glossina species .
this makes the climate in the luangwa and zambezi valley to be more favorable than the upland areas . in zambia ,
host preference of glossina species has been extensively studied by analyzing blood meal contents from mouth parts of tsetse by different scientists [ 25 , 40 ] . as shown in table 3 ,
studies carried out in luangwa and zambezi valley ecosystems have shown that several factors influence the choice of host species as a source of bloodmeal for tsetse .
these factors include the relative abundance of wild hosts , seasonal and daily movement of the host , feeding habits of the host , and the nocturnal or diurnal behavior of the host
. however , tsetse easily adapts and will readily turn to other wildlife species in situations where the preferred species is not available .
newberry et al . observed a switch in the choice of hosts in the mfuwe area of the luangwa valley where a small herd of buffaloes that provided the main meal for tsetse was replaced by warthogs when the buffalo herd was reduced due to predation by lions . the easy way with which tsetse switch from one host species to the other suggests that as long as there are alternative species serving as a source of food the reduction or extinction of one host species may not adversely affect the long - term survival of tsetse .
for example , the extinction of the rhinoceros in the south luangwa np may not have caused a significant decrease in the survival of glossina species given the high presence of alternative host species such as warthogs that have been thriving in large numbers in the same area .
hence , a wide host range is proponent to long - term survival of tsetse populations in an ecological habitat that has to support sufficient interplay between wildlife hosts and vector species .
conservation strategies put in place by the zambian government aimed at reducing poaching to insignificant levels , restocking of extinct species such as the rhinoceros in north luangwa np , protecting endangered species , and control of wildlife diseases have led to the increase in the relative abundance of wild game thereby increasing the longevity of tsetse populations in the luangwa and zambezi valley ecosystems .
as pointed out by hardy , woodrings et al . , and goddard , vector competence refers to the intrinsic permissiveness of arthropods for infection , replication , and onward transmission of the pathogen to nave hosts .
several studies based on dissecting tsetse to determine trypanosome infection rates in the mouth parts , midgut , and other organs of tsetse aimed at determining the infection rates and replication capacity of trypanosomes in glossina species coupled with transmission to laboratory animals and wildlife hosts have been carried out by different scientists in zambia [ 25 , 4446 ] .
intrinsic factors that influence the transmissibility of trypanosomes in tsetse include mature midgut infections , fly species , fly sex , and trypanosome genotype .
these intrinsic factors could account for the varying infection rates among tsetse observed from studies carried out in zambia [ 25 , 4446 ] .
moloo and gooding showed that the vectorial competence of glossina morsitans centralis originating from zambia was comparable to that of tanzania for t. vivax and t. congolense and was superior for t. brucei .
this kind of vector competence is favorable for the longevity of sustaining a viable transmission cycle between wildlife reservoirs and tsetse in such a closed ecosystem .
however , it is important to point out that data on vector competence is limited to the type of diagnostic tests used to determine infection rates in tsetse .
various techniques have been used for vector competence studies ranging from basic microscopy , laboratory animal inoculation , human - resistant - associated ( sra ) gene to detect t.b .
it is likely that using a combination of these tools will increase our understanding of the evolutionary aspects and competence of different vectors in the transmission of different trypanosomes .
complementary to intrinsic factors are the extrinsic factors which also play an important role in the vector competence of tsetse in transmitting trypanosomes from one host to the other .
extrinsic factors include climate and the relative abundance of wild hosts and their ability to carry trypanosomes in their blood for a long time .
temperature has been shown to influence the maturation of trypanosomes into infective forms within tsetse while influencing the growth pattern of tsetse .
the better the climatic condition , the larger the number of adult flies and the more the number of flies with infective tsetse flies .
reported an infection rate that was fives time higher in the luangwa valley than the upland areas from experimentally bred tsetse flies and an infection rate that was 2.5 times higher from naturally infected tsetse in the luangwa valley than the upland areas .
at kakumbi in the luangwa valley , woolhouse et al . estimated the overall per capita rate of infection at 0.37% of the flies acquiring new infections per day which is much higher than infection rates reported elsewhere . hence in a balanced ecosystem that allows for adequate interplay between wildlife hosts and tsetse as observed in the luangwa valley ecosystem , vector competence compliments reservoir competence .
this reflects the ability of animal hosts to maintain infectious trypanosomes transmissible to other nave hosts .
dillman and townstsend , kinghorn and york , and rickman et al . showed infectivity of trypanosomes collected from asymptomatic warthogs , waterbuck , impala , hartebeest , bushbuck , giraffe , and kudu when infected in mice and monkeys suggesting that trypanosomes were adaptive to a wide host range .
table 2 shows different trypanosoma species detected from different wildlife species in the luangwa and zambezi valleys .
recently , anderson et al . detected t. b. rhodesiense in the african buffalo and t. brucei .
. in leopard for the first time showing that the reservoir community for trypanosomes is even wider than previously thought .
infection studies carried out using t. vivax , t. brucei , and t. congolense on nonimmune wild and domestic animals bred in captivity in a tsetse - free area in kenya showed that the incubation period in wild game was longer than in domestic animals and that wildlife developed low parasitaemia with low anaemia compared to domestic animals that had high parasitaemia and anaemia leading to chronic infections .
similarly field observations from game shot in the luangwa valley showed low parasitaemia and low infection rates [ 2022 , 56 ] . based on these observations , dillman and
townsend concluded that several wildlife species live in equilibrium with trypanosomes carrying the hemoparasites without expressing clinical signs by reaching a degree of trypanotolerance in the luangwa valley .
thus far , clinical trypanosomiasis in wild game in zambia has only been reported from a lion obtained from chichele springs in the luangwa valley .
the ability of wild hosts to maintain viable trypanosomes is vital for continuous transmission of the disease between wildlife and tsetse .
immunological responses that permit the survival of trypanosomes in wild game have been reviewed by mulla and rickman .
generally , they observed that the incubation period in wildlife was longer than in domestic animals and that wild game developed low parasitaemia than domestic animals with reservoir ability to maintain trypanosomes for a long time .
the first report of trypanosoma brucei rhodesence in humans dates as far back as 1908 when the first case of sleeping sickness was reported from a person living in the luangwa valley .
although the zoonotic trypanosoma has been isolated by different scientists from different wildlife species in the area ( table 2 ) , its prevalence in humans is highly variable .
rickman [ 2 , 58 ] reported of human infection rates of 12.3% in the petauke area and buyst reported of infection rates of 16.5% in isoka .
recently anderson et al . reported of a low prevalence of 0.5% ( n = 418 ) of t.b .
rhodesiense in wildlife in the luangwa valley indicating that maintaining biodiversity in the luangwa valley could have influenced the limited emergence of this parasite in the luangwa valley ecosystem .
this observation contradicts the common perception that spillover from wildlife is a risk factor for humans living in gmas as earlier indicated by buyst who observed an increase in tsetse populations around the villages during the dry season when wildlife had retreated to the riverine in the nps followed by a more wide spread distribution away from villages in the rain season when wildlife were evenly distributed .
these observations led buyst to conclude that tsetse switch to humans as an alternative source of blood meal when wild animals were scarce during the dry season and that they resorted back to wildlife during the rainy season when wild animals were evenly distributed in gmas and nps .
these assertions have been supported by observations made by other scientists as shown in table 3 that humans living in gmas also serve as sources of blood - meal for tsetse . as shown in figure 2 ,
clinical cases of human trypanosomiasis have been reported in gmas although asymptomatic cases are also common .
however , to fully understand the role of humans living in gmas on the epidemiology of trypanosomiasis , there is need for further investigations .
anthropogenic activities in the luangwa and zambezi valleys adversely affecting the ecosystem include illegal hunting , deforestation , charcoal burning , cultivation , and pastoralist . among these ,
lewis et al . estimated the human population density in the valley floor at less than 10 persons per km except for the mid - luangwa valley area that had a higher density above 30 persons per km due to increased tourism and pastoralists .
timberlake and chidumayo pointed out that in miombo woodlands , areas having population densities above 10 persons per km are threatened by anthropogenic pressure due to increased demand for natural resources .
hence , the low human population density in the valleys ( < 10 persons / km ) would account for reasons why the tsetse population density is high in this area because of less competition for natural resources between humans and wildlife .
on contrast , it has been shown that human dependence on wildlife is high in the luangwa valley .
this has for a long time been exacerbated by the nonpastoralist tribes of northern zambia that relied on illegal hunting as a source of livelihood . by 1999
, it was estimated that 4060% of the valley residents were unable to produce enough food and relied on illegal hunting as an alternative source of income .
lewis et al . have estimated that more than 3,000 hooved animals were killed by illegal hunters in the luangwa valley every year . as a result
, wild animals tend to retreat into the nps where they are protected by patrolling game rangers avoiding the gmas where the hunting pressure is high .
this accounts for reasons why the high population density of both wildlife and tsetse is higher in the nps rendering this area to be part of the common tsetse fly belt having the highest tsetse population density in southern africa .
deforestation due to charcoal extraction and clearing of land for cultivation and livestock production are contributing to loss of habitat for wildlife and tsetse in the gmas .
more than 31,000 tons of charcoal is extracted annually in the nyimba and petauke gmas ( figure 3 ) .
a similar trend has been reported in the chinsali gmas , while more than 21% of the forest cover in lundazi has been cleared for crop cultivation . as pointed out by lawton ,
an ecosystem of human settlement / cultivation / pastoralism is opposite of the wildlife / miombo / tsetse ecosystem that naturally sustains the persistence of trypanosomiasis .
once miombo is cleared , tsetse and wildlife retreat into nps due to loss of habitat in gmas giving way to crop cultivation or pastoralism so long miombo woodlands do not regenerate for reinvasion of tsetse .
similarly , extensive burning of ground cover annually done by local residents to facilitate wild honey collection , hunting and crop cultivation contributes to loss of habitat although early burning is known to favor regeneration of woodlands which creates a favorable habitat for tsetse while late burning in the dry season creates open areas unfavorable for tsetse . to counteract these adverse anthropogenic effects , conservation strategies aimed at empowering local residents with alternative income generating activities are been explored .
more than 25,000 beehives have been established in the area while illegal hunters are encouraged to surrender their firearms and snares in exchange for alternative income sources .
overall , positive attributes gained from these activities include increase in wildlife populations , even distribution of wildlife due to reduced hunting pressure and reduced in deforestation .
it is evident from this paper that trypanosomiasis can be maintained in a closed ecosystem for more than a century so long ecological factors that favor adequate interplay between tsetse and wildlife reservoir hosts are kept in balance in a suitable habitat . although anthropogenic activities in the area seem to adversely affect the expansion of wildlife by shrinking the ecological habitat of wildlife and tsetse , in the nps where human interference is low due to presence of patrolling game rangers and other law enforcement officers , there is high interaction between tsetse and wildlife rendering the luangwa and zambezi valley ecosystems to be one on the most tsetse densely populated areas in southern africa .
table 4 summarizes some of the ecological and biological factors influencing the epidemiology of trypanosomiasis in the luangwa and zambezi valley ecosystems .
it is eminent from the enlisted biological and ecological factors that persistence of wildlife trypanosomiasis in an ecosystem is dependent on interplay of several factors that include vector tsetse flies , wildlife , habitat , and conservation strategy .
it is clearly demonstrated from the historical perspective of trypanosomiasis in the luangwa and zambezi valley ecosystems that the disease which was almost wiped out due to loss of wildlife during the rinderpest pandemic , reemerged and has been maintained through shift in policies that have evolved from traditional ownership of wildlife to state protected properties by introducing game reserves during the precolonial era to establishment of nps and gmas in the 1970s until the current conservation strategies that are aimed at increasing the existing wildlife population and restocking formerly annihilated species such as the black rhinoceros . put together ,
these efforts demonstrate that while conservation of biodiversity is an important preservation strategy of natural resources , it could also serve as long - term reservoir of trypanosomiasis .
Output:
| trypanosomiasis has been endemic in wildlife in zambia for more than a century .
the disease has been associated with neurological disorders in humans .
current conservation strategies by the zambian government of turning all game reserves into state - protected national parks ( nps ) and game management areas ( gmas ) have led to the expansion of the wildlife and tsetse population in the luangwa and zambezi valley ecosystem .
this ecological niche lies in the common tsetse fly belt that harbors the highest tsetse population density in southern africa .
ecological factors such as climate , vegetation and rainfall found in this niche allow for a favorable interplay between wild reservoir hosts and vector tsetse flies .
these ecological factors that influence the survival of a wide range of wildlife species provide adequate habitat for tsetse flies thereby supporting the coexistence of disease reservoir hosts and vector tsetse flies leading to prolonged persistence of trypanosomiasis in the area . on the other hand , increase in anthropogenic activities poses a significant threat of reducing the tsetse and wildlife habitat in the area .
herein , we demonstrate that while conservation of wildlife and biodiversity is an important preservation strategy of natural resources , it could serve as a long - term reservoir of wildlife trypanosomiasis . |
PubmedSumm4877 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: addiction is one of the most important health problems in the world , specially in iran ( 1 ) , and many factors are related to onset and maintenance of this common disorder . since the ancient times , philosophers and scientists have known loneliness as one of the most complex psychological phenomena . at that time loneliness was a positive concept ( 2 ) , which meant withdrawal from daily routine events to achieve more important goals in life ( thinking , meditation , and spiritual connection ) , but nowadays it is not considered as a positive experience in psychological literature and refers to social withdrawal and poor social interaction .
feeling of loneliness is a psychologically destructive and terrifying experience ( 3 ) that makes severe psychological and physical problems ( 4 , 5 ) . in social interaction
sense of loneliness could make problems in social interaction and decrease the self - protective behavior potentials as a social threatening factor ( 6 ) .
it is believed that loneliness is a pervasive and dysphoric experience , which is the outcome of the expectation of individual and his or her current status .
feeling of loneliness has a direct relationship with the emotional domain and individual cognitive function and causes lack of adaptation in cognition , experience , and social expectations ( 7 ) .
( 4 ) reported the prevalence rate about 8% to 10% and the other studies showed that 15% to 30% of people experience loneliness continuously .
heinrich and gullone ( 6 ) believed that one out of four people suffer from chronic loneliness .
a recent review by hawkley and cacioppo ( 9 ) revealed that about 80% of people aged lower 18 and 40% of the over 65 years reported feeling of loneliness at least sometimes .
baumeister and laery ( 10 ) argued about the basic needs and the feeling of belonging as essential motivations in individual`s emotion , thinking , and behavior , which need at least a minimum of positive stable interpersonal relationship ; therefore , an individual who develops problems in making and maintaining satisfactory relationship with the others will develop problems in satisfaction of the feeling of belonging , and this kind of deprivation leads to morbidity ( 10 - 13 ) . generally , drug abuse is a multifactorial disorder in which every factor has its specific and common effects on the development and maintenance of addiction ( 14 ) .
thus , any intervention concerning the prevention and treatment of addicted individuals should consider these factors or variables ( 1 ) .
the current study assessed the status of loneliness as an individual psychological factor and compared it in individuals with and without substance dependence disorder .
the current study aimed to assess emotional , social , romantic , and familial dimensions of loneliness in drug abuser and nondrug abuser individuals .
in the current cross sectional study , 118 drug users who were referred to baharan psychiatric hospital ( affiliated to zahedan university of medical sciences , iran ) and diagnosed as a case of addiction by a psychiatrist , were enrolled through random sampling method , and 110 individuals , without history of using narcotic drugs , were selected through available sampling method from drug abusers ` companions , students or staff of the hospital as non - drug abuser group . to assess
the loneliness , the iranian short version of the social and emotional loneliness scale for adults ( selsa - s ) ( 15 ) was employed .
iranian form of selsa - s was prepared and validated by jowkar and salimi ( 15 ) .
they reported cronbach alpha values of 0.92 , 0.84 and 0.78 for romantic , social , and familial subscales , respectively .
the scale used in the current study is a 14-item scale with three subscales including romantic ( four items ) , social ( five items ) , and familial ( five items ) loneliness .
each item has five degrees of likert rating scale from zero ( completely agree ) to four ( completely disagree ) .
hundred and fifty two participants were men ( 66.7% ) and 76 were women ( 33.3% ) . in the drug abuser group ,
the age range was 16 - 55 ( mean = 29.43 , sd = 7.83 ) , and in the drug non - abuser group the age range was 17 - 50 ( mean = 27.99 , sd = 8.54 ) . table 1 shows demographic characteristics of the participants .
results of the t - test indicate ( table 2 ) that individuals diagnosed with substance dependency scored higher on the romantic , family , social , and emotional subscales of selsa than those of individuals without substance dependency .
although there was no statistically significant difference between substance dependent men and women ( table 3 ) on loneliness scores , results of the t - test showed a significant difference between scores of non - dependent men and women on romantic subscale .
data are presented as mean sd . data are presented as mean sd .
according to the results of the current study , the difference of mean scores on the four dimensions of loneliness were statistically significant between drug abusers and non - abusers , higher in drug abuser group in all domains of social and emotional loneliness scale .
in addition , the difference of the mean score of emotional domain , which is the sum of romantic and familial domains , was statistically significant between two groups .
heinrich and gullone ( 6 ) indicated that feeling of loneliness is a cognitive variable related to worse physical and mental health and has direct relationship with depression and alcohol abuse ( 17 , 18 ) , low self - esteem , low self - confidence , assertiveness , shyness ( 6 , 19 ) , disinhibited , high risk behaviors , anxiety , and tension ( 20 ) . according to the results of the current study , which indicate the higher score of loneliness
, drug abuse and entertaining themselves could be a way out of a feeling of loneliness and acquiring a feeling of security , also drug abuse could be a way to satisfy the emotional and psychological needs ( 20 ) .
non drug abusers , who have real familial support system , do not need any compensation for their conflict by abusing drugs or taking high risk behaviors .
in addition to the difference of the score rate of loneliness in the two groups , there was a more romantic feeling of loneliness in women rather than men in non - drug abusers , which is similar to the results of some other studies ( such as swami ) ( 18 ) .
this negative feeling may cause individuals to develop different kinds of reactive compensations including passive withdrawal reactions such as walking , studying , doing exercise , watching movie , and playing music or passive depressive reactions , in this case individual is overwhelmed with feeling of loneliness and may develop crying , thoughtfulness , or abusing drugs ( 6 )
. in summary , social and emotional feeling of loneliness as a high risk factor may cause initiation of drug abuse and its maintenance , therefore it is suggested to consider this critical variable in prevention and treatment of addiction .
however , it is necessary to conduct further studies to see what biological and environmental factors influence the development of social and emotional loneliness and how those factor can be incorporated in prevention and treatment protocols .
Output:
| background : loneliness is one of the psychological variables related to high risk behaviors that should be investigated more.objectives:the current study aimed to assess emotional , social , romantic , and familial dimensions of loneliness in drug abuser and nondrug abuser individuals.patients and methods : two hundred and twenty eight individuals were enrolled in this cross sectional study .
hundred and eighteen drug abusers were recruited through random sampling among the clients referred to baharan psychiatric hospital , and 110 non - substance dependent individuals were selected from their companions , students , and staffs .
in addition to clinical interview , the iranian short version of the social and emotional loneliness scale for adults ( selsa - s ) was used to evaluate the participants.results:there were statistically significant difference between the scores of all four emotional , social , familial , and romantic dimensions of loneliness in substance dependent individuals .
although there was no difference between the scores of men and women , the mean scores of romantic and emotional dimensions were higher in non - substance dependent women.conclusions:the feeling of loneliness is stronger in drug abusers rather than non - drug abusers that could develop the sense of being different from community and increase the probability of taking high risk behaviors and abusing drugs .
thus , it is suggested to consider the feeling of loneliness in all programs designed to prevent or treat addiction . |
PubmedSumm4878 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: rhodiola rosea ( r. rosea ) is an herb that grows in mountainous regions of north america , europe , and asia .
it has been used in traditional folk medicine for centuries as a treatment for fatigue and mood disorders .
r. rosea has been extensively studied by scientists in the former soviet union and has predominantly been found to result in favourable effects on exercise performance . however , this prior work has been lacking in experimental control .
some recent studies have supported the results of earlier work by identifying antioxidant and anti - inflammatory properties of r. rosea [ 3 , 4 ] . another work has suggested ingestion of r. rosea appears to be effective , either acutely or with daily supplementation , for reducing perceived fatigue and improving cognition [ 5 , 7 ] , as well as reducing markers of physiological and psychological stress [ 7 , 8 ] .
although r. rosea ingestion has been identified as a means to reduce physical fatigue , its efficacy during exercise is unclear .
animal based research has shown increased swim time to exhaustion in rats [ 3 , 9 ] but the impact of r. rosea ingestion on exercise performance in humans is equivocal .
some studies have shown no effect of r. rosea ingestion on exercise performance [ 4 , 1012 ] whilst others have supported its use [ 13 , 14 ] .
the array of protocols and supplementation doses used in prior studies has also limited comparisons between studies and provides one potential explanation for the discrepancy in their findings .
for example , de bock et al . reported that an acute dose of r. rosea increased time to exhaustion during an incremental cycle ergometer protocol .
conversely , in the same study , 4 weeks of r. rosea supplementation did not significantly improve cycling performance .
this was the first study to show an acute impact of r. rosea ingestion on human exercise performance .
more recent research by noreen et al . examined the efficacy of a 3 mgkg body mass dose of r. rosea on 6-mile cycle time trial performance in 18 active women .
they reported that r. rosea significantly decreased submaximal exercise heart rate , reduced rpe , and improved time trial performance time .
noreen et al . subsequently suggested that acute r. rosea ingestion might be employed by active individuals while exercising to complete a set distance in the shortest time .
such data are interesting ; as if r. rosea does positively impact on exercise , it may be safe and legal way to enhance exercise performance in athletes and the exercise experience in recreational gym users .
abidov et al . demonstrated that an extract of r. rosea significantly prolonged the duration of exhaustive swimming in rats and stimulated atp synthesis in muscle during exercise .
these findings led perfumi and mattioli to speculate that , in addition to enhancing the catecholaminergic system , the ability of r. rosea to increase performance involves an improvement in cellular energy metabolism .
however , some studies have suggested that r. rosea acts to acutely increase endogenous opioid production or receptor sensitivity [ 2 , 13 ] which subsequently impacts on brain dopamine and serotonin and cardiac activity and attenuates the perception of effort at a given workload .
however , as only two studies have examined acute r. rosea ingestion on exercise performance to date , further data is needed on this topic . moreover , both de bock et al . and noreen et al .
employed performance based protocols to examine the effect of r. rosea ingestion . while these are valuable in understanding the effect of a nutritional supplement on performance responses , different protocols may be better placed to evidence any effect of r. rosea on exercise performance .
for example , using steady state submaximal exercise in the presence of r. rosea and placebo would allow for power output to remain constant across a given period .
this then allows for better like - for - like comparison of data between the active supplement and placebo trials .
moreover , when employing protocols where intensity is modified throughout ( as is the case with both time trials and time to exhaustion ) understanding any impact of the exercise protocol of substance ingested becomes more difficult because even small increases in exercise intensity have been shown to markedly change feelings of pleasure during exercise . furthermore , given the postulation that r. rosea acts through increased opioid production , it is perhaps surprising that few studies have examined its impact on affect .
noreen et al . reported no effect of r. rosea ingestion on mood state , as assessed using the poms questionnaire .
however , changes in mood state with exercise have been reported following ingestion of a range of substances including caffeine [ 18 , 19 ] and carbohydrate .
hedonic theory postulates that hedonic responses ( i.e. , pleasure versus displeasure ) following a behaviour influence decisions regarding whether or not to repeat that behaviour . as a consequence
if nutritional manipulation enhances the pleasure response to exercise , according to hedonic theory , it may mean individuals are more likely to exercise .
this is important as different exercise intensities and individual fitness will create variability in the affective response to exercise [ 2224 ] and the effect of nutritional manipulation on these responses is not well known .
changes in mood and feelings of pleasure may be one reason why individuals do not participate in regular exercise and physical activity and favourable affective states benefit exercise performance .
has also identified that affective and perceptual responses to exercise differ depending on adiposity status .
assuming that the affective response to exercise is the same in recreational exercises compared to high level performers may therefore lead to erroneous conclusions regarding the exercise - affect relationship .
thus , while the extant literature examining the effect of r. rosea ingestion has focused on performance measures , the current study seeks to develop this work by employing a model that can be applied to recreational exercisers and is more applicable to the exercising public in general .
the aim of this study was to examine the effect of acute r. rosea ingestion on substrate utilisation , mood state , rpe , perceptions of arousal , and pleasure / displeasure in a population of recreationally active men .
it was hypothesized that ingestion of r. rosea would positively influence perceived exertion during exercise as well as enhancing mood and perceptions of arousal and pleasure / displeasure before and after cycling exercise .
testing these hypotheses will address gaps in knowledge on the effect of r. rosea by examining their effects on an active but not performance oriented group , more typical of regularly active individuals in the general population .
the study will also combine physiological and psychological measures to address gaps in the literature base by assessing substrate utilisation , heart rate , rpe , mood state , and perceptions of arousal and pleasure / displeasure to provide a multidisciplinary investigation of the effect of r. rosea during exercise .
this study employed a within - participants double - blind cross - over design whereby participants visited the laboratory on 3 occasions at the same time of day in a well - rested and well - hydrated state .
all participants were asked to refrain from vigorous exercise and maintain normal dietary patterns in the 48 hours prior to testing and were asked not to consume caffeine for 24 hours before testing . during the first visit participants completed a familiarization session with the measures to be used in the subsequent experimental trials and completed an incremental exercise test to assess vo2max. inclusion criteria included being male and habitually engaged in recreational physical activity of more than 3 but less than 10 hours per week and not including formal competitive sports performance .
participants were excluded if they had a musculoskeletal or cardiovascular contraindication to exercise , were taking any medication that could impact mood / affect , engaged in less than 3 or more than 10 hours physical activity per week , or were engaged in competitive sports activity as part of their habitual physical activity .
the incremental exercise test was performed on a mechanically braked cycle ergometer ( monark exercise ab , sweden ) to assess vo2max following previously published guidelines .
initially , participants were fitted to the ergometer and performed a 5 min warm - up at 25 watts .
the initial work rate for the test was 80 watts with the work rate increasing by 40 watts every 3 minutes .
this protocol , using 3-minute stages rather than a ramp protocol , was employed based on prior research suggesting that this form of protocol provides more reliable physiological measures , particular for the population characteristics examined in this study ( i.e. , active but not cycling trained specifically ) .
participants were asked to maintain their pedal cadence at 70 rpm and were given visual feedback from the monark control box in order to do this .
expired air was collected via the douglas bag technique during the final minute of each incremental exercise stage .
samples were analyzed for oxygen and carbon dioxide content ( servomex , crowborough , england ) and expired air volume ( harvard dry gas meter , harvard apparatus , kent , england ) with values for oxygen consumption ( vo2 ) and carbon dioxide production ( vco2 ) subsequently calculated .
heart rate ( polar electro , kempele , finland ) and rating of perceived exertion ( rpe ) , using the borg 620 rpe scale , were recorded during the final 15 seconds of each workload .
participants were judged to have reached vo2max if they presented at least 3 of the following : ( a ) a respiratory exchange ratio of greater than 1.1 , ( b ) a heart rate during the last stage of testing that was 10 beats of age predicted maximum heart rate , ( c ) an rpe of 18 or greater , ( d ) a plateau in vo2 with an increase in workload , and ( e ) volitional fatigue .
. of participants ' baseline vo2max values was 50.5 6.6 mlkgmin ( range : 38.858.4 mlkgmin ) .
descriptive information for the participants is presented in table 1 . on completion of the vo2max testing and following a period of at least 72
hours participants completed two 30-minute submaximal cycling trials at a workload of 70% vo2max in a fasted state .
self - report of dietary intake was employed to assess and control dietary intake in the 24 hours prior to exercise trials .
this was used to ensure that the same / similar per testing meals were consumed prior to experimental trials and that caffeine and alcohol had not been consumed in the 24 hours prior to testing .
the duration and intensity of exercise were chosen as it sits within the american college of sports medicine guidelines for the prescription of exercise for health benefit . on a molecular basis ,
the main active ingredients of r. rosea appear to be tyrosol and its glucoside known as salidroside and following oral ingestion of 100 mgkg salidroside , the half - life of salidroside appears to be 1.32 0.22 h .
therefore , conditions were randomised , separated by 4872 hours , and consisted of a r. rosea condition where 3 mgkg body mass of r. rosea ( indigo herbs , glastonbury , uk ) placed in a coloured , opaque gelatin capsule or a placebo ( 3 mgkg body mass of maltodextrin , ( myprotein , northwich , uk ) ) was ingested with 250 ml water .
the capsules were indistinguishable between r. rosea and placebo conditions and were ingested 60 min before exercise on an empty stomach .
the amount of total maltodextrin ingested was approximately 170 mg and thus highly unlikely to have had any impact on exercise performance or metabolism .
the dose of r. rosea used was based on the previous work of de bock et al . and
noreen et al . who observed improvements in endurance performance following acute ingestion of r. rosea .
during each of the cycling trials , heart rate was monitored ( polar rs400 , polar electro oy , kempele , finland ) continuously and assessed every 10 minutes .
participants were also asked to provide ratings of perceived exertion ( rpe ) using the borg 620 scale . prior to commencing the experimental trials the memory - anchoring approach was employed whereby participants
were asked to remember a time when they were at rest ( attributed to rpe of 6 ) and a time when they had reached a level of exertion that was maximal attributed to rpe of 20 .
the rpe scale was presented to students for 1 minute prior to their rating of perceived exertion at each time point and was not visible other than this .
prior to any substance ingestion , 60 min after ingestion ( at the onset of each exercise bout ) and immediately on completion of each exercise bout , participants also completed the feeling scale ( fs ) as a measure of pleasure and displeasure .
this is an 11-item single - item scale ranging from + 5 ( very good ) to 5 ( very bad ) that is used to quantify pleasure / displeasure .
the felt arousal scale ( fas ) was also used as a measure of arousal .
this is a six - item scale ranging from 1 ( low arousal ) to 6 ( high arousal ) .
mood state was also assessed using the fatigue and vigour subscales of the brunel mood state inventory ( brums ) .
this is a well - established , reliable , and valid measure of mood state that has been previously employed to assess the mood state response to various exercise modes [ 18 , 35 , 36 ] .
the fatigue and vigor subscales were chosen in particular as prior research [ 1 , 7 ] has suggested r. rosea may particularly influence feelings of fatigue and/or vigor .
participants were introduced to these scales during their first visit to the laboratory ( prior to establishment of vo2max ) . standardised instructions for completing the fs and fas were read to participants at the beginning of each trial .
prior to cycling ( but whilst seated on the exercise bike ) at 14 min and 29 min during each exercise bout expired air samples were collected using the douglas bag technique to estimate fat and carbohydrate ( cho ) oxidation rates .
the collection time was 60 s and samples were analysed for oxygen and carbon dioxide content ( servomex , crowborough , england ) that was calibrated at two points before each assessment using gases of known concentrations ( 15.12% o2 , 5.1% co2 ) in accordance with manufacturers guidelines and expired air volume ( harvard dry gas meter , harvard apparatus , kent , england ) with values for oxygen consumption ( vo2 ) and carbon dioxide production ( vco2 ) subsequently calculated .
energy expenditure ( kcalmin ) and the oxidation rates for carbohydrate and fat ( gmin ) were then calculated according to the weir and frayn equations , respectively .
a series of 2 ( substance ingested ) 4 ( time point ) ways repeated measures analysis of variance was used to examine any differences in heart rate and rpe .
a series of 2 ( substance ingested ) x 3 ( time point , before ingestion , after ingestion but before exercise , and after exercise ) ways repeated measures analysis of variance was used to examine any differences in mood state and perceptions of arousal and pleasure / displeasure and substrate utilisation . where any significant differences were discovered , bonferroni pairwise multiple comparisons were used to determine where the differences lay .
partial was used as a measure of effect size , statistical significance was set at p = 0.05 a priori , and the statistical package for social sciences ( version 20 ) was used for all analysis ( spss inc . , il , usa ) .
in respect to heart rate , results indicated no significant interactions or main effect due to the substances ingested .
there was however a significant main effect for time ( f 3 , 27 = 266.7 , p = 0.0001 , p = 0.967 ) where heart rate was significantly increased throughout the exercise bout irrespective of substance ingested .
mean se of heart rate ( bpm ) was 77 4 at rest compared to 151 4 , 158 4 , and 162 4 at 10 , 20 , and 30 minutes into the exercise bout , respectively .
bonferroni comparisons indicated that heart rate was significantly different at all time points ( p = 0.001 in all cases ) . in the case of rpe , results indicated a significant substance time interaction ( f 3 , 27 = 6.12 , p = 0.003 , p = 0.405 , see figure 1 ) .
rpe data were not significantly different at rest and at 10 and 20 minutes into the exercise bout between the two conditions . however , rpe in the placebo condition was significantly higher than that in the r. rosea condition 30 minutes into the exercise bout ( p = 0.003 ) .
scores from the fatigue subscale of the brums indicated a significant main effect across time ( f 2 , 18 = 12.879 , p = 0.0001 , p = 0.589 ) where scores were significantly higher after exercise compared to before exercise ( p = 0.028 ) and compared to before exercise but after ingestion ( p = 0.008 ) .
there were no other significant main effects of interactions for fatigue subscale data . in regard to the vigor subscale of the brums , there was no significant substance time interaction .
there were however significant main effects for time ( f 2 , 18 = 4.435 , p = 0.027 , p = 0.350 ) and for the substance ingested ( f 2 , 9 = 11.692 , p = 0.008 , p = 0.565 ) .
scores for vigor were significantly lower at after exercise compared to after ingestion but before exercise ( p = 0.04 ) .
mean se for vigor scores was 6.9 0.56 before ingestion , 7.4 0.44 after ingestion but before exercise , and 5.6 0.74 after exercise .
for the substance ingested , scores for vigor were significantly higher in the r. rosea condition ( p = 0.008 ) compared to the placebo .
mean se for vigor was 7.6 0.52 in the r. rosea condition compared to 5.7 0.57 in the placebo condition .
perceptions of arousal were also significantly different in the presence of r. rosea compared to placebo ( f 1 , 9 = 5.0 , p = 0.05 , p = 0.357 ) with scores for arousal being higher ( 3.1 0.19 ) in the presence of r. rosea compared to placebo ( 2.8 0.11 ) .
when data for feeling of pleasure / displeasure were assessed , there was however a significant condition time effect ( f 2 , 18 = 12.795 , p = 0.0001 , p = 0.587 , see figure 2 ) .
this followed a similar pattern to rpe with no significant difference evident before ingestion ( p = 0.591 ) or after ingestion but before exercise ( p = 0.08 ) .
there was however significantly lower scores for pleasure after exercise in the placebo condition compared to the r. rosea condition ( p = 0.003 ) .
energy expenditure was significantly higher during exercise ( f 2 , 18 = 130.921 , p < 0.001 , p = 0.936 ) ( see figure 3 ) , irrespective of the trial ( f 1 , 9 = 1.198 , p = 0.302 , p = 0.117 ) .
the rate of total carbohydrate oxidation ( figure 4 ) was not significantly different between trials ( f 1 , 9 = 0.317 , p = 0.587 , p = 0.034 ) .
carbohydrate oxidation remained relatively constant throughout exercise but was higher compared with the rest ( f 2 , 18 = 13.902 , p < 0.001 , p = 0.770 ) .
the rate of fat oxidation ( figure 5 ) was higher than that at rest during exercise ( f 1 , 11 = 25.131 , p < 0.001 , p = 0.736 ) but there was no significant main effect due to the substances ingested ( f 1 , 9 = 0.950 , p = 0.355 , p = 0.095 ) .
acute r. rosea ingestion has been reported to improve exercise performance [ 13 , 14 ] in performance based tasks .
authors have suggested that this performance enhancement may result from r. rosea 's action as an opioid producer [ 2 , 13 ] .
however , use of performance based exercise tasks ( e.g. , time trial ) in prior studies makes it difficult to assess the effect of the substance ingested apart from the exercise intensity in tasks where intensity will fluctuate . arguably , the sue of a constant load exercise protocol for 30 minutes is a more externally valid form of exercise for most individuals as it mirrors the minimum exercise recommendations for healthy adults .
no study to date has assessed the effects of r. rosea ingestion on mood , perceptions of exertion , arousal , and feelings of pleasure / displeasure during steady state exercise . in the current study , rpe and affect
were measured prior to , during , and after 30-minute submaximal cycling at a moderate exercise intensity after ingestion of 3 mgkg r. rosea of placebo .
this study is novel in that results demonstrated dampened rpe , greater vigor , perception of arousal , and pleasure in the presence of r. rosea compared to placebo . in the case of rpe and feelings of pleasure ,
thus , this data indicate that acute r. rosea ingestion positively modifies affect during relatively brief , steady state exercise at moderate intensity .
previous studies have speculated that the ingestion of r. rosea can improve exercise performance via altered energy metabolism , activated by the synthesis or resynthesis of atp in mitochondria and stimulated restorative energy processes after intense exercise .
however , the results of the present study suggest that altered substrate utilization is not responsible for the improved performance .
the discrepancy between the findings of the present study in this respect and those of prior work [ 15 , 16 ] may be due to varying preexercise fed state across studies . in the present study
the frayn equation was employed to assess fat oxidation as this is the most widely applied equation for fat oxidation available .
however , we acknowledge that other equations are also available and may be preferable in future work .
it is also important to note that there is no gold standard to validate whole body substrate oxidation but that assessment of substrate oxidation using indirect calorimetry may be prone to large errors .
therefore , the acute increase in endogenous opioid production may play a role in enhancing exercise performance in the presence of r. rosea and is evidenced through changes in perceived exertion and exercise affect rather than changes in physiological markers .
prior research has tended to employ protocols involving time trial performance or time to exhaustion , neither of which is applicable to the typical exercising public . while the protocol employed in the present study may be valid when examining steady state exercise at a moderate intensity
, it also might not fully address the typical training session undertaken by many recreational exercisers and athletes .
however , given the lack of studies examining the effect of r. rosea on exercise performance such steady state protocols are useful in developing the extant literature in this area .
we do acknowledge that by controlling exercise intensity based on a percentage of vo2max we are unable to determine if participants were exercising below , at , or above their lactate threshold .
future research might subsequently benefit from using a standardised protocol to mimic the type of exercise session commonly undertaken in gyms ( e.g. , combined aerobic and resistance exercise ) in order to determine if r. rosea ingestion is practically useful in a more ecologically valid exercise task .
the current study also examined participants who were recreationally active but were not specifically cycling trained .
it has been suggested that less fit individuals may experience greater fatigue and discomfort during exercise which may reduce feelings of pleasure compared to more highly trained individuals .
it may therefore be useful to compare the responses of participants of different training status in order to make more conclusive statements regarding the effect of r. rosea on variables such as perception of exertion , arousal , and pleasure .
furthermore , a posteriori power calculations indicated a sample size of 28 would have been required to detect a difference of p = 0.05 at 95% power . however , due to the paucity of data on effects of r. rosea on exercise performance this study was exploratory in nature and subsequently used a relatively small number of participants .
finally , the assessment of affect immediately on completion of the cycling bout might have resulted in elevated scores for feeling states due to the cessation of exercise as has been suggested previously .
it may be that the trajectory of pleasure and displeasure during and after exercise exhibits two distinct phases .
the first phase involves a decline or increase of affective responses during exercise , whereas the second phase involves an improvement or rebound of affective responses after exercise . as measures of affect
were only taken on completion of the exercise bouts , the data presented here are only representative of the rebound phase of exercise in the presence of r. rosea and placebo .
future research should therefore attempt to assess affect during exercise in addition to immediately on cessation in order to more effectively capture the time course of affective responses to exercise following ingestion of different substances .
ingestion of r. rosea favourably influenced rpe and exercise affect without changes in energy expenditure or substrate utilization during 30 minutes of submaximal cycling performance at moderate intensity in regularly active adults .
these changes support the efficacy of acute r. rosea ingestion in positively enhancing psychophysiological responses to submaximal exercise performance .
Output:
| the aim of this study was to examine the effect of acute rhodiola rosea ( r. rosea ) ingestion on substrate utilisation ,
mood state , rpe , and exercise affect .
ten males ( mean age s.d .
= 26 6 years ) completed two 30-minute cycling trials at an intensity of 70% of vo2max following ingestion of either 3 mgkg1 body mass of r. rosea or placebo using a double - blind , crossover design . during exercise ,
heart rate and rpe were recorded .
participants completed measures of mood state and exercise affect before and after exercise .
expired air samples were taken during exercise to determine substrate utilisation .
repeated measures analysis of variance indicated that rpe was significantly lower at 30 minutes into exercise versus placebo ( p = 0.003 ) .
perceptions of arousal ( p = 0.05 ) and pleasure were significantly higher after exercise with r. rosea compared to placebo ( p = 0.003 ) .
mood state scores for vigor were also higher in r. rosea condition compared to placebo ( p = 0.008 ) .
there were no significant differences in energy expenditure , carbohydrate , or fat oxidation between conditions ( p > 0.05 ) . ingestion of r. rosea favourably influenced rpe and exercise affect without changes in energy expenditure or substrate utilization during 30-minute submaximal cycling performance . |
PubmedSumm4879 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: postprandial glucose homeostasis is controlled by insulin release in response to the absorbed nutrients and to gastric inhibitory polypeptide ( gip ) and glucagon - like peptide 1 ( glp-1 ) [ 14 ] , which are responsible for the so - called incretin effect , that is , the enhanced insulin secretion after oral versus intravenous administration of glucose . in healthy , nondiabetic subjects ,
the quantitative contribution of this incretin effect to the overall postprandial insulin secretion has been estimated to be 5070% [ 6 , 7 ] , depending on meal size and composition . on the contrary , a marked reduction of the incretin effect
was demonstrated in type 2 diabetes patients , thereby contributing to their excess in postprandial glucose excursions .
although the exact mechanisms underlying the loss of incretin activity in type 2 diabetes patients are unclear , it is evident that while the effects of glp-1 are largely preserved [ 911 ] , the insulinotropic effect of gip is almost lost in type 2 diabetes , potentially due to a defective expression of gip receptors , a downregulation of gip signaling , or a general reduction of beta cell function and mass [ 1118 ] .
it is well known that hyperglycemia enhances the endogenous nonenzymatic glycosylation of proteins , lipids , and nucleic acids .
this process might result in the accumulation of heterogeneous molecules , such as the advanced glycation end products ( ages ) .
several studies showed a positive correlation between the accelerated formation of ages and the complications of diabetes . in the last decade , our research group demonstrated a direct role of ages on pancreatic beta cell dysfunction , showing that exposure of pancreatic beta cells to ages was able to increase oxidative stress and decrease their antioxidant activity [ 2123 ] .
furthermore , evaluating the effects of ages in glutag , an enteroendocrine cell line that produces and secretes glp-1 , we found that the exposure of glutag cells to ages results in impaired glp-1 secretion and induction of insulin resistance .
the aim of this study is to investigate whether ages impair pancreatic beta cell responsiveness to gip , thus altering gip - induced insulin secretion .
glycated serum ( gs ) was prepared by adding 50 mmol / l ribose to heat - inactivated ( 56c for one hour ) fbs , as described previously .
aliquots of fbs were processed the same way but without ribose ( nonglycated serum ( ngs ) ) and used for standard medium preparation .
the concentration of pentosidine in the experimental media containing ngs was 70 pmol / ml , whereas the concentration of pentosidine in the experimental media containing gs was 400 pmol / ml which corresponds to the levels within the pathophysiological range detected in the plasma of diabetic patients [ 2527 ] .
hit - t15 cells were grown in rpmi 1640 supplemented with 10% fetal bovine serum ( fbs ) , 2 mmol / l l - glutamine , 100 iu / ml penicillin , and 100 g / ml streptomycin . before each experiment ,
the cells were split into 6-well plates and cultured for 5 days in the following experimental conditions : rpmi 5.6 mmol / l ( ctr ) or 11.1 mmol / l glucose ( hg ) supplemented with gs . at the end of the culture we evaluated the expression of gip receptor , the secretion of insulin and glp-1 in response to gip , and the intracellular gip signaling .
insulin release was evaluated under static conditions . to study secretion of insulin in response to gip
, hit - t15 cells were preincubated 1 h in kreb 's ringer bicarbonate buffer ( 118.5 mmol / l nacl , 2.54 mmol / l cacl2 , 1.19 mmol / l kh2po4 , 4.75 mmol / l kcl , 25 mmol / l nahco3 , 1.19 mmol / l mgso4 , 10 mmol / l hepes , 0.1% bsa , ph 7.4 ) , then cells were challenged for 60 min either with 4 mmol / l glucose alone or in presence of 10 nmol / l gip [ 18 , 28 ] .
results were shown as percentage change from ctr level ( 100% ) . in order to evaluate gipr activation ,
hit - t15 cells were incubated in serum - free medium supplemented with 1% bsa and then exposed for 5 min to 100 nmol / l gip [ 2931 ] .
then , cells were lysed and phosphorylation of members of the gipr signaling cascade was evaluated in western blot using specific antibodies . at the end of the experiments
, hit - t15 cells were lysed in ripa buffer ( 50 mm tris hcl ph 7.5 , 150 mm nacl , 1% np40 , 0.1% sds , supplemented with protease and phosphatase inhibitors ) , and protein concentrations were determined using the bca protein assay kit .
thirty micrograms of total cell lysate was separated on a sds - page and transferred onto nitrocellulose .
filters were blocked in 5% bsa and incubated overnight at 4c with primary specific antibodies ( anti - gip receptor ( h-70 ) and anti - gapdh ( fl-335 ) from santa cruz biotechnology , inc .
santa cruz , ca , usa ; anti - phosphoakt ( ser473 ) , -pi3 kinase ( 19h8 ) , and -phospho - p44/42 mapk ( erk1/2 ) ( thr202/tyr204 ) from cell signaling technology , beverly , ma , usa ) .
secondary specific horseradish - peroxidase linked antibodies were added for 1 hour at room temperature .
bound antibodies were detected using an enhanced chemiluminescence lighting system ( luminata classico , millipore , billerica , ma , usa ) , according to manufacturer 's instruction . to verify equal loading of the proteins , membranes were stripped , reblocked , and reprobed to detect gapdh .
all analyses were carried out with the graphpad prism 5.0 software ( graphpad software , san diego , ca , usa ) .
data were expressed as the mean se . comparison between control and single treatments was done using unpaired t - test .
firstly , we confirmed the protein expression of gipr in the pancreatic beta cell lines hit - t15 ( figures 1(a ) and 1(b ) ) .
then , we investigated whether treatments with hg or gs would affect gipr protein expression .
incubation with gs or hg alone did not affect gipr expression , while combined treatment with gs and hg significantly decreased gipr protein expression ( figures 1(a ) and 1(b ) ) .
activation of gipr signaling is coupled to increased phosphorylation of several substrates including p44/42 erk and akt . in order to investigate whether decreased gipr expression is associated with altered intracellular signaling , we stimulated hit - t15 cells with 100 nmol / l gip and then analyzed the phosphorylation of p42/44 erk and akt , two validated intracellular kinases downstream gipr . treatment with gs and
hg ( alone or in combination ) did not affect gip - induced p42/44 erk phosphorylation ( figures 2(a)2(c ) ) .
on the contrary , gs and hg ( alone and in combination ) abrogated gip - induced akt activation ( figures 3(a ) and 3(b ) ) .
since pi3k is known to be the upstream activator of akt , we determined whether hg or gs regulates pi3k protein expression .
treatment with hg alone or in combination with gs , but not gs alone , significantly reduced the expression of pi3k in hit - t15 cells ( figures 4(a ) and 4(b ) ) . to verify whether decreased expression of gipr and altered intracellular signaling induced by gip were associated with loss of beta cell function , we evaluated gip - induced insulin secretion in hit - t15 cells grown at low or high glucose levels in presence of gs . under static incubation conditions in krb buffer containing 4 mmol / l glucose , the rate of insulin secretion
was significantly decreased in cells cultured at low glucose concentration with gs as compared to cells cultured with low glucose alone ( ctr ) ( figure 5(a ) ) .
intracellular insulin content in hit - t15 cells grown with gs alone was comparable to control cells but significantly decreased in cells cultured under hyperglycemic condition ( figure 5(b ) ) .
the rate of insulin secretion in response to 10 nmol / l gip stimulation was significantly reduced in cells grown with hg in combination with gs ( figure 5(c ) ) .
in this study , we demonstrated that stimulation with ages might be associated with the loss of gip responsiveness in pancreatic beta cells .
indeed , our results showed that high glucose levels might modulate pancreatic beta cell function , reducing intracellular insulin content and affecting activation of gip substrates .
however , these alterations did not result in loss of gip - induced insulin secretion .
in fact , the secretory response to gip was lost , only when cells were cultured under hyperglycemic conditions in combination with gs .
the direct and deleterious role of ages on microvascular diabetic complications and on pancreatic beta cell function is well validated .
evidence also from our group previously identified the adverse effects of ages in hit - t15 cell pathophysiology [ 2123 ] . as expected , treatment with gs alone was able to alter gip - triggered intracellular signaling and reduce glucose - induced insulin secretion .
however , cells grown under this condition were found to maintain a gip - induced insulin secretion that was comparable to control cells .
the binding of gip to its cognate receptor gipr triggers several intracellular signaling pathways , including pi3k , akt , and mapk , which potentiate glucose - stimulated exocytosis of insulin - containing granules . in this study
, we showed that treatment with gs and hg was able to alter gip - triggered intracellular signaling by selectively abrogating akt activation .
although both gs and hg were able to abrogate gip - induced akt phosphorylation , their inhibition did not affect gip - induced insulin secretion .
indeed the loss of increment in insulin secretion in response to gip was associated with significant reduction in gipr expression , suggesting that the loss of gip - stimulated insulin secretion was mainly related to the levels of gipr expression rather than to gip - triggered intracellular signaling .
these findings are consistent with the hypothesis that the unresponsiveness to gip could be due to a decreased expression of its receptor [ 16 , 18 , 35 ] .
ages have been suggested as key mediators in the metabolic memory . this hypothesis explains how diabetic complications are evolving even after glucose control is achieved [ 3638 ] . since molecular alteration of ages is permanent , culture in the presence of gs alone may represent the milieu of improved glucose control reached after chronic hyperglycemia .
it has been reported that an improved control of hyperglycemia may reverse gipr expression downregulation and resistance to gip in zucker rats .
our finding suggests that improved glucose control was associated with recovery of gip- but not glucose - induced insulin secretion .
therefore , the memory of hyperglycemia may compromise the complete recovery of pancreatic beta cells even when glucose control is improved .
since chronic hyperglycemia leads to formation of ages , an hg combined with gs might be more representative of a
our findings suggest that pancreatic beta cells are capable of counteracting detrimental action of chronic hyperglycemia . however , when hyperglycemia is combined with ages , beta cells are not able to react to the insults and become insensitive to gip .
our results are in agreement with findings reported by meier and nauck , showing that at hyperglycemic clamp conditions the insulin response to gip was relatively normal in the individuals with fasting glucose concentrations of less than ~100 mg / dl , but , when glucose concentrations exceeded this level , there was a progressive decline in gip activity on insulin secretion , with an almost complete loss of response in patients with 150250 mg / dl serum glucose .
these results suggest that the loss of gip responsiveness might be due to the downregulation of its receptor .
this condition was related to the deterioration of beta cell function due to the combined stimulation in the presence of hg and gs .
these findings may contribute to explain the loss of gip responsiveness in type 2 diabetes patients ( figure 6 ) .
Output:
| glucose - dependent insulinotropic peptide ( gip ) is an incretin hormone produced in the gastrointestinal tract that stimulates glucose dependent insulin secretion .
impaired incretin response has been documented in diabetic patients and was mainly related to the inability of the pancreatic beta cells to secrete insulin in response to gip .
advanced glycation end products ( ages ) have been shown to play an important role in pancreatic beta cell dysfunction .
the aim of this study is to investigate whether the exposure to ages can induce gip resistance in the pancreatic beta cell line hit - t15 .
cells were cultured for 5 days in low ( ctr ) or high glucose ( hg ) concentration in the presence of ages ( gs ) to evaluate the expression of gip receptor ( gipr ) , the intracellular signaling activated by gip , and secretion of insulin in response to gip .
the results showed that incubation with gs alone altered intracellular gip signaling and decreased insulin secretion as compared to ctr .
gs in combination with hg reduced the expression of gipr and pi3k and abrogated gip - induced akt phosphorylation and gip - stimulated insulin secretion . in conclusion , we showed that treatment with gs is associated with the loss of the insulinotropic effect of gip in hyperglycemic conditions . |
PubmedSumm4880 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: beta - thalassemia major is an autosomal recessive hereditary anemia , which is incurable , caused by defective synthesis of hemoglobin , ineffective erytropoiesis and rapid erythrocyte breakdown , resulting in advanced heart failure and death in early childhood[1 , 2 ] .
the combination of transfusion and chelation therapy has dramatically extended the life expectancy of thalassemic patients who can now survive into their fourth and fifth decades of life .
nevertheless , frequent blood transfusion in turn can result in iron overload which may lead to various complications , including various endocrine complications such as thyroid dysfunction .
so , bone marrow transplantation remains the only definitive cure for thalassemics at present[57 ] .
the widespread form of thyroid dysfunction seen in thalassaemics is primary hypothyroidism - caused abnormalities of the thyroid gland which results in insufficient production of the thyroid hormones .
nonetheless , the frequency of hypothyroidism shows a discrepancy depending on the region , quality of management and treatment protocols[9 , 10 ] .
thyroid dysfunctions are well documented in patients with thalassemia major requiring frequent and recurrent blood transfusions .
it is a general belief that thyroid dysfunctions appear with a frequency of 13 - 60% in these patients after 10 years of age regardless of difference in the rate of prevalence , largely as in the form of subclinical hypothyroidism[9 , 10 ] .
this work aimed to investigate the frequency of hypothyroidism in children with beta - thalassemia major in their earlier period .
the parent of all patients gave informed consent prior to the study entry and the study was conducted in accordance with the declaration of helsinki .
ninety patients ( 55 boys and 35 girls ) with beta - thalassemia major aged 1 - 13 years ( mean age 7.173.78 years ) were enrolled in this study , admitted to the department of pediatrics , faculty of medicine university of dicle between 21/03/05 and 31/07/09 .
an age - sex matched control group of 60 healthy children ( 36 boys and 24 girls with a mean age of 6.983.66 years ) was also formed .
patients with beta - thalassemia minor and intermedia and those with acute illness , any hormonal therapy or with a family history of hypothyroidism were excluded from the study .
diagnosis of beta - thalassemia major was based on family history , complete transfusion dependence and hemoglobin electrophoresis .
patients received an average of 7.62.4 ml packed cells per kilogram body weight with a mean of 17.25.4 transfusions over a period of 12 months to maintain hemoglobin concentration not to exceed 9.5 g / dl .
after transfusion , chelation therapy was employed using deferoxamine by subcutaneous infusion with a dose of 20 - 40 mg / kg/24 hr over 8 - 12 hr via portable infusion device .
thyroid function and iron load status were evaluated by measurements of serum total thyroxin ( t3 ) , serum total triiodothyronine ( t4 ) , serum free triiodothyronine ( ft3 ) , serum free thyroxin ( ft4 ) , thyroid - stimulating hormone ( tsh ) and serum ferritin levels .
a standard trh testing ( 7g / kg bolus intravenously ) was applied to three patients with high levels of tsh .
serum tsh levels were measured at 0 , 20 , 40 and 60 minutes intervals after trh administration .
blood samples were taken from all patients at least 15 days after the transfusion , preferably after an overnight fasting on the transfusion day .
total serum t3 , t4 , ft3 , ft4 , tsh and ferritin levels were studied in basal blood sample employing electrochemiluminescence immuno - assay ( eclia ) method using roche diagnostic e 170 autoanalyzer .
antithyroglobulin and anti thriod peroxidase ( tpo ) antibody titers were measured by radioimmunoassay ( ria ) .
the thyrotropin releasing hormone ( trh ) warning test was applied to the patients whose basal tsh value was detected to be over the age - appropriate reference range .
statistical analyses were carried out using the software packages spss 12.0 ( spss , inc . ,
chicago , usa ) using student 's t - test and spearman correlation and regression analyses were applied in statistical evaluations .
all patients underwent comprehensive physical examination and were examined if they had any other complaints except beta - thalassemia at the time of presentation to the hematology polyclinic .
a total of 90 patients were enrolled in the study , 35 ( 38.9% ) of them were female and 55 ( 61.1% ) male .
mean hemoglobin ( hb ) levels before and after blood transfusions were reported as 8.70.6 and 12.81.2 .
biochemical parameters measured in serum of patients and healthy children are recorded in table 1 .
t3 : total thyroxin / t4 : total triiodothyronine / ft3 : free triiodothyronine / ft4 : free thyroxin / tsh : thyroid - stimulating hormone serum ferritin levels were found as 0 - 1000ng / ml in 6 , 1000 - 2000
ng / ml in 22 , 200 - 4000 ng / ml in 35 and > 4000ng / ml in 12 patients .
the total t3 , t4 , serum ft3 and ft4 levels were normal in these 3 patients .
all three patients were classified as subclinical primer hypothyroidism , normal ft3 and ft4 , increased basal tsh levels and increased tsh response to trh . they were started on treatment with levotrion .
tsh : thyroid - stimulating hormone / trh : thyrotropin releasing hormone the correlation between parameters studied was as follows .
a negative correlation between t3 and the age of the patients ( r=-242 ; p=0.037 ) , and between tsh and t4 ( r=-0.268 ; p=0.002 ) was observed while a positive correlation between t3 and ft3 ( p<0.001 ) , between t3 and ft4 ( r= 0.241 ; p=0.035 ) , between ft3 and ft4 ( r=0.556 ; p<0.001 ) , between ferritin and ft3 ( r=0.261 ; p=0.024 ) , ferritin and the age of patients ( r=0.309 ; p=0.007 ) was observed .
it was observed that transfusion frequency had a significant increasing effect on the serum ferritin level ( p<0.001 ) as well as on basal tsh levels ( p=0.037 ) .
splenectomy was applied to 20 patients ( 22.2% ) with an average age of 10.604.10 years .
the effect of blood transfusion frequency ( btf ) on laboratory parameters was also investigated .
those receiving blood transfusion every 3 - 4 weeks had higher ferritin levels ( 37451926 ng / ml ) compared with those ( 2008946 ng / ml ) receiving transfusion every 4 - 12 weeks ( p=0.05 ) .
it was also seen that there was a correlation between the application of splenectomy and blood transfusion rate ( p=0.05 ) .
16 out of 20 patients treated with splenectomy received blood transfusion every 4 - 12 weeks while 4 out of 20 received blood transfusion every 3 - 4 weeks .
the effects of chelation therapy using desferrioxamine ( dfo ) and supplementary therapy ( zinc , folic acid , vitamin c , vitamin e ) on parameters and their relationship with other applications such as splenectomy and btf were studied and analyzed .
55 patients ( 61.1% ) were receiving dfo while 35 ( 28.9% ) patients were not on use of dfo .
it was found that the use of dfo had no statistically significant effect ( p>0.05 ) on the biochemical parameters but a significant correlation ( p=0.001 ) was found between the age of patients and dfo treatment .
the mean age of those treated and not treated with dfo was 8.683.62 and 4.762.61 , respectively .
it was indicated that supplementary therapy has not a significant effect on biochemical parameters and the applications ( p>0.05 ) .
it was also observed that there is no effect of the sex of patients on biochemical parameters and applications such as splenectomy , btf , dfo treatment and supplementary therapy .
one important aspect of management in polytransfused thalassemic patients is early recognition and treatment of endocrine dysfunction .
this is particularly true for thyroid dysfunction , because hypothyroidism could be associated with growth problems so commonly seen in these patients .
the present study showed that t3 , t4 and ft3 , ft4 levels in all patients were in normal range compared with those in controls while tsh level was found to be high in only 3 patients and normal in the remaining 87 patients .
however , mean tsh and ferritin levels were significantly higher in patients compared to those of controls ( table 1 ) . since anti - thyroglobulin and anti - thriod peroxidase ( anti - tpo ) antibody titers were negative in three patients with high tsh they might be classified as subclinical primer hypothyroidism .
other manifestations of hypothyroidism such as overt primary hypothyroidism and secondary hypothyroidism were not found in the presented patients . in a recent paper ,
de sanctis et al and malik et al reported the ratio of primary hypothyroidism as 2.1% ( in a study group of 238 patients aged 2 - 17 years ) and as 25.7% ( in a study group of 70 patients aged 5 - 14 years ) with tm . in our study
, this was quite low but it is still comparable with the work of de sanctis .
the reason for the lower frequency may be attributed to the fact that the majority ( 80% ) of patients in the present work were under 10 years old .
hypothyroidism may be partly related to the accumulation of iron in thyroid glands due to blood transfusion by iron overload leading to gland dysfunction .
iron overload of tissue is the most important complication of beta - thalassemia and is a major subject of management .
although most clinical signs of iron loading do not appear until the second decade of life in patients with inadequate chelation , evidence from serial liver biopsies in very young patients presents that the toxic effects of iron begins much earlier .
after approximately one year of transfusions , iron starts to be accumulated in parenchymal tissues , where it may bring about substantial toxicity as compared with that within reticuloendothelial cells[21 , 22 ] . despite the reports relating endocrine dysfunction with iron overload
it was recently demonstrated that the degree of iron overload , at least reflected by ferritin levels , was not associated with the development of endocrine complications[23 , 24 ] .
our study also showed that there is no correlation between serum ferritin level and thyroid function but a positive correlation between transfusion frequency , an indirect indication of ferritin overload , and hypothyroidism .
it indicated that tsh levels were higher in the patients receiving blood transfusion every 3 - 4 weeks compared to those receiving blood transfusion every 4 - 12 weeks .
the absence of the relationship between ferritin and hypothyroidism may be explained by suggesting that the damage of endocrine glands caused by chronic hypoxia is more pronounced than that caused by hemosiderosis as a consequence of the collapse of iron .
thyroid failure is expected to be more prevalent in older patients ( as it is true for other endocrine deficits ) and hence a correlation between older age and reduction of serum t3 and ft3 levels is predicted .
the mean age of patients in our work ( 7.17 years old ) is lower than in most studies . since a large number ( 80% ) of patients in our study were under the age of 10 years ( the age of all 3 patients with thyroid dysfunction was around 10 years ) , the relationship between the age of patients and thyroid function may not be observed .
gulati et al also mentioned the possibility of endocrine dysfunction in patients with thalassemia in earlier periods .
consistently the study illustrated that thyroid functions are not correlated with the age of patients .
this is inevitable since the older patients would have longer blood transfusion period and as a result chelation therapy is recommended to reduce iron overload . although the use of iron chelation therapy has been known to delay or reverse the development of iron - induced cardiac damage and to improve survival , the ability of deferoxamine ( dfo ) to prevent iron - induced endocrine complications is less well defined , but with increased survival , the consequences of endocrine failure become more important . in our study , three patients assigned as subclinical primary hypothyroidism were approximately 10 years old and they were not receiving regular dfo treatment .
we also detected that there was no significant relationship between the gender and thyroid dysfunction .
it was shown that splenectomised patients ( n=20 ) were older ( 10.64.1 ) than those ( 6.63.38 ) not - splenectomised ( p<0.001 ) and also found that splenectomised patients had higher blood transfusion rate ( p=0.05 ) .
the result also indicated that splenectomy has no effect on thyroid function , which is consistent with previous studies .
further investigation is needed to associate the relationship between iron - overload and thyroid function in children with beta - thalassemia .
since serum ferritin is a poor marker in heavily overloaded individuals , it is possible that the effect of iron on thyroid functions was underestimated in this study .
therefore , thyroid function should be followed periodically , particularly when other iron overload - associated complications occur .
early recognition and hence prevention of these complications might help improve the quality of life of these patients .
Output:
| objectivehypothyroidism usually appears in the second decade of life and is thought to be associated with iron overload in patients with thalassemia major .
this study aimed to evaluate thyroid dysfunctions in patients with beta - thalassemia major and to see if they appear in the earlier period of life.methodsthyroid function and iron load status were evaluated in 90 children with a mean age of 7.173.78 years with beta - thalassemia major by measuring serum free thyroxin ( ft4 ) , serum free triiodothyronine ( ft3 ) , total thyroxin ( t3 ) , serum total triiodothyronine ( t4 ) , thyroid - stimulating hormone ( tsh ) and ferritin levels from serum of patients admitted to the pediatric department , faculty of medicine university of dicle between march 2005 and july 2009 .
a control group formed from an age - sex matched healthy children with a mean age of 6.983.66 years was also included .
a standard thyrotropin releasing hormone test was applied to 3 patients who had high tsh levels and were classified as subclinical primer hypothyroidism .
the study was designed according to the declaration of helsinki and informed consent was obtained from the parents of all participants.findingsall thyroid parameters in patients were in the normal ranges compared with the controls except three of them which had high tsh levels .
serum ferritin level ( 27031649 ng / ml ) in patients was significantly higher than in controls ( 81.515.5 ng / ml).conclusionthe work implies that hypothyroidism could be even seen in the first decade of life in patients with beta - thalassemia major in spite of improved hematological cares . |
PubmedSumm4881 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: juvenile idiopathic arthritis ( jia ) is a chronic and progressive inflammatory arthritis of childhood which often results in persistent and disabling foot impairments [ 13 ] .
synovitis , has a predilection for the lower limb joints and results in well - recognised clinical features including joint pain , swelling , limited joint range - of - motion and development of deformity [ 35 ] .
inflammatory pathology is not limited to joints and studies employing musculoskeletal ultrasonography have also detected tenosynovitis , enthesitis , and bursitis in the periarticular ankle region .
unsurprisingly disruption to global gait patterns has been frequently reported as an early and common consequence of jia .
the impact of jia on global function has been studied extensively with the use of patient reported outcome measures ( proms ) such as the childhood health assessment questionnaire ( chaq ) , a widely used 30 item measure of childhood disability .
studies employing proms have demonstrated strong associations between clinical symptoms such as pain or radiographically detected joint destruction , with poor long - term functional outcomes . at a local level , the impact of active disease and related impairments remain unclear .
the development of juvenile arthritis foot disability index questionnaire ( jafi ) , a 27 item measure organised by three dimensions related to impairment , activity limitation , and participation restriction , has allowed researchers to quantify levels of disease - related foot impairments and disability .
recent studies of foot function have improved our understanding of foot impairments in adults with rheumatoid arthritis ( ra ) .
in particular , studies employing three - dimensional ( 3d ) multi - segmented foot models have demonstrated an ability to quantify subtle but functionally important changes to foot segment kinematics and kinetics at an early disease stage .
in contrast , little is known about the functional consequences of active foot disease and/or residual impairments such as foot deformity in patients with jia .
patients with jia who have lower limb involvement tend to walk slower , as a result of a reduced step length , reduced cadence and an increased period of double limb support . reduced peak pressures have been recorded in those with forefoot pain , metatarso - phalangeal ( mtp ) joint and lesser toe deformity . while elevated focal pressures in the forefoot have previously been associated with pes cavus foot types .
abnormal ankle - joint - complex motion has been described where the foot has been modelled as a single segment .
however this approach provides limited information concerning other foot joint function compared to the multi - segment approach .
accordingly , the aim of this study was to compare disease activity , impairments , disability , foot function and gait characteristics between a well described cohort of jia patients and normal healthy controls using a 7-segment foot model and 3d gait analysis .
fourteen patients with a definitive diagnosis of jia , based on the international league of associations for rheumatology ( ilar ) criteria were consecutively recruited from a phase ii randomised controlled trial of a multi - disciplinary foot - care programme .
participants had a documented history of active inflammatory foot disease affecting the joints and/or soft tissues .
ten community dwelling healthy children and adolescents matched as closely as possible by age and gender , with no history of trauma , neuromuscular or musculoskeletal diseases were recruited for comparison .
this study was approved by the glasgow west local research ethics committee on the 18th march 2008 ( reference number 08/s0709/36 ) .
all participants and parents / guardians provided their informed consent to participate in this study .
age , gender , body mass index , disease subtype , disease duration , and current pharmacological therapy were recorded for each patient .
localised disease activity was estimated by a podiatrist [ gh ] who recorded tender and swollen joint scores in the foot for the ankle , subtalar , calcaneocuboid , talonavicular , mtp , interphalangeal joint of the hallux and proximal interphalangeal joints of the lesser toes ( range 014 ) .
tender and swollen soft tissue sites in the foot were also recorded for the tibialis posterior , flexor digitorum longus , flexor hallucis longus , peroneus longus and peroneus brevis tendons , the retro - calcaneal bursa ( rcb ) , and the calcaneal tendo - achilles ( ta ) and calcaneal plantar fascia entheses ( pf ) ( range 08 ) .
the si summates hallux valgus , 5th mtp exostosis , lesser toe deformities and mtp subluxation for the forefoot ( range 012 ) and calcaneal valgus / varus , ankle range of motion and pes planus / cavus deformities of the rearfoot ( range 07 ) .
the weight - bearing varus / valgus alignment of the heel was measured using a standard hand - held goniometer .
a fully trained paediatric musculoskeletal ultra - sonographer [ det ] independently assessed localised disease activity in the foot .
those joints from the clinical examination were assessed for effusion , synovial hypertrophy ( sh ) , and power doppler signal ( pds ) .
tendons were assessed for grey - scale features of fluid within the tendon sheath and pds ; the ta and pf for abnormal thickening , and rcb for bursal effusion ( bursitis ) .
standardised definitions for ultrasound ( us ) -derived pathology ( defined by the outcome measures in rheumatology 7 consensus statement ) were employed throughout .
us imaging was conducted using an esaote mylab 25 gold ( genova , italy ) with la435 ( 1018 mhz ) probe ( footprint size 40 mm 10 mm ) .
an 8 camera 120 hz motion analysis system ( qualysis oqus , gothenburg , sweden ) was used to track the motion of 25 surface - mounted , spherical , and retro - reflective markers ( 5 mm and 10 mm diameter ) placed on the shank and foot which were positioned in order to represent the underlying skeletal structure .
this model was adapted from the original model proposed by hyslop et al . previously to measure foot function in adults with psoriatic arthritis ( see supplementary online material for full model description ) , and was selected for use on the basis that jia is an inflammatory arthropathy with similar disease features .
rockville , md , usa ) was used to build segmented foot models which comprised the shank , a single foot segment , rearfoot , midfoot , lateral forefoot , 1st metatarsal and hallux , based on the surface marker coordinates
. ground reaction forces ( 120 hz ) and plantar pressure distributions were measured separately using force ( kistler , winterthur , switzerland ) and pressure ( emed - x , novel gmbh , munich , germany ) platforms .
an instrumented walkway ( gaitrite , cir systems , clifton , nj , usa ) was used to measure spatial and temporal gait parameters . a pre - determined core
set of foot biomechanical variables were selected a priori for analysis based on previous survey and gait analysis data in ra , psoriatic arthritis and jia [ 2,1315,23 ] .
these included walking velocity , cadence , step length , double support time and cycle time as objective measures of global function .
intersegment kinematics , kinetics and plantar pressure distribution parameters were selected to best capture the functional changes associated with joint and soft - tissue damage in jia .
initial foot contact angle , rearfoot terminal stance range - of - motion in the sagittal plane , peak vertical ground reaction forces , ankle joint moment and ankle joint power were selected to describe the three rocker functions of the foot .
peak rearfoot eversion , peak lateral forefoot abduction , peak 1st metatarsal dorsiflexion , peak hallux dorsiflexion , minimum navicular height , midfoot and lesser toe contact areas , and peak pressures in the rear- and forefoot were selected to describe localised functional impairments , compensations and deformities .
the average velocity and duration of the centre - of - pressure ( cop ) throughout the foot , heel , midfoot , forefoot and toe regions was recorded to quantify compensatory foot - loading strategies associated with degraded and adapted ( antalgic ) gait .
peak midfoot dorsiflexion was selected for exploratory analysis as both high- and low - arched midfoot posture is a frequent clinical finding in jia . a relaxed standing ( static ) trial
was collected for the foot from each participant in order to define 0 ( neutral ) for the kinematic data .
kinematic and kinetic and parameters were collected from 5 barefoot walking trials in each patient .
spatial and temporal parameters were recorded from 5 barefoot self - selected walking speed trials over the walkway .
plantar pressure distribution parameters were collected separately from 5 barefoot trials using a two - step protocol .
kinematic , kinetic and plantar pressure measurements were estimated from 5 trials of the right limb for all participants .
automated software routines ( novel gmbh , munich , germany ) were used to define the rearfoot , midfoot , forefoot , lesser toe and hallux regions of the foot for plantar pressure distribution .
clinical and biomechanical variables were summarised as mean and standard deviation ( sd ) or median ( range ) .
the small sample size did not permit formal inferential hypothesis testing , therefore mean differences between groups and associated 95% confidence intervals ( ci ) were calculated using the t distribution .
mean motion patterns of intersegment kinematics were normalised to 101 time points ( 0100% stance ) and both groups ensemble averages ( 1sd ) were superimposed and displayed graphically .
discrete gait variables were normalised where appropriate to dimensionless quantities using the formulae described by hof .
fourteen patients with a definitive diagnosis of jia , based on the international league of associations for rheumatology ( ilar ) criteria were consecutively recruited from a phase ii randomised controlled trial of a multi - disciplinary foot - care programme .
participants had a documented history of active inflammatory foot disease affecting the joints and/or soft tissues .
ten community dwelling healthy children and adolescents matched as closely as possible by age and gender , with no history of trauma , neuromuscular or musculoskeletal diseases were recruited for comparison .
this study was approved by the glasgow west local research ethics committee on the 18th march 2008 ( reference number 08/s0709/36 ) .
all participants and parents / guardians provided their informed consent to participate in this study .
age , gender , body mass index , disease subtype , disease duration , and current pharmacological therapy were recorded for each patient .
localised disease activity was estimated by a podiatrist [ gh ] who recorded tender and swollen joint scores in the foot for the ankle , subtalar , calcaneocuboid , talonavicular , mtp , interphalangeal joint of the hallux and proximal interphalangeal joints of the lesser toes ( range 014 ) .
tender and swollen soft tissue sites in the foot were also recorded for the tibialis posterior , flexor digitorum longus , flexor hallucis longus , peroneus longus and peroneus brevis tendons , the retro - calcaneal bursa ( rcb ) , and the calcaneal tendo - achilles ( ta ) and calcaneal plantar fascia entheses ( pf ) ( range 08 ) .
the si summates hallux valgus , 5th mtp exostosis , lesser toe deformities and mtp subluxation for the forefoot ( range 012 ) and calcaneal valgus / varus , ankle range of motion and pes planus / cavus deformities of the rearfoot ( range 07 ) .
the weight - bearing varus / valgus alignment of the heel was measured using a standard hand - held goniometer .
a fully trained paediatric musculoskeletal ultra - sonographer [ det ] independently assessed localised disease activity in the foot .
those joints from the clinical examination were assessed for effusion , synovial hypertrophy ( sh ) , and power doppler signal ( pds ) .
tendons were assessed for grey - scale features of fluid within the tendon sheath and pds ; the ta and pf for abnormal thickening , and rcb for bursal effusion ( bursitis ) .
standardised definitions for ultrasound ( us ) -derived pathology ( defined by the outcome measures in rheumatology 7 consensus statement ) were employed throughout .
us imaging was conducted using an esaote mylab 25 gold ( genova , italy ) with la435 ( 1018 mhz ) probe ( footprint size 40 mm 10 mm ) .
an 8 camera 120 hz motion analysis system ( qualysis oqus , gothenburg , sweden ) was used to track the motion of 25 surface - mounted , spherical , and retro - reflective markers ( 5 mm and 10 mm diameter ) placed on the shank and foot which were positioned in order to represent the underlying skeletal structure .
this model was adapted from the original model proposed by hyslop et al . previously to measure foot function in adults with psoriatic arthritis ( see supplementary online material for full model description ) , and was selected for use on the basis that jia is an inflammatory arthropathy with similar disease features .
rockville , md , usa ) was used to build segmented foot models which comprised the shank , a single foot segment , rearfoot , midfoot , lateral forefoot , 1st metatarsal and hallux , based on the surface marker coordinates .
ground reaction forces ( 120 hz ) and plantar pressure distributions were measured separately using force ( kistler , winterthur , switzerland ) and pressure ( emed - x , novel gmbh , munich , germany ) platforms .
an instrumented walkway ( gaitrite , cir systems , clifton , nj , usa ) was used to measure spatial and temporal gait parameters . a pre - determined core
set of foot biomechanical variables were selected a priori for analysis based on previous survey and gait analysis data in ra , psoriatic arthritis and jia [ 2,1315,23 ] .
these included walking velocity , cadence , step length , double support time and cycle time as objective measures of global function .
intersegment kinematics , kinetics and plantar pressure distribution parameters were selected to best capture the functional changes associated with joint and soft - tissue damage in jia .
initial foot contact angle , rearfoot terminal stance range - of - motion in the sagittal plane , peak vertical ground reaction forces , ankle joint moment and ankle joint power were selected to describe the three rocker functions of the foot .
peak rearfoot eversion , peak lateral forefoot abduction , peak 1st metatarsal dorsiflexion , peak hallux dorsiflexion , minimum navicular height , midfoot and lesser toe contact areas , and peak pressures in the rear- and forefoot were selected to describe localised functional impairments , compensations and deformities .
the average velocity and duration of the centre - of - pressure ( cop ) throughout the foot , heel , midfoot , forefoot and toe regions was recorded to quantify compensatory foot - loading strategies associated with degraded and adapted ( antalgic ) gait .
peak midfoot dorsiflexion was selected for exploratory analysis as both high- and low - arched midfoot posture is a frequent clinical finding in jia . a relaxed standing ( static ) trial
was collected for the foot from each participant in order to define 0 ( neutral ) for the kinematic data .
kinematic and kinetic and parameters were collected from 5 barefoot walking trials in each patient .
spatial and temporal parameters were recorded from 5 barefoot self - selected walking speed trials over the walkway .
plantar pressure distribution parameters were collected separately from 5 barefoot trials using a two - step protocol .
kinematic , kinetic and plantar pressure measurements were estimated from 5 trials of the right limb for all participants
. automated software routines ( novel gmbh , munich , germany ) were used to define the rearfoot , midfoot , forefoot , lesser toe and hallux regions of the foot for plantar pressure distribution .
clinical and biomechanical variables were summarised as mean and standard deviation ( sd ) or median ( range ) .
the small sample size did not permit formal inferential hypothesis testing , therefore mean differences between groups and associated 95% confidence intervals ( ci ) were calculated using the t distribution .
mean motion patterns of intersegment kinematics were normalised to 101 time points ( 0100% stance ) and both groups ensemble averages ( 1sd ) were superimposed and displayed graphically .
discrete gait variables were normalised where appropriate to dimensionless quantities using the formulae described by hof .
fourteen jia patients ( 10 female , 4 male ) with a mean age of 12.4 years ( sd 3.2 ) were studied .
this was a heterogeneous sample including patients with variable jia disease subtype , disease duration and medication .
all patients were in receipt of disease - modifying anti - rheumatic drugs ( dmards ) and/or biologic therapies .
ten control subjects ( 6 female , 4 male ) with a mean age of 12.5 years ( sd 3.4 ) were studied for comparison .
control subjects were closely matched to jia case subjects by age and bmi , but had a greater proportion of m : f than the jia subjects .
functional impairment scores ( chaq ) were typically in the mild - to - moderate category ( > 0.13 to < 0.63 ) for jia patients , although these ranged from no impairment to moderate impairment .
jafi scores for localised foot impairments and disability were in the mild - to moderate category ( 1 to 2 ) but were variable between jia subjects .
median ( range ) scores for each domain were 1 ( 03 ) ( impairment and activity limitation ) and 1.5 ( 03 ) ( participation restriction ) .
there were low levels of clinically detected disease activity in the joints and soft tissues as indicated by tender and swollen joint and soft tissue counts .
foot joint effusions detected using us were a typical finding in patients with jia , suggesting that subclinical disease was present in several patients .
mild forefoot and moderate rearfoot deformities were recorded in patients with jia , who typically exhibited a marginally more valgus foot posture than controls .
ensemble average kinematic - time and kinetic - time variables are summarised in fig . 1 and core biomechanical variables in table 3 .
the magnitude and timing of the kinematic and kinetic variables during the stance phase of gait were similar for both groups .
the average patterns for the jia patients did not deviate outside normal limits ( fig .
trends were observed for reduced peak ankle joint plantarflexor moment , joint power , and the peak vertical ground reaction force at initial contact and terminal stance in the children with jia , however 95% cis of the mean differences for each variable crossed zero ( table 3 ) .
no difference could be detected for in the initial and terminal stance contact angles for the foot relative to the ground .
medial longitudinal arch posture , as indicated by the navicular height , was not different between the two groups .
the rearfoot rom and peak eversion and 1st metatarsal dorsiflexion were the same in both groups .
the jia group showed trends towards slight increases in midfoot dorsiflexion ( 95% ci of mean differences did not cross zero ) , reductions in lateral forefoot abduction and decreases in peak hallux dorsiflexion ( 95% cis of mean differences crossed zero ) .
the distribution of plantar pressure was not different between the two groups in terms of midfoot and lesser toe contact areas ( table 3 ) .
pressure in the rearfoot , 1st metatarsal and lateral forefoot regions were on average 35 kpa and 43 kpa lower respectively , and 1 kpa respectively higher in the children with jia .
the jia children walked with a reduced step length , reduced walking velocity , and increased cadence , in comparison with control subjects although double - support time was unaffected ( table 3 ) .
the average velocity of the cop through the foot regions was similar for both groups ( table 4 ) .
the duration of the cop was slightly increased in the midfoot and slightly decreased in the forefoot regions in the jia patients in comparison with control subjects .
fourteen jia patients ( 10 female , 4 male ) with a mean age of 12.4 years ( sd 3.2 ) were studied .
this was a heterogeneous sample including patients with variable jia disease subtype , disease duration and medication .
all patients were in receipt of disease - modifying anti - rheumatic drugs ( dmards ) and/or biologic therapies .
ten control subjects ( 6 female , 4 male ) with a mean age of 12.5 years ( sd 3.4 ) were studied for comparison .
control subjects were closely matched to jia case subjects by age and bmi , but had a greater proportion of m : f than the jia subjects .
functional impairment scores ( chaq ) were typically in the mild - to - moderate category ( > 0.13 to < 0.63 ) for jia patients , although these ranged from no impairment to moderate impairment .
jafi scores for localised foot impairments and disability were in the mild - to moderate category ( 1 to 2 ) but were variable between jia subjects .
median ( range ) scores for each domain were 1 ( 03 ) ( impairment and activity limitation ) and 1.5 ( 03 ) ( participation restriction ) .
there were low levels of clinically detected disease activity in the joints and soft tissues as indicated by tender and swollen joint and soft tissue counts .
foot joint effusions detected using us were a typical finding in patients with jia , suggesting that subclinical disease was present in several patients .
mild forefoot and moderate rearfoot deformities were recorded in patients with jia , who typically exhibited a marginally more valgus foot posture than controls .
ensemble average kinematic - time and kinetic - time variables are summarised in fig . 1 and core biomechanical variables in table 3 .
the magnitude and timing of the kinematic and kinetic variables during the stance phase of gait were similar for both groups .
the average patterns for the jia patients did not deviate outside normal limits ( fig .
trends were observed for reduced peak ankle joint plantarflexor moment , joint power , and the peak vertical ground reaction force at initial contact and terminal stance in the children with jia , however 95% cis of the mean differences for each variable crossed zero ( table 3 ) .
no difference could be detected for in the initial and terminal stance contact angles for the foot relative to the ground .
medial longitudinal arch posture , as indicated by the navicular height , was not different between the two groups .
the rearfoot rom and peak eversion and 1st metatarsal dorsiflexion were the same in both groups .
the jia group showed trends towards slight increases in midfoot dorsiflexion ( 95% ci of mean differences did not cross zero ) , reductions in lateral forefoot abduction and decreases in peak hallux dorsiflexion ( 95% cis of mean differences crossed zero ) .
the distribution of plantar pressure was not different between the two groups in terms of midfoot and lesser toe contact areas ( table 3 ) .
pressure in the rearfoot , 1st metatarsal and lateral forefoot regions were on average 35 kpa and 43 kpa lower respectively , and 1 kpa respectively higher in the children with jia .
the jia children walked with a reduced step length , reduced walking velocity , and increased cadence , in comparison with control subjects although double - support time was unaffected ( table 3 ) .
the average velocity of the cop through the foot regions was similar for both groups ( table 4 ) .
the duration of the cop was slightly increased in the midfoot and slightly decreased in the forefoot regions in the jia patients in comparison with control subjects .
this is the first study to report selected 3d kinematics and kinetics , spatio - temporal parameters , and plantar pressure distribution in a group of jia children and adolescents in receipt of optimised medical management .
these findings are in contrast to past studies which have shown marked changes in foot function . in an era of optimal medical management exploiting dmard and biological therapies
, the findings may indicate that suppression and tight control of active foot disease prevents or reduces the frequency and severity of joint destruction and the associated structural and functional impairments .
the patients with jia described in this study were heterogeneous for age , disease subtype and disease duration . with established disease
this optimised medical approach appears to have lessened the overall foot disease burden as indicated by low levels of self / parent - reported pain , functional loss and disability .
ultrasound examination indicated on - going active disease in approximately one - third of children .
however , it is acknowledged that significant discrepancies still exist between clinical and us examinations of foot disease in jia . despite this detailed analysis of foot function revealed only subtle changes some indicative of degraded and some of adapted gait . by contrast , studies reported in the pre - biological and tight control era , often where disease factors and treatment regimes are not reported , demonstrate marked degenerative and adapted gait disturbances .
these include changes to overall gait pattern characterised by reduced walking velocity and shortened step and stride length altered load and pressure distribution characteristic of both high - arch and flat - foot posture ; disturbance of the normal sagittal rocker function ; and muscle imbalance and reduced muscle strength . in terms of joint kinematics , reduced ankle plantarflexion in terminal stance has been demonstrated where the foot was modelled as a single segment . in many of these studies
there is little or no information provided on disease subtype , disease activity , active joint disease , morbid foot state , or medical and non - pharmacological interventions making direct comparisons difficult .
. demonstrated strong relationships between disease activity and foot - related impairments and disability using the jafi questionnaire .
the jafi scoring system may be vulnerable to a moderate floor effect , resulting in insensitivity for detecting impairments .
nevertheless in the present study active disease was low and this was associated with low levels of self - reported foot impairment and functional disability measured using the jafi .
this study adds additional evidence suggesting the articular function in the foot can be well preserved when disease activity is suppressed using optimised medical care . in other inflammatory joint diseases , in particular rheumatoid arthritis , marked changes in foot function has been demonstrated in a number of studies in both early and established disease [ 1315 ] .
the failure to detect important functional changes in the jia group in comparison can be explained by the cumulative effects of destructive joint disease in the ra patients who , in most studies , have longer disease duration and sub - optimal drug management .
however , even in jia patients the lag time in which to gain optimised case with disease remission or low disease state can take time and in that time joint and soft - tissue damage can occur .
subtle changes were observed in the present study including reduced walking speed and some changes to mid - foot arch posture . at the individual patient level
some children did have marked impairments and this would indicate that on - going studies , in particular inception cohort designs from onset of symptoms / diagnosis are warranted to understand disease progression across all subtypes .
firstly the sample size is small and the inclusion of all disease subtypes precludes wider generalisation of the findings .
secondly , the foot model was developed and tested in adults with inflammatory joint disease .
landmark identification around the rearfoot , in particular , the peroneal tubercle , the dorso - lateral apex of the cuboid , and the dorsal aspect of the intermediate cuneiform was challenging .
as such the rear- and mid - foot segment rotation data may have been vulnerable to errors different from those reported for the original model .
we attempted to limit this by using one experienced paediatric clinician with experience in multi - segment foot model use in disease populations . utilising a similar protocol with adult subjects with and without psoriatic arthritis hyslop et al
. demonstrated excellent within - day and between - day reliability characteristics for spatio - temporal , plantar pressure , kinematic and kinetic variables .
however peak rearfoot eversion performed poorly with within - group variance exceeding between group variance .
therefore comparison between cases and controls for peak rearfoot eversion in the present study may be vulnerable to error , particularly since this is the first application of the model to measure children and adolescents with and without jia . furthermore , the shortage of control subjects due to time constraints resulted in an imbalance when matching cases ( n = 14 ) to controls ( n = 10 ) . as a result
, group means from heterogeneous groups were compared via an independent t test as opposed to the preferred paired t test , which may have reduced the validity of the comparative analysis .
lastly it is acknowledged that the plantar pressure region identification software is not operator independent and may be vulnerable to variability .
in conclusion , in this optimally medically managed sample of children with jia , foot function as determined by a multi - segment foot model , did not differ from that of normal age- and sex - matched subjects .
this was in spite of many patients reporting mild - to - moderate levels of foot - related impairments and disability via the jafi .
further work is necessary to extend and confirm these observations in specific subtypes linked with close assessment of underlying joint and soft - tissue pathology and foot - related impairment and disability .
gj hendry , r barn and de turner were supported through funding from arthritis research uk ( ref gjh ; 18076 , rb;187381 , det ; 17832 ) .
Output:
| highlights foot kinematics were compared between children with and without juvenile idiopathic arthritis .
gait measurements and ultrasound features were explored as measures of structure and function .
magnitude and timing parameters for foot kinetics and pressure distribution were similar .
foot function did not differ despite moderate foot impairments and disability levels . |
PubmedSumm4882 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: in the last decade , the prevalence of dementia was rapidly growing with a considerable impact on daily live of all involved parties including the broader community . due to the overcrowd in residential care and to emotional restraints in family carers to have their relative with dementia admitted ,
dementia patients are most likely to be cared for at home at least for several years . today , more than 60% of the dementia patients receive home care [ 13 ] . in belgium as well as in other western european countries ,
there is only a restricted admittance to residential care when people suffer from dementia mainly due to the very complex care demands . with an expected increase of dementia prevalence of about 0.5% every five year together with decreasing residential care provisions ,
family carers will become indispensable partner in dementia care besides , the economic impact of dementia home care exceeds the total costs of home care of other chronically ill patients [ 1 , 3 ] .
caring for a community - dwelling elder with dementia puts a high burden on family carers [ 6 , 7 ] .
compared to carers of patients with other chronic diseases , carers of patients with dementia are more often confronted with depressive feelings , experience a higher burden and have been shown to be in a worse general health [ 8 , 9 ] .
the negative impact of the care situation is caused by inefficient coping strategies in carers , rather than by the objective workload [ 1013 ] .
however , depressive feelings in the carer are the main direct motive for premature ending of home care , resulting in institutionalization of the dementia patient [ 1416 ] .
interventions in dementia home care have been reported as highly appreciated but mainly ineffective [ 1719 ] . on average ,
carers attach great value to all kinds of support but finally they do not feel less depressed or burdened .
multidisciplinary , hierarchically structured care programs are mostly addressed to the patient without assessing the carers ' daily needs [ 2022 ] . as a consequence , in spite of the presence of an extensive or sophisticated support system ,
an abrupt end to the home care situation remains more rule than exception [ 15 , 23 ] . in this trial , we tested the hypothesis that the intervention of a care counselor , coordinating home care in a nonhierarchical and quasi - unstructured way during one year , will alleviate carers ' feelings of depression .
will an intervention , consisting in monthly phone calls , a three monthly visit to inventory care needs , organizing formal support and a continuous availability of a care counselor over the course of one year decrease the rate of depression in family carers of community dwelling elder with cognitive decline ?
the study population was recruited among frail community - dwelling elder , characterized by their carers as cognitively impaired . a local home nursing organization , the white - yellow cross , listed their elder patients with minimum care dependence ( washing , bathing , dressing , transfers and continence ) and labeled as cognitively impaired .
the care dependence corresponds with at least the lowest home care forfeit reimbursed by the social insurance institute and implies the intervention of a nurse at least once daily .
previous research demonstrated that frailty in older people with a cognitive decline sensitively predicts the presence of a dementia syndrome [ 1 , 24 ] .
second , the recruitment strategy was justified by the findings that family carers are reliable indicators of a cognitive decline and that the negative impact of home care is evoked by the relative 's assumption of a dementia state .
, all patients were tested with a mini mental state examinations and those scoring above 22 were excluded . to meet the final inclusion criteria , patients had to be accompanied by a family carer .
exclusion criteria were the absence of minimum care dependence , a severe or terminally ill patient , a definitive institutionalization planned on a short term , no available carer , or an impaired carer .
the region were recruitment was conducted can be described as a mixed rural - city area of leuven , belgium .
the intervention study was performed in a controlled design with random assignment to intervention or control group .
randomization for an eighty subjects sample was performed in blocks of ten recruited subjects using the software of www.randomization.com .
the elders were consequently visited by the research assistant after their general practitioners had formally been asked permission to visit their patients .
the involved general practitioners were formally asked permission for these visits by the trial assistant . above
, general practitioners had first been invited to an information session about the objective of the study in collaboration with the local general practitioners network .
not one general practitioner refused cooperation , mainly due to the absence of a need for active involvement . because study blinding of the subjects in this matter is impossible , the included population was not informed about the exact nature of the trial .
family carers and patients were only asked to participate in interviews with the trial assistant over the course of one year .
the trial assistant who did the baseline and outcome interviews and performed all measurements was blinded for the group assignment of the patients .
the care counselor was a primary care professional with a bachelor degree and was selected on excellence in social and communicative skills and because of her experience in dementia home care .
an extra training included a theoretic guidance through local community services addressing dementia home care provided by a skilled general practitioner .
beside , the care counselor was introduced to the home nursing organization , a local service centre for the elder and the local general practitioners network . during the ongoing of the study and in particular with each new intervention , the care counselor was supervised and given feedback by a skilled general practitioner .
the care counselor was asked to write down an unstructured report on every provided and extra contact with the carer .
over a course of 12 months , the care counselor guided the family carer in organizing home care . at a first visit ,
additionally , the care counselor arranged a monthly phone call with the family carer and a three monthly visit . during the intervention period twelve phone calls and four home visits were scheduled . additionally , the care counselor was within permanent reach for advice by phone , for adjusting home care or for an extra visit .
no structured or hierarchical care plan was provided but drawn out following the needs of the family carer and patient .
general practitioners were informed about each change in formal or informal home care of their patients .
subjects in the control group were not guided or visited by the care counselor but were passively directed to the usual care systems .
both the control group and the intervention group were visited six - monthly by the trial assistant interviewing the family carer and the elder relative . for both groups , an accurate inventory of all support installed outside the reach of the trial
contamination of the effect of the trial intervention by outside support was taken into account in the final analysis .
baseline features were recorded after the informed consent and directly following randomization and repeated after six and twelve months ; see table 3 .
outcome measures and instruments were chosen in accordance with other trials on this topic and based upon the experience with the qualidem study .
primary outcome measure was defined as depression in the family carer and measured by the beck depression inventory with a score of 10 or more implying mild to moderate depression .
secondary outcome measures were coping behavior , anxiety , and burden in the family carer .
burden was measured with the 14 item zarit burden inventory [ 28 , 29 ] .
this shortened version of the original burden inventory has proved its validity in family caregiving topics .
this subscale points out if subjects are prone to anxiety rather than it does reflect a state of mind during a limited period .
the patient 's status was measured with the aid of frail , the activities and instrumental activities of daily living , the mini mental state examination for cognitive status , and the neuro psychiatric inventory for behavior .
the symptoms described in this instrument were grouped into four categories : psychotic symptoms , disturbing behaviour , mood swings and neurovegetative alterations ( sleeping and eating problems , fears ) . additionally , an extensive quantitative assessment of formal and informal care support was made . finally , for each newly installed care support , the general practitioner was contacted .
sample size calculations were made with a 95% confidence interval and an estimated change in mean depression scores of 2 units . in anova - analysis
( one way analysis of variables ) a total sample of 46 subjects or 23 in each group was needed to reach a power of 0.9 with a significance level of 0.05 . in logistic regression analysis , including two interaction terms , 80 subjects were needed to reach a 0.9 power with a significance level of 0.05 .
baseline measures , including the available support , were compared between control and study group by mean differences ( expressed in t - test ) and odds ratios for dichotomized variables .
the effect of the intervention was determined by the evolution of depressive scores in the carer with depression ( 10 ) being the dependent variable .
bivariate analysis was performed to estimate the odds ratio for depression in the intervention versus the control group . in a multiple logistic stepwise regression analysis ,
the influence of the patient and carer features on the prevalence of depression was calculated .
for power reasons , all covariables were sequentially modeled together with the main independent factors .
repeated measures analysis following the hierarchical linear model was used to estimate the mean change differences in depression scores in control and study group over time ( longitudinal ) .
the technique used for this analysis allowed the adequate handling of at random missing data and compared both within as between subject changes .
second , general practitioners were only passively involved and were neither aware of the controlled design of the study .
third , the local and regional support systems remained stable over time which supported the assumption that minor changes in the usual care did not dramatically influenc the intervention effect .
the medical ethical board of the medical school of the catholic university of leuven granted formal permission for this trial on 27 january 2005 .
permission was given after the reassurance that control and intervention group subjects were not restrained from the usual care systems .
each patient and carer signed a written informed consent at the first visit of the trial assistant .
the consent asked permission for participation in a trial studying the care needs of community dwelling elder with cognitive decline and their family carers .
the ethical board agreed with this strategy on condition that the involved general practitioner was previously informed about each proposed intervention .
if the patient with cognitive decline was not aware of the consequences of study participation , the nearest family member was allowed to sign the informed consent .
over a course of 6 months , 346 inhabitants of the target region were eligible for initial screening .
all these patients were caredependent , visited daily by a home nurse , and living together with a carer .
the drop out ( n = 49 ) was mainly due to a normal cognitive status in the patient , recent hospitalization of the patient , the absence of a carer , or an extreme care depending carer . after this stage , 297 were selected for a home visit by the trial assistant . of these , only 62 patients with their carers were included in the trial .
the most frequent reason of noninclusion was the absence of a carer in home ( n = 127 ) .
carers not living together with the patient were difficult to reach for the simultaneous interviews .
not one of the selected patients had a score higher than 22 on the mini mental state examination .
shortly after the inclusion phase , two patients died and one patient was hospitalized for a long term .
six and twelve months after inclusion 52 and 46 carers and patients were available for the follow - up interviews . within six months
four patients died , one patient and two carers were hospitalized . within the second half year two additional patients died , one patient and one carer were hospitalized , and two carers refused further participation mainly due to the emotional impact of the interviews .
baseline characteristics did not significantly differ between control and study group . in the intervention group ,
thanks to the recruitment mechanism all patients were supported by a home nurse . over half of them
however , it should be noted that in the intervention group 10 carers were also caredependent .
most carers mentioned that no interdisciplinary contact moment had been organized . at baseline ,
one third of all carers showed at least a mild depression as scored on the bdi - scale ( 30.5% ) .
most carers felt seriously overloaded , with a mean score of 12 on the burden screen .
the carers showed a mix of problem - solving , supporting , and emotional coping behavior .
there was no difference in mean scores on these items between the control and intervention group .
as expected , the patient population was highly care - dependent ( see inclusion criteria ) .
patients showed moderate to high frailty , were limited in performing instrumental tasks of daily living and showed a mild to moderate cognitive decline .
mood swings and disruptive behavior ( screaming , aggressions , etc . ) were present in one third of all patients .
one year after the start of the intervention the odds ratio for depression in the treatment arm versus the control group was 0.16 ( 95% ci 0.030.86 ) .
sequentially , taking each carer characteristic and its interaction terms into account , no significant change in the odds ratio for depression was found when gender and having a relationship were introduced .
lower burden levels are followed by a further reduction in depression prevalence in the intervention group as compared to the depression prevalence in the control group ( p = .06 ) .
patient characteristics did not change the odds ratio for depression in a significant way except for neuro - vegetative behavioral disturbances .
intervention group carers confronted with this type of behavior are less prone to depression than their colleagues in the control group . besides the regular phone calls and home visits , the care counselor was contacted only once by a carer .
day care was introduced , two personal alarms , and one offer for extra in - home help were proposed .
three proposals ( two alarms , one day - care stay ) were effectively carried out .
characteristics of these carers and their relatives were not different from average scores at baseline . in both groups ,
formal care support did not change from baseline to end time , nor was there a difference between intervention and control group ( table 4 ) .
in this randomized intervention trial , we studied the presence of a care counselor , coordinating home care on the dementia family carers ' depression risk rate . at the end of the trial ,
the effect of the intervention on the prevalence of depression remained stable when features of patients and carers were taken into account .
the recruitment strategy based upon carers ' indication of a cognitive decline in their relative combined with a minimum care dependence , proved reliable to detect patients with at least a mild dementia ( mean score on mmse 16/23 ) .
a highly sensitive diagnosis of dementia was not required since the awareness in carers of a cognitive decline of their relative appeared a sufficient criterion to negatively influence the impact of home care .
ten carers applied for extra support and only one carer called the care counselor outside the provided appointments .
remarkably , it was not the most stressed or loaded carer that applied for an extra intervention .
most community - dwelling elders with cognitive decline are cared for by a close female relative ( spouse , daughter ) .
carers rate their general health as good although this might be an overestimate due to self - scoring and selection bias .
it is likely that carers rate their health as good but that they are reluctant to admit that they can not offer help . besides
, it should be noted that a small sample of carers was not included at baseline due to health related problems ( n = 16 ) . at baseline
, both control and intervention group appeared to be comparable on patient carers and formal support features .
one third of the carers seemed at least mildly depressed with a score of ten or more on the bdi .
however , the cutoff score of 10 or more which implies mild to moderate depression on the bdi is debatable
. nevertheless , it was not the purpose of this trial to provide a formal diagnosis of depression but to screen carers at risk of it in a sensitive way .
the most important disadvantage of the bdi is the score deviation in patients with an important somatic disease .
depression was pointed as primary outcome measure in accordance with other publications in this domain and with conclusions drawn from the preceding population survey .
depression , more than burden or anxiety , reflects the mental wellbeing of the carer and appears to be a sensitive predictor of premature ending of home care [ 37 , 38 ] . beside a depressive mood ,
it is known from other publications that these feelings of being overburdened are rather unrelated to the objective care burden .
the lack of an accessible support system together with inadequate coping strategies and feelings of loneliness , cause carers to feel burdened .
besides , the unpredictable character of dementia and the inherent social isolation make carers very anxious , as reflected in the high scores on the stai - instrument . to cope with this , carers tend to combine a supporting coping behavior with problem solving behaviour , which is known to be an efficient survival strategy .
the formal support present at baseline reflects a common dementia home care situation . due to the recruitment mechanism
half of the patients were regularly visited by family help , cleaning service , or physiotherapist .
the high cost of paid private help , a personal alarm , day care , and meals on wheels are the reasons the absence of these services in common home care situations .
most patients and carers also considered the monthly visit of their general practitioner as organized care management .
general practitioners play their key role in home care and communicate in an unstructured way with other disciplines , mainly when problems occur [ 40 , 41 ] .
the in - between groups as well as the over - time comparison of this parameter did not reveal any difference .
one exception was the item paid private help with an increase over time .
this observation was due to a new system of reimbursing private home services , introduced by the government .
since no important changes in formal support were noted , a contamination of the trial intervention was not suspected . beside , interference of support installed independently of the trial
both groups were free to apply for extra professional help , which was accurately inventoried .
only half of these interventions were effectively carried out . in spite of high levels of burden , anxiety and depressive feelings ,
even with the aid of the care counselor , the gap between requesting care support and effectively implementing it in the home care situation still appears to be large . there is some evidence in the literature that carers feel reluctant to appeal for professional help [ 42 , 43 ] . besides getting lost in the labyrinth of support systems
secondly , carers feel shame as well as worries about their cognitively and functionally impaired relative . although the support strategy reported in our trial is not unknown in geriatric and psychiatric setting , only a very limited amount of trials in dementia research were comparable with the design of our study [ 44 , 45 ] .
callahan and colleagues proposed the intervention of a care coordinator concentrating on an extended training of patient and carer .
as compared to the results in our trial , the gains in the carer wellbeing might not justify the socioeconomic costs of training both carer and patient .
the trial on befriending with relatives of dementia patients did not redeem the expectation of improved carer wellbeing .
in contrast with our trial , the amount of visits was reduced to the minimum to avoid the negative feelings related to another professional intruder .
other trials addressing dementia home care related issues by offering a coordinated support used a more hierarchical intervention strategy [ 4648 ] .
carers were expected to run through a fix program integrating different levels of support . only on indication of the carer or
when situations required , the support program was adapted to the actual needs . as appeared in our trial ,
the strength of the study is the randomized design , with homogenous study groups and the extensive inventory of formal and informal home care in both groups .
as compared to other similar trials a major strength is the clean control conditions guaranteed by the subjects ' unawareness of an ongoing intervention . in several trials the control group received , due to ethical concerns , an augmented usual care , were put on a waiting list for treatment , or simply received another active intervention [ 44 , 46 , 49 ] .
another important advantage of this support strategy is the low impact on the carers ' daily living .
there is no burden of attending a training session outdoors and no inconvenient presence of another professional indoors [ 45 , 50 ] .
previously , it has been demonstrated that carers might lack time and supervising volunteers to organize home care during their absence ( services ) . on the other hand ,
carers report also some extra burden related to the presence of a professional taking over or judging their care - giving tasks .
as known from other publications on this topic , carers often feel too burdened and report lack of the time to participate in a study .
this means that the included sample of carers could belong to the best surviving group surrounded by an adequate support system .
nevertheless , prevalence of depression and burden in the carer and the amount of formal support is in accordance with the features of a general sample drawn before in a cross - sectional population survey .
consequently , it is defendable to assume that a representative sample of carers and patients was drawn .
most reports on this research issue deal with a selected study population caused by recruitment via day care centers , local departments of the alzheimer society , memory clinics , and service centers for elder people [ 48 , 5053 ] .
a potential bias related to the inclusion of help seeking dyads carer and patient is likely to be present .
evidence exists that this former population is not the most burdened one and handle rather active problem solving strategies [ 54 , 55 ] .
another plausible explanation could be that the intervention is mainly effective in mildly depressive carers . in case
the cutoff point on the depression instrument was lowered to eight , no significant difference was noted between both groups after one year followup .
additionally , the estimated differences of mean depression scores between control and index group appeared not significant . in the range of the baseline moderate or severe depressive carers , no such changes were detected .
carers do not need to be surrounded with more formal carers , but they want to feel more supported . in terms of policy , this could have some important implications .
instead of inventing new , sophisticated , or complex support mechanisms , home care should become more accessible .
a care counselor , familiar with the local care systems , could guide carers through the difficult pathway of home care . in future
research , this observation should be repeated in larger groups and over a longer period to assess outcomes such as institutionalization and cost of care .
an extended cost analysis should be made to estimate the effect of the intervention on the increasing community costs of dementia home care .
Output:
| objective . caring for a patient with cognitive decline has an important impact on the general well - being of family caregivers .
although highly appreciated , interventions in dementia home care remain mainly ineffective in terms of well - being .
consequently , in spite of an extensive support system , abrupt ending of home care remains more rule than exception .
method .
the hypothesis was that the intervention of a care counselor , coordinating care in quasi - unstructured way during one year , will alleviate caregivers ' feelings of depression .
the study population was composed of community - dwelling patients with cognitive decline .
a care counselor was at the exclusive disposal of the intervention group .
primary outcome measure was caregiver depression .
results . finally , depression was 6.25 times less frequent in the intervention group .
the actual intervention appeared minimal with only ten applications for more support followed by only three interventions effectively carried out . although caregivers felt burdened and depressed , formal support remained stable . on the other hand , the availability of the care counselor made caregivers feel less depressed with the same amount of support .
conclusion .
carers do not always need to be surrounded with more professionals , but they want to feel more supported . in terms of policy , this could have some important implications . |
PubmedSumm4883 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: morphological changes including disruptions of sarcomeres , cytoskeletal elements , and sarcolemma are accompanied by muscle damage .
loss of muscle function such as reduced force production , an indirect marker of muscle damage , is followed by delayed - onset muscle soreness ( doms ) and leakage of muscle proteins including myoglobin ( mb ) and creatine kinase ( ck ) , into the bloodstream . among these markers of muscle damage ,
although the resting value of ck ranges from 45 to 267 u / l , it increases over 10,000 u / l following exercise - induced muscle damage .
previous studies reported that ck activity varies after eccentric muscle contractions , ranging from 6,740~24,200 u / l , 500~34,500 u / l and 73~82,011 u / l .
many researchers have suggested that the main contributors to inter - subject variability include gender , age , ethnicity , training status , mode of exercise , and genetic factors .
body composition has also been a potent contributor to inter - subject variability of ck activity .
reported that overweight individuals showed higher ck activity following eccentric exercise than those with normal body weight based on the body mass index ( bmi ) .
heled et al . also reported that individuals with higher ck activity after exercise have higher % body fat compared to those with less ck activity .
although several factors such as muscle mass and fat mass have been suggested to explain the relationship between body composition and ck variability , other factors need to be clarified . since ck activity in the blood
is believed to reflect muscle membrane disruption , maximal isometric strength and muscle soreness following eccentric muscle contractions might be correlated . however
, several studies have reported that there is no clear correlation between increased ck activity and decreased maximal isometric strength or muscle soreness . despite the results from these studies ,
therefore , the purpose of the study was to investigate the relationship between ck activity and body composition as well as muscle damage markers including maximal isometric strength and muscle soreness in a larger population .
they did not attend any resistance training within the previous 6 months , had no neuromuscular diseases and took no medications or dietary supplements .
each subject was familiarized with all the procedures of the study prior to signing the informed consent form .
the study was approved by the institutional review board at kookmin university , seoul , korea .
each subject was assigned to one of the following groups after eccentric muscle contractions based on their peak ck activity : high responder ( > 2,000 u / l ) , medium responder ( 500 - 2,000 u / l ) , or low responder ( < 500
high responders contained 66 subjects , medium responders had 26 , and low responders had 27 .
anthropometric measures including height , body weight , % body fat , muscle mass , and body mass index ( bmi ) were obtained using an anthropometer ( ds-102 , dongsan , korea ) and bioelectrical impedance ( inbody 520 , biospace , korea ) .
each subject was asked to abstain from severe exercise or using a sauna and to fast overnight to obtain consistent measurements during the study . in this study ,
the elbow flexor model was used for eccentric muscle contraction [ 21 - 23 ] .
each subject placed his non - dominant arm on the pad attached to a modified preacher curl machine with the elbow joint at 90 degrees .
when the subjects pulled the pad toward their trunk , the investigator pulled down on the lever attached to the pad in a direction opposite the subjects . in this way
maximal isometric strength ( mis ) was measured using a strain gauge ( pks-1250 , poong kwang , korea ) attached to a modified preacher curl machine .
each subject s non - dominant arm was placed on the pad of the preacher curl machine with the elbow joint at 90 degrees .
then , when subjects pulled the pad maximally toward to their trunk , mis was measured pre and post , and at 24 , 48 , 72 and 96 hours after exercise .
three trials were attempted and averaged to calculate % mis . the pre - value for mis
the post - value of mis was used to identify whether each subject performed maximally during eccentric muscle contractions .
when post mis was less than 30% of baseline ( pre mis ) , subjects were excluded from the study .
muscle soreness ( sor ) was measured using a visual analog scale ( vas ) . on the vas ,
a 100 mm horizontal line was drawn , with 0 as no soreness and 100 as very sore .
each subject drew a vertical line on the vas indicating how they felt around the elbow flexor area .
sor was recorded pre and at 24 , 48 , 72 , and 96 hours after exercise .
5 ml of blood samples were taken from the antecubital vein to analyze ck activity pre and at 24 , 48 , 72 and 96 hours after exercise .
each sample was allowed to sit for 20 minutes at room temperature and then centrifuged ( 2500~3000 rpm for 15 minutes ) to separate the serum .
the serum samples were stored in a -80 degree freezer prior to analyzing the ck activity using an automated blood analyzer ( vitros dt60ii , kodak , usa ) .
all variables were presented as mean and standard deviation . to evaluate the effect of ck variability on muscle damage markers , 2 5 factorial repeated measures anova was used and tukey s test was used as a post - hoc test when there was significant group - by - time interaction between variables . to evaluate the effect of ck variability on body composition , one - way anova was used .
additionally , pearson correlation was used to detect the relationship between peak ck activity and muscle damage markers with respect to the time course and body composition .
spearman correlation was also used to detect the relationship between the peak ck value and peak sor value as well as the lowest % mis value .
they did not attend any resistance training within the previous 6 months , had no neuromuscular diseases and took no medications or dietary supplements .
each subject was familiarized with all the procedures of the study prior to signing the informed consent form .
the study was approved by the institutional review board at kookmin university , seoul , korea .
each subject was assigned to one of the following groups after eccentric muscle contractions based on their peak ck activity : high responder ( > 2,000 u / l ) , medium responder ( 500 - 2,000 u / l ) , or low responder ( < 500
high responders contained 66 subjects , medium responders had 26 , and low responders had 27 .
anthropometric measures including height , body weight , % body fat , muscle mass , and body mass index ( bmi ) were obtained using an anthropometer ( ds-102 , dongsan , korea ) and bioelectrical impedance ( inbody 520 , biospace , korea ) .
each subject was asked to abstain from severe exercise or using a sauna and to fast overnight to obtain consistent measurements during the study .
in this study , the elbow flexor model was used for eccentric muscle contraction [ 21 - 23 ] .
each subject placed his non - dominant arm on the pad attached to a modified preacher curl machine with the elbow joint at 90 degrees .
when the subjects pulled the pad toward their trunk , the investigator pulled down on the lever attached to the pad in a direction opposite the subjects . in this way
maximal isometric strength ( mis ) was measured using a strain gauge ( pks-1250 , poong kwang , korea ) attached to a modified preacher curl machine .
each subject s non - dominant arm was placed on the pad of the preacher curl machine with the elbow joint at 90 degrees .
then , when subjects pulled the pad maximally toward to their trunk , mis was measured pre and post , and at 24 , 48 , 72 and 96 hours after exercise .
three trials were attempted and averaged to calculate % mis . the pre - value for mis
the post - value of mis was used to identify whether each subject performed maximally during eccentric muscle contractions .
when post mis was less than 30% of baseline ( pre mis ) , subjects were excluded from the study .
muscle soreness ( sor ) was measured using a visual analog scale ( vas ) . on the vas ,
a 100 mm horizontal line was drawn , with 0 as no soreness and 100 as very sore .
each subject drew a vertical line on the vas indicating how they felt around the elbow flexor area .
sor was recorded pre and at 24 , 48 , 72 , and 96 hours after exercise .
5 ml of blood samples were taken from the antecubital vein to analyze ck activity pre and at 24 , 48 , 72 and 96 hours after exercise .
each sample was allowed to sit for 20 minutes at room temperature and then centrifuged ( 2500~3000 rpm for 15 minutes ) to separate the serum .
the serum samples were stored in a -80 degree freezer prior to analyzing the ck activity using an automated blood analyzer ( vitros dt60ii , kodak , usa ) .
all variables were presented as mean and standard deviation . to evaluate the effect of ck variability on muscle damage markers , 2 5 factorial repeated measures anova was used and tukey s test was used as a post - hoc test when there was significant group - by - time interaction between variables . to evaluate the effect of ck variability on body composition , one - way anova was used .
additionally , pearson correlation was used to detect the relationship between peak ck activity and muscle damage markers with respect to the time course and body composition .
spearman correlation was also used to detect the relationship between the peak ck value and peak sor value as well as the lowest % mis value .
there was a significant group - by - time interaction between ck variability and mis ( p<0.001 ) by repeated measure anova .
there was a significant group effect ( p<0.001 ) and time effect ( p<0.001 ) .
mis was significantly different in the low responder group ( 47% decrease of baseline ) immediately after exercise compared to the high responder group ( 62% decrease of baseline ) indicating that the low responder group showed less initial muscle damage .
in addition , the low responder group demonstrated faster mis recovery after exercise by 96 hours compared to the high responder group , indicating that the lower responder group might have less muscle damage as shown in fig .
1 . there was a significant group - by - time interaction between ck variability and sor ( p<0.01 ) analyzed by repeated measures anova .
there was also a significant group effect ( p<0.001 ) and time effect ( p<0.001 ) .
both groups demonstrated significant increases in sor after exercise but the low responder group had less sor compared to the high responder group as shown in fig .
2 . according to one - way anova analysis , there were significant differences in % body fat ( p=0.006 ) , muscle mass ( p=0.047 ) , and bmi ( p=0.001 ) among the three groups .
the medium responder group had significantly higher % body fat , muscle mass , and bmi compared to the low and high responder groups .
when the medium responder group was eliminated , there was a significant difference in % body fat , with the high responder group showing higher % body fat compared to the low responder group ( p=0.014 ) .
however , there were no significant differences in muscle mass ( p=0.25 ) and bmi ( p=0.135 ) between the low and high responder groups .
there was a significant correlation between peak ck and mis , analyzed by pearson correlation as shown in table 2 .
however , there was no significant correlation in sor using pearson correlation , although spearman correlation indicated a significant correlation .
additionally , there was no significant correlation between peak ck and body composition variables including % body fat , muscle mass , and bmi as shown in table 3 .
there was a significant group - by - time interaction between ck variability and mis ( p<0.001 ) by repeated measure anova .
there was a significant group effect ( p<0.001 ) and time effect ( p<0.001 ) .
mis was significantly different in the low responder group ( 47% decrease of baseline ) immediately after exercise compared to the high responder group ( 62% decrease of baseline ) indicating that the low responder group showed less initial muscle damage .
in addition , the low responder group demonstrated faster mis recovery after exercise by 96 hours compared to the high responder group , indicating that the lower responder group might have less muscle damage as shown in fig .
1 . there was a significant group - by - time interaction between ck variability and sor ( p<0.01 ) analyzed by repeated measures anova .
there was also a significant group effect ( p<0.001 ) and time effect ( p<0.001 ) .
both groups demonstrated significant increases in sor after exercise but the low responder group had less sor compared to the high responder group as shown in fig .
according to one - way anova analysis , there were significant differences in % body fat ( p=0.006 ) , muscle mass ( p=0.047 ) , and bmi ( p=0.001 ) among the three groups .
the medium responder group had significantly higher % body fat , muscle mass , and bmi compared to the low and high responder groups .
when the medium responder group was eliminated , there was a significant difference in % body fat , with the high responder group showing higher % body fat compared to the low responder group ( p=0.014 ) .
however , there were no significant differences in muscle mass ( p=0.25 ) and bmi ( p=0.135 ) between the low and high responder groups .
there was a significant correlation between peak ck and mis , analyzed by pearson correlation as shown in table 2 .
however , there was no significant correlation in sor using pearson correlation , although spearman correlation indicated a significant correlation .
additionally , there was no significant correlation between peak ck and body composition variables including % body fat , muscle mass , and bmi as shown in table 3 .
this study was performed to elucidate the relationship between ck variability and muscle damage parameters including maximum isometric strength and muscle soreness as well as body composition following eccentric muscle contractions .
it is well documented that eccentric muscle contractions induce morphological changes including z - disk streaming and sarcolemma disruption , leading to increased membrane permeability and subsequent leakage of ck into the circulation .
the measurement of ck activity , therefore , has been used as an indicator of membrane integrity after muscle damage .
the factors that affect membrane integrity include estrogen , dystrophin , and genotypes . in general
, females show lower ck activities than males due to the protective effect of estrogen on cell membranes .
since dystrophin is also known to be related to membrane integrity and individuals with dystrophin deficient conditions such as duchene s or becker s muscular dystrophy showed higher ck activity up to 25~200 fold .
reported lower ck activity in the dd allele compared to the ii allele for ace polymorphisms following eccentric muscle contractions .
reported higher ck activity in the gg allele for interleukin-6 -174g / c polymorphism following eccentric exercise .
in early studies , ck activity was closely related to the magnitude of muscle damage , while later studies demonstrated that ck activity was not correlated with the degree of muscle damage .
later studies biopsied the vastus lateralis muscle after high - force eccentric exercise in young and old males and then observed morphological changes using an electron microscope .
the authors concluded that older individuals had greater morphological disruption compared to young individuals but there was no significant difference in ck activity between the two groups .
several studies have also reported no significant relationship between ck activity and maximum isometric strength .
margaritis et al . demonstrated that maximum isometric strength returned to baseline at 4 days after competition but ck activity continued to increase when muscle damage markers were analyzed among triathlon athletes after competition .
these results have raised the question of whether ck activity is a sensitive marker of muscle damage . however , several recent studies showed a significant relationship between peak ck activity and maximum isometric strength .
reported that there is a negative relationship between peak ck activity and muscle strength in the leg extensors .
additionally , nosaka et al . reported that maximum isometric strength immediately after eccentric exercise is negatively correlated with peak ck activity .
therefore , most studies to date have shown controversial results but the sample sizes were small . in this study , we used a relatively larger sample size compared to previous studies and could confirm peak ck activity and other muscle damage markers as well as maximum isometric strength .
we found a significant difference in maximum isometric strength based on ck variability , where high responders showed a greater decline in maximum isometric strength immediately after exercise and a slower recovery compared to low responders .
the results also indicated a significant negative relationship between peak ck activity and maximum isometric strength following eccentric exercise .
this may suggest that peak ck activity is closely related to the magnitude of muscle damage .
nosaka and clarkson reported that the t2 relaxation time for magnetic resonance imaging is higher in individuals with high ck activity after eccentric exercise and evans et al .
additionally , nurenberg et al . reported that t2 relaxation time is negatively correlated with normal muscular structure and function , suggesting that both ck activity and t2 relaxation time could be markers for muscle function . in the current study
, there was a significant difference in muscle soreness based on ck variability , with high responders showing higher muscle soreness compared to low responders .
although the pearson correlation did not show a significant relationship between peak ck activity and muscle soreness in the time course after eccentric exercise , spearman correlation showed a significant relationship between the two variables .
previous studies have reported no relationship between ck activity and muscle soreness following eccentric exercise .
a recent study however , reported that there was a significant relationship between myoglobin levels and the number of neutrophils as well as between myoglobin levels and muscle soreness .
myoglobin is also an indirect blood marker of muscle and cell membrane damage while neutrophil is known to induce an inflammatory response , leading to muscle soreness .
although the mechanism is not well elucidated , it may be that the inflammatory response following muscle damage increases ck activity as well as muscle soreness . finally , when body composition was compared with ck variability , high responders had higher % body fat compared to low responders .
also reported that overweight females with an average of 31% body fat and 29.5 body mass index ( bmi ) showed higher ck activity after eccentric exercise compared to individuals with normal % body fat and bmi .
although the relationship between body fat and muscle damage is not fully clarified , the mechanisms can be inferred from several obesity studies .
kriketos et al . reported that obese individuals with high % body fat had more type ii muscle fibers in biopsied muscle compared to non - obese individuals .
it is well known that type ii fibers are more prone to damage than type i fibers .
in addition , obese individuals generally had reduced physical activity , leading to less exposure to eccentric muscle contractions .
therefore , obese individuals showed more muscle damage due to less adaptation to eccentric contractions . in an animal study ,
however , since the subjects in this study did not show excessive body fat , the aforementioned factor provides limited explanation .
ck variability following eccentric exercise is closely related to maximum isometric strength and muscle soreness based on the peak ck activity .
Output:
| [ purpose]the purpose of the study was to investigate the relationship between ck variability and body composition and muscle damage markers following eccentric exercise.[methods]total 119 healthy male subjects were recruited to perform 50 eccentric contractions consisted of 2 sets of 25 contractions .
then , blood creatine kinase ( ck ) activity was analyzed to divide into three groups based on their ck activity levels .
maximum isometric strength ( mis ) , muscle soreness ( sor ) and body composition data were obtained before and after exercise.[results]the results showed that high ck responders had a significant decrease in mis ( p<0.001 ) and greater sor ( p<0.01 ) following eccentric exercise compared to low ck responders .
percent body fat was also higher in high responders compared to low responders ( p=0.014 ) .
peak ck activity was significantly correlated with mis and sor but no correlation with % body fat , muscle mass , and body mass index.[conclusion]ck variability following eccentric exercise is closely related to mis and sor and % body fat may be a potent factor for ck variability . |
PubmedSumm4884 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: angiomatosis is a complex vascular malformation of infancy and childhood consisting of proliferating blood vessels with accompanying mature fat , fibrous tissue , lymphatics and nerves which may involve skin , subcutaneous tissue , skeletal muscle and occasionally bone .
it is extremely rare and benign but a clinically extensive vascular lesion of soft tissue which usually becomes symptomatic during childhood or adolescence . according to rao and weiss ,
angiomatosis has been defined as a histologically benign vascular lesion that affects a large segment of the body in a contiguous fashion , either by vertically involving multiple tissue types ( e.g. subcutis , muscle , bone ) or by involving similar types of tissues ( e.g. multiple muscle ) .
it has no malignant potential , but because of its infiltrative nature , it could be misdiagnosed as a malignancy using imaging techniques . for these reasons diagnosis based on clinical and radiographic findings in correlation with histologic features would be desirable .
its diffuse infiltrative nature makes surgical resection difficult ; hence , recurrence is a common feature in angiomatosis [ 2 , 3 ] .
the aim of this paper is to present three cases of angiomatosis which were clinically mimicking hemangioma , lipoma and arteriovenous ( av ) malformation at rare sites such as within the masseter , malar region and in the mandible , respectively .
a 13-year - old female presented with the complaint of swelling in the right side of face since 2 years .
the swelling had slowly progressed in size during the period . on examination , a diffuse swelling in the right side of the face extending from the ala - tragal plane superiorly to the lower border of mandible , from the anterior to posterior border of masseter , was seen .
intraorally , bluish discolouration of the right buccal mucosa with telengiectasia or spider nevi appearance was evident ( fig .
the swelling was non tender , collapsible on digital pressure and filled up on releasing the pressure .
1a lesion seen on buccal mucosa , b small opacities depicting phleboliths , c proliferating vessels infiltrating in between the muscle bundles , d dilated thick walled vessel between the muscle bundles a lesion seen on buccal mucosa , b small opacities depicting phleboliths , c proliferating vessels infiltrating in between the muscle bundles , d dilated thick walled vessel between the muscle bundles the orthopantamogram ( opg ) showed calcified scattered masses lateral to the right ramus of the mandible ( fig .
ultrasonography revealed the presence of hypoechoic areas showing the distorted fibers of the masseter muscle and hyperechoic areas showing phleboliths .
excision was done under general anesthesia and operative findings presented the buccal pad of fat infiltrated with vascular tissues and involving the right masseter muscle .
gross specimen showed soft tissues which were black in color with a few calcified masses ( possibly phleboliths ) .
the microscopic findings revealed disorganized proliferation and randomly arranged blood vessels of varying sizes in between muscle bundles ; endothelial proliferation and canalization was also seen ( fig .
an extensive area of hemorrhage was evident and so were calcification depicting phleboliths . based on clinical , radiological and histopathological findings
, a diagnosis of angiomatosis was derived . a 19-year - old female presented with a chief complaint of swelling in left side of the face since 34 years . on examination , a well circumscribed solitary swelling of the left malar region
was seen which measured approximately 3 3 cm ( fig .
radiographically , no significant findings were seen and a provisional diagnosis of lipoma was considered.fig .
2a circumscribed swelling on left malar region , b gross specimen with nodular surface and irregular borders , c blood vessels of varying caliber , infiltrating into the stroma rich in adipose tissue , d proliferating capillaries around feeder vessel , e canalization and new blood vessel formation , f nerve bundle infiltrated by proliferating capillaries a circumscribed swelling on left malar region , b gross specimen with nodular surface and irregular borders , c blood vessels of varying caliber , infiltrating into the stroma rich in adipose tissue , d proliferating capillaries around feeder vessel , e canalization and new blood vessel formation , f nerve bundle infiltrated by proliferating capillaries excision was done under general anesthesia .
gross specimen showed soft tissue mass floating in formalin , with irregular borders and white to brownish in color ( fig .
microscopically the excised specimen revealed blood vessels of varying caliber infiltrating into to the stroma rich in adipose tissue ( fig . 2c ) .
2d ) and areas of canalization and new blood vessel formation were also evident ( fig .
2f ) , prompting a final diagnosis of angiomatosis . a 16-year - old male presented with the chief complaint of swelling on lower right region of the jaw since 2 months .
the lesion presented with facial asymmetry at the lower third of the face , with bony hard swelling extending from the symphysis to angle of the mandible ( fig .
intraoral examination revealed diffuse bony swelling extending from the mandibular right central incisor to second molar and presented with egg shell crackling .
3a large diffuse swelling on the right side of the mandible , b panoramic radiograph showing large ill - defined radiolucency extending from 41 to 47 , c angiography showing mild increase in vascularity of right external carotid artery , d gross specimen showing large vascular channels inside the body of the mandible , e vascular channels infiltrating into the bone , f periosteal infiltration a large diffuse swelling on the right side of the mandible , b panoramic radiograph showing large ill - defined radiolucency extending from 41 to 47 , c angiography showing mild increase in vascularity of right external carotid artery , d gross specimen showing large vascular channels inside the body of the mandible , e vascular channels infiltrating into the bone , f periosteal infiltration opg revealed radiolucency extending from mandibular right central incisor to second molar ( fig .
magnetic resonance imaging ( mri ) hard tissue window showed lytic lesion in the medulla of the mandible , with erosion of buccal and lingual cortical plates , thus giving a sun - ray appearance ( reactive periostitis ) .
angiography presented with mild increase in vascularity of the right external carotid artery ( fig .
the gross specimen showed areas of dark brown to bluish lesion on both medial and lateral aspect of the mandible . on opening ,
histopathological findings revealed numerous vascular channels of capillary and cavernous caliber infiltrating into the bone ( fig .
areas of periosteal infiltration with reactive new bone formation were also evident ( fig .
a 13-year - old female presented with the complaint of swelling in the right side of face since 2 years .
the swelling had slowly progressed in size during the period . on examination , a diffuse swelling in the right side of the face extending from the ala - tragal plane superiorly to the lower border of mandible , from the anterior to posterior border of masseter , was seen .
intraorally , bluish discolouration of the right buccal mucosa with telengiectasia or spider nevi appearance was evident ( fig .
the swelling was non tender , collapsible on digital pressure and filled up on releasing the pressure .
1a lesion seen on buccal mucosa , b small opacities depicting phleboliths , c proliferating vessels infiltrating in between the muscle bundles , d dilated thick walled vessel between the muscle bundles a lesion seen on buccal mucosa , b small opacities depicting phleboliths , c proliferating vessels infiltrating in between the muscle bundles , d dilated thick walled vessel between the muscle bundles the orthopantamogram ( opg ) showed calcified scattered masses lateral to the right ramus of the mandible ( fig .
ultrasonography revealed the presence of hypoechoic areas showing the distorted fibers of the masseter muscle and hyperechoic areas showing phleboliths .
excision was done under general anesthesia and operative findings presented the buccal pad of fat infiltrated with vascular tissues and involving the right masseter muscle .
gross specimen showed soft tissues which were black in color with a few calcified masses ( possibly phleboliths ) .
the microscopic findings revealed disorganized proliferation and randomly arranged blood vessels of varying sizes in between muscle bundles ; endothelial proliferation and canalization was also seen ( fig .
an extensive area of hemorrhage was evident and so were calcification depicting phleboliths . based on clinical , radiological and histopathological findings
a 19-year - old female presented with a chief complaint of swelling in left side of the face since 34 years . on examination , a well circumscribed solitary swelling of the left malar region was seen which measured approximately 3 3 cm ( fig .
radiographically , no significant findings were seen and a provisional diagnosis of lipoma was considered.fig .
2a circumscribed swelling on left malar region , b gross specimen with nodular surface and irregular borders , c blood vessels of varying caliber , infiltrating into the stroma rich in adipose tissue , d proliferating capillaries around feeder vessel , e canalization and new blood vessel formation , f nerve bundle infiltrated by proliferating capillaries a circumscribed swelling on left malar region , b gross specimen with nodular surface and irregular borders , c blood vessels of varying caliber , infiltrating into the stroma rich in adipose tissue , d proliferating capillaries around feeder vessel , e canalization and new blood vessel formation , f nerve bundle infiltrated by proliferating capillaries excision was done under general anesthesia .
gross specimen showed soft tissue mass floating in formalin , with irregular borders and white to brownish in color ( fig .
microscopically the excised specimen revealed blood vessels of varying caliber infiltrating into to the stroma rich in adipose tissue ( fig . 2c ) .
2d ) and areas of canalization and new blood vessel formation were also evident ( fig .
2e ) . nerve bundles too , were infiltrated by proliferating blood vessels ( fig .
a 16-year - old male presented with the chief complaint of swelling on lower right region of the jaw since 2 months .
the lesion presented with facial asymmetry at the lower third of the face , with bony hard swelling extending from the symphysis to angle of the mandible ( fig .
intraoral examination revealed diffuse bony swelling extending from the mandibular right central incisor to second molar and presented with egg shell crackling .
3a large diffuse swelling on the right side of the mandible , b panoramic radiograph showing large ill - defined radiolucency extending from 41 to 47 , c angiography showing mild increase in vascularity of right external carotid artery , d gross specimen showing large vascular channels inside the body of the mandible , e vascular channels infiltrating into the bone , f periosteal infiltration a large diffuse swelling on the right side of the mandible , b panoramic radiograph showing large ill - defined radiolucency extending from 41 to 47 , c angiography showing mild increase in vascularity of right external carotid artery , d gross specimen showing large vascular channels inside the body of the mandible , e vascular channels infiltrating into the bone , f periosteal infiltration opg revealed radiolucency extending from mandibular right central incisor to second molar ( fig .
hard tissue window showed lytic lesion in the medulla of the mandible , with erosion of buccal and lingual cortical plates , thus giving a sun - ray appearance ( reactive periostitis ) .
angiography presented with mild increase in vascularity of the right external carotid artery ( fig .
the gross specimen showed areas of dark brown to bluish lesion on both medial and lateral aspect of the mandible . on opening ,
histopathological findings revealed numerous vascular channels of capillary and cavernous caliber infiltrating into the bone ( fig .
areas of periosteal infiltration with reactive new bone formation were also evident ( fig .
the co - existence of vascular proliferation and abundant fat in this infiltrating lesion previously inspired the now obsolete term
if only muscles are predominantly involved , it may also be termed as intra - muscular hemangioma , which is once again a subjective diagnosis .
arteriovenous malformation , a term well founded in the radiologic literature , implies functional arteriovenous communications and may correspond in some instances to what pathologists term angiomatosis .
because of nomenclature issues , it has been very difficult to gain a clear understanding of this lesion and in particular to compare the experience derived from one speciality to another . to promote a more standardized approach to diagnosis
angiomatosis be used to connote a histologically benign vascular lesion that extensively involves a region of the body or several different tissue types in a contiguous fashion .
the congenital form may be seen sporadically or accompanying certain types of syndromes such as klippel trenaunay
rao and weiss s study bears similarities to our reports in that the lesions commonly occurs in the second decade of life , there is a female predilection to its occurrence and it presents as a diffuse persistent swelling having two histological patterns .
these lesions probably begin during early intra - uterine life , grow proportionately with the fetus and consequently affect large areas of the body [ 2 , 4 ] .
the most common pattern consists of a haphazard proliferation of varying sized vessels , particularly large veins .
however , the most distinctive feature is the clusters of capillary vessels residing within or adjacent to the vein walls .
a second but uncommon pattern is the clusters of capillary - sized vessels arranged in nodules around a large vessel in the center .
both types are typically associated with large amounts of adipose tissue and hence these lesions have lead previous authors to use the term infiltrating angiolipoma , suggesting that these are more generalized mesenchymal proliferations rather than exclusive vascular pathology .
because of its infiltrative nature , angiomatosis may resemble many of the vascular tumors and malformations .
angiolipoma can be considered as an important differential diagnosis , but it is well circumscribed and proliferating vessels are usually concentrated at the periphery of intratumoral lobules of adipocytes .
angiomyolipoma can be distinguished from angiomatosis as they are composed of varying amounts of blood vessels , smooth muscle and fat .
infiltrating lipoma consist of lesional fat tissue infiltrating in the form of long thin streaks radiating from the intratumoral mass .
angiomyxolipoma usually resembles angiomatosis due to presence of adipose tissue component and blood vessels with thick and thin walls .
it can be distinguished by the presence of myxoid change in adipose tissue and absence of haphazard blood vessel proliferation .
liposarcoma can also be considered as a differential diagnosis ; however , mitotic figures , cellular atypia and lipoblasts ( signet ring appearance ) are not seen in angiomatosis .
the treatment of choice in extensive angiomatosis is either radiotherapy or interferon -2a treatment . in localized cases ,
angiomatosis has no tendency to progress or evolve histologically to a more aggressive lesion . on
follow up , nearly 90% of patients experienced local recurrence and approximately 40% encountered more than one local recurrence within a period of 5 years .
the possibility of angiomatosis should be considered whenever a persistent swelling in the head and neck region in early childhood is seen .
Output:
| angiomatosis is a diffuse vascular lesion which involves a large segment of the body in a contiguous fashion involving multiple tissues ( e.g. subcutis , muscle , bone , adipose tissue etc . ) in different planes .
such lesions usually present in the first two decades of life with female predilection and are commonly seen in lower extremities .
it clinically mimics hemangioma or vascular malformation and its surgical removal is difficult because of its infiltrative nature and thus has high recurrence rate ( 90% ) .
therefore a precise histopathological diagnosis of angiomatosis is important to achieve a curative resection .
histopathologically it consists of proliferating blood vessels of varying caliber , infiltrating into the soft tissues .
proliferating capillaries are seen within or adjacent to major vessels .
few cases are reported in head and neck region .
this article highlights three unusual cases of angiomatosis reported as benign lesions , in rare sites such as the malar region ( predominantly infiltrating the adipose tissue ) , within the masseter ( predominantly infiltrating the muscle ) and in the mandible ( infiltrating the bone ) .
histopathological differential diagnosis is also discussed . |
PubmedSumm4885 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: cardiovascular disease ( cvd ) is the largest killer of women internationally . women often suffer inferior outcomes following an acute cardiac event as compared to men and are often diagnosed less promptly and treated less aggressively .
fewer women attend cardiac rehabilitation ( cr ) than men , despite its proven benefits to functioning and psychosocial wellbeing .
it has been argued that it is the older age at which women get cvd rather than gender issues that contribute to their worse outcomes .
however , it is impossible to discuss the context of women living with heart disease without considering a gendered approach . according to williams and kurina , of all the social determinants of health ,
a gendered approach considers the unique social , cultural , and economic circumstances that being a woman brings to the health encounter .
a focus on the reproductive health care needs of women is still prominent and there is a disregard for women 's health problems that still may be evident today .
they have more hypertension , diabetes , longer icu stays , and poorer outcomes .
this may be related to problems with referrals , women 's experiences , or their perceptions of themselves and their illness .
numerous studies suggest that women 's inferior health outcomes exist because women do not prioritise their own personal health needs . delaying seeking help for symptoms can have catastrophic implications for heart disease as there is an inverse relationship between time to accessing medical treatment at the onset of symptoms and health outcomes . despite this common assertion ,
few studies have attempted to identify reasons for women not prioritising their health , and as a consequence , there are fewer interventions targeting women specifically .
the success of the go red for women campaigns confers some optimism that if interventions are developed for women using a gendered approach within a social marketing framework , alterations in women 's experience in the illness trajectory of heart disease can be achieved .
the multiple roles enacted by many women , including wife , employee , and mother , are broadly considered beneficial to their health ; yet this is potentially mediated by socioeconomic circumstances . particularly for women experiencing socioeconomic deprivation or who are single parents , multiple roles
in addition to the aforementioned roles , women are twice as likely as men to assume unpaid caregiving responsibilities for young children , the elderly , the disabled , and mentally and physically ill family members and spouses and often this is in addition to other paid works [ 11 , 12 ] .
caregiving takes a toll on health and wellbeing , the effects of which can compound the disproportionate incidence of various chronic diseases in women . in a national representative survey of women 's health in the usa , one in four women caregivers rated themselves as being in poor or fair health .
more than half of these women had one or more chronic conditions compared to approximately 41% of the noncaregiver women .
women caregivers were also twice as likely to report a time in the past year when they did not get needed medical care in that time [ 12 , 14 ] . furthermore , schulz and beach found that being an older caregiver who is experiencing mental or emotional strain is an independent risk factor for mortality .
caregivers can be especially vulnerable in that they are significantly more likely to be in poor health and are more likely to report having difficulties getting needed medical care .
the stress of caregiving can render caregivers more susceptible to illness and health complications than other women . despite interacting with doctors and other medical professionals in a caregiver capacity ,
caregivers are less likely than other women to perceive and report difficulties in accessing medical care for themselves .
roles enacted by women entail demands on time and psychological , emotional , physical , and financial resources .
feelings of stress and being overwhelmed can result from an inability or a perceived inability to meet these demands and , as such , can tax coping skills . stress reactions can instigate physiological and behavioural changes that can increase risks for cardiovascular disease . attempting to fulfill these roles may impact on whether and how women attend to their own health including getting enough sleep , exercise , good nutrition , respite , and psychological and emotional support .
depression itself is a risk factor for cardiovascular disease and is associated with physiological and behavioural changes .
caregivers have been found to have significantly higher levels of depression and stress , and lower levels of general subjective wellbeing than noncaregivers , particularly in women . given that many female caregivers also have paid jobs , the strong evidence of job strain as a risk factor for cardiovascular disease in women suggests further detriment [ 20 , 21 ] .
furthermore , excessive household and family demands and low control at home predict coronary heart disease in women . for cr programs to be successful
, they must consider these issues that women face . in order to more fully understand the impact of the roles of women and how these impact on health , a questionnaire assessing women 's role perceptions was administered to participants of the heart awareness for women program ( hafw ) .
briefly , the hafw program was a nurse - facilitated mutual aid model cr program in which groups of 510 women met weekly for 6 weeks to learn about and discuss cvd in women , strategies for behavior change , social support , and coping with stress and change .
the aim of this paper is to describe women 's perceptions and experiences with caregiving and the different roles that comprise their lives in order to assist them to engage in strategies to address their health care needs .
women participating in a group cr program tailored to the needs of women at two hospitals in western sydney , australia , were asked to complete the women 's role inventory protocol - modified questionnaire as well as participate in group discussions .
the majority of these women had had an acute coronary syndrome event while a minority had coronary artery bypass grafting and chronic heart failure .
the women 's role interview protocol ( wrip ) was developed to determine the degree of stress and satisfaction derived from five traditional female gender roles including wife / partner , mother , housework , caregiver , and paid employee .
for each role , women were asked to rate their level of stress and satisfaction along a 10-point scale .
the stress ratings for each role ranged from 1 ( not stressful at all ) to 10 ( very stressful ) , and the satisfaction ratings for each role ranged from 1 ( not satisfying at all ) to 10 ( very satisfying ) .
the wrip - modified was used to facilitate group discussion about these issues as well as to guide the exploration of the impact of roles on health - seeking behaviours .
we assessed the impact of traditional gender roles on women 's recovery from an acute cardiac event and their capacity to address cardiovascular risk factor modification .
group discussion enabled women to freely comment on these topics to provide contextual information not captured by questionnaire items .
participants provided rationale for their ratings , often sharing examples from their daily lives .
fieldnotes containing dialogue and observations were recorded by two researchers facilitating the groups . the first level of analysis involved the two researchers separately interpreting proceedings by reading and note - taking .
the researchers then met to explore , debate , and synthesize their interpretations . during the final stage of analysis , themes which emerged from the qualitative findings
approval to undertake this study was granted by the area health service human research ethics committee and informed consent was obtained from all participants .
fifty - four women enrolled in the program and took part in discussions . of those , 45 participants completed the wrip - modified .
the mean age of participants was 60.85 years ( sd 9.1 ) with a range of 4280 years and the majority ( 71% ; n = 32 ) were married and living with their spouse or intimate partner . among the remainder of participants , 11% ( n = 5 ) were divorced , 20% ( n = 9 ) were widowed , and 14% ( n = 6 ) were living alone .
most participants had no children living at home , but 18% ( n = 8) had between 1 and 4 children , ranging in age from 1 to 48 years old , living with them .
eleven percent ( n = 5 ) of participants were caregivers for people living outside their homes .
participants in paid employment comprised 16% ( n = 7 ) of the sample and a further 7% ( n = 3 ) held volunteer positions in various organizations . as depicted in figure 1 , participants rated each of the five domains of the wrip - modified as more satisfying than stressful .
despite marked differences in perceptions of satisfaction and stress for the majority of roles , the spousal role was described as almost equally stressful and satisfying , a finding similar to that reported by meleis and stevens .
alternatively , motherhood was perceived as much more satisfying than stressful and potentially highlights an area of further research .
this was in contrast to the paid work role for which less satisfaction was reported .
although these domains were stressful to an extent , they also were satisfying , indicating that conceptualization of caregiving roles as always burdensome to women is inaccurate .
caregiving is often described in academic literature as informal , unpaid care provided to address an individual 's health needs or to support daily living activities .
participants in this study described their meaning of caregiving in broader terms . for them , caregiving was enacted within each of the five domains .
they provided care to children and grandchildren in their maternal role , their husbands in their spousal role , their family / household in their housework role , infirmed family and friends ( out of household ) in the caregiver role , and family / household in their employment role by contributing monetary resources . therefore , caregiving was not just about caring for a sick relative but rather was a part of every role they enacted in their lives .
participants valued and appreciated the connections these roles engendered with friends and families , the feeling of being needed and being useful , and the sense of purpose and meaning in their lives .
one woman described how doing household chores contributed to her self - esteem :
i know i do not have to do all that stuff , like cleaning windows but you know , it makes me feel good about myself .
i know i do not have to do all that stuff , like cleaning windows but you know , it makes me feel good about myself .
engaging in these multifaceted caregiving roles supported and contributed to some of the women 's self - esteem , self - concept , identity , and social ties .
this finding supports the multiple attachment hypothesis which asserts that these roles provide attachment to the community , a likely benefit to women 's health [ 26 , 27 ] .
alternatively , employment status of women and inequality in division of household tasks have been described as stressors in previous research .
one participant depicted how her husband 's attempts to alleviate what he perceived as strain from her daily life resulted in feelings of loss and despair .
following her heart attack , her husband insisted that he will do all the cooking and cleaning , activities that she previously enacted in the household :
he would not let me do anything .
although potentially well - intentioned , limiting his wife 's activities had negative psychological consequences for her .
she went on to describe being tearful , despairing , and depressed during this period .
approximately 1520% of patients have depression following a coronary event and this impacts on their quality of life and engagement in cr and other behavior change activities .
instances such as these contribute to our understanding of the complexities of the spousal relationship , particularly following this life event .
these findings have implications for health professional communication with not only patients but also their spouses and families regarding how best to support their loved one following this event and how to promote communication of needs within this partnership .
difficulties of managing multiple roles and incorporating advised exercise and stress minimisation strategies were discussed .
some women reported that they either did not attend or missed cr sessions due to caregiving activities or their concomitant effects of emotional or physical exhaustion .
although motherhood was described by some participants as rewarding in the form of reciprocated love and affection and a sense of satisfaction and connectedness , the following excerpts from different women depict less desirable outcomes :
i love taking care of my grandchildren and helping my kids get on their feet , but i get so tired .
i love taking care of my grandchildren and helping my kids get on their feet , but i get so tired .
in contrast to the previously discussed limiting of activities by family , more common were statements depicting the enduring expectations of children and family and the toll it takes as women continued to fulfill these roles , despite fatigue .
although giving support was apparently second nature to the participants , asking for help was perceived as more difficult .
some participants described not wanting to add to family members ' stress by disclosing physical symptoms or psychological burdens :
i did not want to worry anyone .
i did not want to worry anyone .
delaying seeking treatment for symptoms that may be related to cvd or waiting to see if symptoms will dissipate unassisted is dangerous and can result in irreparable damage or death .
several participants shared similar statements depicting caregiving roles as barriers to cvd management and risk factor modification , again highlighting implications for health professionals to intervene by raising awareness and assisting women to understand that only by taking care of themselves , they can take care of their families .
the small , convenience sample and the limited psychometric validation of the wrip are limitations of this study .
the instrument , however , was used not only to garner quantifiable levels of stress and satisfaction but also to extrapolate meaning and context of such perceptions .
this study is one of the few studies that has tried to unpack the notion of juggling multiple roles and discriminating between the positive and negative impacts of the caregiving role .
the burden of caregiving roles for women underscores the importance of addressing this factor in primary , secondary , and tertiary cardiovascular prevention strategies . in spite of the plethora of data relating to the negative effects of the caregiving role in women ,
in addition , there is commonly an emphasis on the negative impacts of caregiving , as reflected in instruments such as the caregiver strain index , so there is a need to develop better ways to conceptualise the construct , and to do so , we need to obtain women 's perspectives . on the basis of our work
it gives a sense of purpose , meaning and community connection as well as burden and conflict .
our intervention emphasized to women that without caring for themselves , their ability and capacity to undertake their caregiving role would be impaired , and therefore self - care enables caregiving .
women found that taking the time to address their own needs helped them achieve a sense of balance with their multiple roles . in many areas of women 's lives where they experience transition in roles , for example , motherhood and menopause , women derive benefit from connecting and communicating with other women .
we have found that in parallel with other settings , support from other women can assist in balancing the positive and negative aspects of caregiving . until recently
, heart disease has been perceived as a man 's disease and cardiovascular care has commonly focused on the needs of men .
emphasis must be placed on promoting strategies in women to achieve a balance between caregiving responsibilities and prioritisation of cardiovascular health , particularly as the altered population dynamics of ageing mean that women will comprise a higher proportion of the patient population for cardiology health professionals .
Output:
| cardiovascular disease is the largest killer of women internationally and women often suffer inferior outcomes following an acute cardiac event as compared to men .
a gendered approach to investigating cardiovascular disease in women incorporates the unique social , cultural , and economic circumstances that being a woman brings to the health encounter .
the multiple roles enacted by many women may be important factors in this health discrepancy . in order to more fully understand the impact of the roles of women on health , a questionnaire was administered to participants of the heart awareness for women group cardiac rehabilitation program which assessed women 's role perceptions followed by discussions .
we found that caregiving can be both positive and negative .
it gives a sense of purpose , meaning , and community connection as well as burden and conflict .
emphasis must be placed on promoting strategies in women to achieve a balance between caregiving responsibilities and prioritisation of cardiovascular health . |
PubmedSumm4886 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: clostridium perfringens , which was previously known as clostridium welchii , is a gram - positive , anaerobic , non - motile rod - shaped bacterium and is able to form environmentally resistant spores ( 1 ) .
this ubiquitous microorganism could be found in a variety of habitats such as soil , water and lower mammals and human intestine .
the bacterium can be found widely all over the world due to its genomic variation .
it produces numerous toxins which may cause various diseases such as diarrhea , necrotizing bowel disease and gas gangrene in humans as well as diarrhea , necrotic enteritis and fatal enterotoxemia in animals .
the bacterium produces 17 toxins from which epsilon is the major one ( 2 ) . c. perfringens has a circular chromosome of approximately 3.6 mbp with a low g+c content of approximately 25% ( 3 , 4 ) .
its genome includes extra chromosomal genetic elements in the form of plasmids and phages encoding mobile genes that vary in size and composition ( 5 , 6 ) . c. perfringens is a model for genetic engineering studies due to its striking physiological features ( 7 ) and several studies on the cloning and expression of its toxin genes
epsilon toxin is the third most potent clostridial toxin after botulinum and tetanus neurotoxins ( 8) and is active in a wide range of animal species and plays a central role in enterotoxemia of sheep and lambs ( 9 ) . in 1992
, epsilon toxin gene of c. perfringens type d had been cloned and expressed in e. coli .
studies have shown that the etx gene has 987bp and is located between base nucleotide 188 ( start codon ) and the stop codon at position 1174 ( 10 ) .
type d epsilon toxin gene of c. perfringens has been cloned and expressed and its n terminal 20 amino acids sequence has been determined ( 11 ) . the recombinant toxin has been strongly recognized by anti - native epsilon antibodies .
the antibodies against this recombinant toxin recognized the native epsilon toxin and neutralized its action in mice models ( 12 ) .
the recombinant type b and the native type d toxins have similar molecular weights and isoelectric points and both of them react with the specific monoclonal antibodies . in 2010 , etx gene was cloned and the potency of e. coli expressed recombinant epsilon toxoid was evaluated through administration to the goats , sheep and cattle .
numerous items can modify the current manufacturing procedure of clostridial vaccines and their efficiency but the biological process is often economically permanent .
thus , heterologous expression systems are good alternative tools for production of these toxins . in the present study , expression of epsilon toxin in e. coli rosetta(de3 )
c. perfringens type d vaccine strain ( cwd cn409 ) , e. coli top10f and rosetta ( de3 ) ( 14 ) strain were purchased from razi institute .
c. perfringens type d vaccine strain was cultured anaerobically in the liver extract medium using anoxomat chambers ( mart microbiology , netherlands ) at 37 c , ph 7.5 for 18 hours .
primers were designed for amplification of epsilon toxin encoding gene from c. perfringens genomic dna .
complete nucleotide sequence of etx gene was retrieved from the gene deposited in genbank under accession number hq179546 .
etx gene was amplified using pfu dna polymerase and specific forward ( 5-aatcatatgaaaaaaaatcttgtaaaaagt-3 ) and reverse primers ( 5-aatctcgagttttattcctggtgccttaat-3 ) including ndei and xhoi restriction sites , respectively .
linearized pjet1.2/blunt vector was ligated with amplified etx gene in order to develop the recombinant cloning vector , pjet. screening of recombinant e. coli top10 clones was done via colony pcr using universal sequencing primers .
identity of recombinant cloning vector , pjet , was confirmed thorough restriction digestion with ndei and xhoi enzymes ( fermentas ) .
sequencing analysis of the purified recombinant vector was also performed and blast and phylogenetic analysis was accomplished .
the expression vector , pet22b ( + ) , was digested with ndei and xhoi and ligated with etx gene digested from the cloning vector .
recombinant e. coli cells were inoculated into lb broth medium and incubated at 37 c to reach 0.60.7 od
600
.
final 0.5 mm iptg concentration was used to induce the expression of recombinant protein and bacterial incubation was continued for 18 hours . to optimize the expression of recombinant protein , different concentrations of iptg ( 0.5 , 1 and 1.5 mm ) ,
different incubation temperatures ( 25 , 31 and 37 c ) and times ( 3 , 6 and 18 h. ) were examined .
protein expression was analyzed by sds - page . to purify the recombinant epsilon protein which had a c - terminal his - tag ,
the bacterial pellet was re - suspended in lysis buffer and the cells were lysed by sonication on ice .
the cell lysate was centrifuged at 13 , 680( g ) and the clarified supernatant was loaded on ni - nta resin at the flow rate of 1 ml / min .
the column was washed with 5 volumes of washing buffer and finally the protein was eluted by adding elution buffer ( 17 ) .
c. perfringens type d vaccine strain ( cwd cn409 ) , e. coli top10f and rosetta ( de3 ) ( 14 ) strain were purchased from razi institute .
c. perfringens type d vaccine strain was cultured anaerobically in the liver extract medium using anoxomat chambers ( mart microbiology , netherlands ) at 37 c , ph 7.5 for 18 hours .
primers were designed for amplification of epsilon toxin encoding gene from c. perfringens genomic dna .
complete nucleotide sequence of etx gene was retrieved from the gene deposited in genbank under accession number hq179546 .
etx gene was amplified using pfu dna polymerase and specific forward ( 5-aatcatatgaaaaaaaatcttgtaaaaagt-3 ) and reverse primers ( 5-aatctcgagttttattcctggtgccttaat-3 ) including ndei and xhoi restriction sites , respectively .
linearized pjet1.2/blunt vector was ligated with amplified etx gene in order to develop the recombinant cloning vector , pjet. screening of recombinant e. coli top10 clones was done via colony pcr using universal sequencing primers .
identity of recombinant cloning vector , pjet , was confirmed thorough restriction digestion with ndei and xhoi enzymes ( fermentas ) .
sequencing analysis of the purified recombinant vector was also performed and blast and phylogenetic analysis was accomplished .
the expression vector , pet22b ( + ) , was digested with ndei and xhoi and ligated with etx gene digested from the cloning vector .
recombinant e. coli cells were inoculated into lb broth medium and incubated at 37 c to reach 0.60.7 od
600
.
final 0.5 mm iptg concentration was used to induce the expression of recombinant protein and bacterial incubation was continued for 18 hours . to optimize the expression of recombinant protein , different concentrations of iptg ( 0.5 , 1 and 1.5 mm ) ,
different incubation temperatures ( 25 , 31 and 37 c ) and times ( 3 , 6 and 18 h. ) were examined .
to purify the recombinant epsilon protein which had a c - terminal his - tag , the bacterial pellet was re - suspended in lysis buffer and the cells were lysed by sonication on ice .
the cell lysate was centrifuged at 13 , 680( g ) and the clarified supernatant was loaded on ni - nta resin at the flow rate of 1 ml / min .
the column was washed with 5 volumes of washing buffer and finally the protein was eluted by adding elution buffer ( 17 ) .
genomic dna of c. perfringens type d was extracted and used for pcr amplification of etx gene ( approximately 927 bp ) ( fig .
1 ) . colony pcr on top10 colonies containing the recombinant pjet cloning vector using etx forward and reverse primers confirmed the presence of a 927 bp dna fragment via 1% agarose gel electrophoresis ( fig .
2 ) . identity confirmation was done through restriction digestion with ndei and xhoi ( fig .
pcr on recombinant e. coli top10fcolonies containing pjet. lanes 111 : pcr products ( 927 bp ) ; lane 6:100 bpdna ladder .
lane1 : 100 bpdna ladder ; lane 2 : undigested vector ; lane 3 : digested pjet. double digested etx gene was purified using agarose gel extraction kit according to the manufacturer and its sequence was confirmed through sequencing .
subcloning of the gene into pet22b ( + ) expression vector was done and the recombinant vector was transformed into e. coli rosetta ( de3 ) strain .
iptg induction of protein expression was tested through sds - page analysis showing the expression of recombinant protein 3 h after induction ( fig .
the effect of different temperatures and incubation times , after iptg induction , on protein expression was significant ( figs . 6 and 7 ) .
lane 1 : protein molecular weight marker ; lane 2 : negative control ( e. coli rosettade3 strain containing empty pet22b+ ) ; lane 3 & 4 : recombinant e. coli strain before and after 3 h induction ; arrow indicates the recombinant epsilon toxin band .
lane1 : protein molecular weight marker ; lanes 24 : bacterial lysate 3h after induction with 0.5 , 0.1 and 1.5 mm iptg at 37 c ; lane 5 : bacterial lysate before induction ; lane 6 : negative control lysate ( e. coli rosetta containing empty pet22b+ ) ; arrow shows recombinant epsilon toxin band .
lane 1 : protein molecular weight marker ; lanes 24 : bacterial lysate at 25 , 31 and 37 c , 3 h after induction with 0.5 mm iptg ; lane 5 : bacterial lysate before induction ; lane 6 : negative control ( e. coli rosetta strain containing empty pet22b+ ) ; arrow shows recombinant epsilon toxin band . effect of time on expression of recombinant epsilon toxin .
lane1 ; protein molecular weight marker ; lanes 24 : bacterial lysate after 3 , 6 and 18h after induction with 0.5 mm iptg ; lane 5 : bacterial lysate before induction ; lane6 : negative control ( e. coli rosetta containing empty pet22b+ ) .
purified protein appeared as an approximately 35 kda protein on sds - page and western blot using sheep primary and anti - sheep hrp conjugated secondary antibody ( fig .
( a ) sds - page analysis of purified protein ; lane 1 : protein molecular weight marker ; lane 2 : bacterial lysate 3hours after induction ; lane 3 : purified epsilon toxin ; ( b ) western blot analysis of purified protein ; lane 4 : protein molecular weight marker ; lane 5 : western blot of the purified recombinant epsilon toxin .
genomic dna of c. perfringens type d was extracted and used for pcr amplification of etx gene ( approximately 927 bp ) ( fig .
1 ) . colony pcr on top10 colonies containing the recombinant pjet cloning vector using etx forward and reverse primers confirmed the presence of a 927 bp dna fragment via 1% agarose gel electrophoresis ( fig .
2 ) . identity confirmation was done through restriction digestion with ndei and xhoi ( fig .
pcr on recombinant e. coli top10fcolonies containing pjet. lanes 111 : pcr products ( 927 bp ) ; lane 6:100 bpdna ladder .
lane1 : 100 bpdna ladder ; lane 2 : undigested vector ; lane 3 : digested pjet.
double digested etx gene was purified using agarose gel extraction kit according to the manufacturer and its sequence was confirmed through sequencing .
subcloning of the gene into pet22b ( + ) expression vector was done and the recombinant vector was transformed into e. coli rosetta ( de3 ) strain .
iptg induction of protein expression was tested through sds - page analysis showing the expression of recombinant protein 3 h after induction ( fig .
different concentrations of iptg had no significant effect on protein expression ( fig . 5 ) .
the effect of different temperatures and incubation times , after iptg induction , on protein expression was significant ( figs . 6 and 7 ) .
lane 1 : protein molecular weight marker ; lane 2 : negative control ( e. coli rosettade3 strain containing empty pet22b+ ) ; lane 3 & 4 : recombinant e. coli strain before and after 3 h induction ; arrow indicates the recombinant epsilon toxin band .
lane1 : protein molecular weight marker ; lanes 24 : bacterial lysate 3h after induction with 0.5 , 0.1 and 1.5 mm iptg at 37 c ; lane 5 : bacterial lysate before induction ; lane 6 : negative control lysate ( e. coli rosetta containing empty pet22b+ ) ; arrow shows recombinant epsilon toxin band .
lane 1 : protein molecular weight marker ; lanes 24 : bacterial lysate at 25 , 31 and 37 c , 3 h after induction with 0.5 mm iptg ; lane 5 : bacterial lysate before induction ; lane 6 : negative control ( e. coli rosetta strain containing empty pet22b+ ) ; arrow shows recombinant epsilon toxin band .
lane1 ; protein molecular weight marker ; lanes 24 : bacterial lysate after 3 , 6 and 18h after induction with 0.5 mm iptg ; lane 5 : bacterial lysate before induction ; lane6 : negative control ( e. coli rosetta containing empty pet22b+ ) .
purified protein appeared as an approximately 35 kda protein on sds - page and western blot using sheep primary and anti - sheep hrp conjugated secondary antibody ( fig .
( a ) sds - page analysis of purified protein ; lane 1 : protein molecular weight marker ; lane 2 : bacterial lysate 3hours after induction ; lane 3 : purified epsilon toxin ; ( b ) western blot analysis of purified protein ; lane 4 : protein molecular weight marker ; lane 5 : western blot of the purified recombinant epsilon toxin .
in spite of using traditional methods in production of effective vaccines , large scale production of such vaccines from different clostridium species needs high safety conditions and precise quality control steps .
therefore , production of these candidate vaccines in a safe host is beneficial ( 19 ) .
recombinant dna technology has enabled researchers to produce vaccines for diseases which could not be treated using the traditional methods such as infections caused by c. perfringens species ( 19 ) . c. perfringens is a potent pathogen because of its ability to generate several toxins . in this study pjet1.2 blunt vector was used due to its advantages over the other available ta cloning vectors .
blunt ends of this vector avoided self - ligated vector products ( 16 , 17 ) . in this study ,
the recombinant vector was used in dna sequencing , protein expression or gene expression functional analysis . in a previous study , souza and
the colleagues cloned etx gene in pet11a expression vector and expressed the recombinant epsilon toxin as inclusion bodies which were successfully used in animal immunization ( 12 ) .
toxicity of the fusion epsilon - beta gene of c. perfringens types d and b revealed that toxigenesis of vaccine strains is one of the factors playing an important role in the effectiveness of the designed vaccines ( 17 ) .
this finding made us to select c. perfringens vaccine strain ( cwd cn409 ) for the present study . in 2010 , a vaccine candidate containing detoxified recombinant epsilon toxin and aluminum hydroxide as the adjuvant was developed and co - administered with sheep pox vaccine to sheep and it was shown that sheep were being protected against both sheep pox and enterotoxemia ( 20 ) . in the present study , experimental optimizations revealed that different concentrations of iptg have no obvious effect on the level of protein expression .
our findings revealed that different temperatures and incubation times had significant effects on the expression of epsilon toxin protein as optimal thermal condition was 37 c and the highest yield of the recombinant protein was achieved 6h after iptg induction .
this study enabled us to express recombinant vaccine candidates indicating the possibility of prevention of clostridial diseases through manufacturing vaccine candidates under safer conditions and lesser costs .
Output:
| background and objectives : clostridium perfringens , a gram - positive obligate anaerobic bacterium , is able to form resistant spores which are widely distributed in the environment .
c. perfringens is subdivided into five types a to e based on its four major alpha , beta , epsilon and iota toxins .
the aim of the present study was cloning and expression of c. perfringens type d vaccine strain epsilon toxin gene.materials and methods : genomic dna was extracted and the epsilon toxin gene was amplified using pfu dna polymerase . the pcr product was cloned into pjet1.2/blunt cloning vector . the recombinant vector ( pjet ) was sequenced using universal primers . at the next step epsilon toxin gene was subcloned into pet22b(+ ) expression vector and transformed into e. coli rosetta ( de3 ) host strain.results:the recombinant protein has been expressed in e. coli rosetta ( de3 ) cells after subcloning of c. perfringens etx gene ( 1008 bp ) into the expression vector.conclusion:we concluded that e. coli rosetta strain was suitable for the expression of recombinant c. perfringens epsilon toxin protein from pet22 expression vector . this recombinant cell can be used for further research on recombinant vaccine development . |
PubmedSumm4887 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: coronary heart disease ( chd ) is the second leading cause of death among chinese adults now - a - day .
health - related quality of life ( hrqol ) is useful for assessing the socio - economic impact and burden of illness , effectiveness of interventions and treatments , and long - term mortality among patients after a cardiac event .
so far , only a few studies assessed the hrqol of chinese chd patients , yielding inconsistent results .
the purpose of this study was to evaluate hrqol outcomes of chd patients in china using european quality of life 5-dimensions ( eq-5d ) questionnaire and identify important hrqol factors for this special population .
this was a cross - sectional study conducted from august to october , 2010 in rural communities of fangshan district , beijing , china , using a stratified cluster sampling technique .
eligible subjects are native residents aged 40 years or older living locally for at least 5 years , with a confirmed diagnosis of myocardial infarction or angina by a class - two or higher hospital with electrocardiography findings , or a surgical history of coronary revascularization , coronary artery bypass or coronary stent implantation .
subjects who were unable to answer the questionnaire and take part in physical examination personally were excluded .
all questionnaires were administered through personal interview , information collected on socio - demographic characteristics ( age , sex , marital status , educational level , the family 's population , household income per month ) , lifestyle factors ( physical activity , cigarette smoking and alcohol consumption ) and comorbidities , including hypertension , type 2 diabetes mellitus ( t2 dm ) and stroke .
marital status is divided into married and unmarried ( including single , divorced or widowed ) .
past smokers were those who had smoked more than 100 cigarettes in the past but had quit smoking during the last month .
current smokers were those who had smoked at least 100 cigarettes and had smoked during the last month .
past drinking was defined as consuming alcohol at least once a week in the past but not in the previous month .
current drinking was defined as drinking at least once per week and still drank at that frequency in the previous month .
the average daily intake of current drinkers was calculated by dividing the total weekly amount of pure alcohol by 7 days . according to the daily intake of alcohol , current drinkers
were categorized into four groups : low , moderate , high , and very high group ( for men 40 , 4160 , 61100 and > 100 g / d , for women 20 , 2140 , 4160 and > 60
physical activity was defined as performing physical exercise for at least 30 min at least once per week during the previous 6 months , not including housework or job - related work .
the frequency of physical activity was measured as : rarely / never , 14 times / week or 5 times / week .
household income per month ( in renminbi , rmb ) was classified as 3000 rmb or higher , 20002999 rmb , 15001999 rmb , and < 1500 rmb for first- to fourth - class rural areas , respectively .
classification for body mass index ( bmi ) was : underweight as bmi 18.5 , normal weight as bmi 18.524.9 , overweight as bmi 25.029.9 and obesity as bmi 30.0 .
subjects were defined as having hypertension if they were taking antihypertensive medications and/or having systolic blood pressure ( bp ) 140 mmhg , or diastolic bp 90 mmhg .
subjects were considered as having t2 dm if they had been diagnosed as t2 dm in hospitals , or self - reported current treatment with insulin or oral hypoglycemic drugs .
subjects were defined as having a stroke if they had a history of language or physical dysfunction continuing for more than 24 h and diagnosed using computerized tomography or magnetic resonance imaging .
body weight was measured without heavy clothes and shoes to the nearest 0.1 kg by a calibrated weighing scale and height was measured barefoot using a fixed stadiometer to the nearest 0.1 cm .
bmi is calculated as the ratio of weight to height squared ( kg / m ) .
health - related quality of life was measured by the eq-5d scales , developed by the euroqol group ( www.euroqol.org ) , well - validated and reliable in different cultures and various diseases including cardiac disease .
the eq-5d descriptive system consists of five dimensions of health on mobility , self - care , usual activities , pain / discomfort , and anxiety / depression .
each dimension has three levels of response ( no problems , moderate problems , and severe problems ) , level 1 ( no problems ) was coded as a 1 and level 2 ( moderate problems ) was coded as a 2 and level 3 ( severe problems ) was coded as a 3 . for example , state 11111 indicates no problems on any of the 5 dimensions .
the eq-5d index score was generated by applying societal preference weights to each of the above five health dimensions according to a japan population - based time trade - off model and was calculated by adding up the weighted scores for all five dimensions .
european quality of life 5-dimensions also includes a separate 20 cm eq visual analog scale ( eq - vas ) to measure self - assessed health status .
respondents were asked to indicate how good or bad his / her own health state on the day of assessment on a 100-point scale , the end - points of which were labeled best imaginable health state and worst imaginable health state anchored at 100 and 0 ( rather like a thermometer ) , respectively .
this information can be used as a quantitative measure of health as judged by the individual respondents .
the compliance with drug treatment was evaluated in chd patients by the morisky - green test , which is a 4-item medication adherence questionnaire ( maq ) containing the following questions : ( 1 ) have you ever forgotten to take your medicines ? ( 2 ) were you careless at times about taking your medicines ? ( 3 ) when you felt better , did you sometimes stop taking your medicines ?
( 4 ) sometimes , if you felt worse , did you stop taking your medicines ?
score 1 for answering no to each of four questions and 0 for choosing yes .
score equal to four points means good compliance and score less than four points means poor compliance .
health quality was measured by eq-5d index and eq - vas scores and compared using one - way anova or t - test among groups defined by sex , age , education level , marital status , household income per month , family 's population , bmi , physical activity , smoking status , drinking status , comorbidities , compliance with drug treatment and the five dimensions of eq-5d .
the dimensions of eq-5d were dichotomized as no problems versus moderate / severe problems .
continuous variables were presented as the means with standard deviations , and categorical variables were presented as percentages .
stepwise multiple linear regression and unconditional logistic regression were used to explore the determinants of health quality using sex , age , education level , marital status , monthly household income , family 's population , bmi , physical activity , smoking status , alcohol drinking , comorbidities , compliance with drug treatment and duration of chd as independent variables .
odds ratios ( ors ) and 95% confidence intervals ( cis ) were obtained from logistic regression analysis .
analyses were performed using spss version 22.0 ( ibm corp . , armonk , ny , usa ) , a p < 0.05 as statistically significant .
this was a cross - sectional study conducted from august to october , 2010 in rural communities of fangshan district , beijing , china , using a stratified cluster sampling technique .
eligible subjects are native residents aged 40 years or older living locally for at least 5 years , with a confirmed diagnosis of myocardial infarction or angina by a class - two or higher hospital with electrocardiography findings , or a surgical history of coronary revascularization , coronary artery bypass or coronary stent implantation .
subjects who were unable to answer the questionnaire and take part in physical examination personally were excluded .
all questionnaires were administered through personal interview , information collected on socio - demographic characteristics ( age , sex , marital status , educational level , the family 's population , household income per month ) , lifestyle factors ( physical activity , cigarette smoking and alcohol consumption ) and comorbidities , including hypertension , type 2 diabetes mellitus ( t2 dm ) and stroke .
marital status is divided into married and unmarried ( including single , divorced or widowed ) .
past smokers were those who had smoked more than 100 cigarettes in the past but had quit smoking during the last month .
current smokers were those who had smoked at least 100 cigarettes and had smoked during the last month .
past drinking was defined as consuming alcohol at least once a week in the past but not in the previous month .
current drinking was defined as drinking at least once per week and still drank at that frequency in the previous month .
the average daily intake of current drinkers was calculated by dividing the total weekly amount of pure alcohol by 7 days .
according to the daily intake of alcohol , current drinkers were categorized into four groups : low , moderate , high , and very high group ( for men 40 , 4160 , 61100 and > 100 g / d , for women 20 , 2140 , 4160 and > 60
physical activity was defined as performing physical exercise for at least 30 min at least once per week during the previous 6 months , not including housework or job - related work .
the frequency of physical activity was measured as : rarely / never , 14 times / week or 5 times / week .
household income per month ( in renminbi , rmb ) was classified as 3000 rmb or higher , 20002999 rmb , 15001999 rmb , and < 1500 rmb for first- to fourth - class rural areas , respectively .
classification for body mass index ( bmi ) was : underweight as bmi 18.5 , normal weight as bmi 18.524.9 , overweight as bmi 25.029.9 and obesity as bmi 30.0 .
subjects were defined as having hypertension if they were taking antihypertensive medications and/or having systolic blood pressure ( bp ) 140 mmhg , or diastolic bp 90 mmhg .
subjects were considered as having t2 dm if they had been diagnosed as t2 dm in hospitals , or self - reported current treatment with insulin or oral hypoglycemic drugs .
subjects were defined as having a stroke if they had a history of language or physical dysfunction continuing for more than 24 h and diagnosed using computerized tomography or magnetic resonance imaging .
body weight was measured without heavy clothes and shoes to the nearest 0.1 kg by a calibrated weighing scale and height was measured barefoot using a fixed stadiometer to the nearest 0.1 cm .
bmi is calculated as the ratio of weight to height squared ( kg / m ) .
health - related quality of life was measured by the eq-5d scales , developed by the euroqol group ( www.euroqol.org ) , well - validated and reliable in different cultures and various diseases including cardiac disease .
the eq-5d descriptive system consists of five dimensions of health on mobility , self - care , usual activities , pain / discomfort , and anxiety / depression .
each dimension has three levels of response ( no problems , moderate problems , and severe problems ) , level 1 ( no problems ) was coded as a 1 and level 2 ( moderate problems ) was coded as a 2 and level 3 ( severe problems ) was coded as a 3 .
for example , state 11111 indicates no problems on any of the 5 dimensions .
the eq-5d index score was generated by applying societal preference weights to each of the above five health dimensions according to a japan population - based time trade - off model and was calculated by adding up the weighted scores for all five dimensions .
european quality of life 5-dimensions also includes a separate 20 cm eq visual analog scale ( eq - vas ) to measure self - assessed health status .
respondents were asked to indicate how good or bad his / her own health state on the day of assessment on a 100-point scale , the end - points of which were labeled best imaginable health state and worst imaginable health state anchored at 100 and 0 ( rather like a thermometer ) , respectively .
this information can be used as a quantitative measure of health as judged by the individual respondents .
the compliance with drug treatment was evaluated in chd patients by the morisky - green test , which is a 4-item medication adherence questionnaire ( maq ) containing the following questions : ( 1 ) have you ever forgotten to take your medicines ? ( 2 ) were you careless at times about taking your medicines ? ( 3 ) when you felt better , did you sometimes stop taking your medicines ? ( 4 ) sometimes , if you felt worse , did you stop taking your medicines ?
score 1 for answering no to each of four questions and 0 for choosing yes .
score equal to four points means good compliance and score less than four points means poor compliance .
health quality was measured by eq-5d index and eq - vas scores and compared using one - way anova or t - test among groups defined by sex , age , education level , marital status , household income per month , family 's population , bmi , physical activity , smoking status , drinking status , comorbidities , compliance with drug treatment and the five dimensions of eq-5d .
the dimensions of eq-5d were dichotomized as no problems versus moderate / severe problems .
continuous variables were presented as the means with standard deviations , and categorical variables were presented as percentages .
stepwise multiple linear regression and unconditional logistic regression were used to explore the determinants of health quality using sex , age , education level , marital status , monthly household income , family 's population , bmi , physical activity , smoking status , alcohol drinking , comorbidities , compliance with drug treatment and duration of chd as independent variables .
odds ratios ( ors ) and 95% confidence intervals ( cis ) were obtained from logistic regression analysis .
, armonk , ny , usa ) , a p < 0.05 as statistically significant .
there were 1989 eligible chd patients , of whom 1928 completed the questionnaires , aged 4088 ( mean age 61.64 9.24 ) years , 29.4% men and 70.6% women , and were enrolled for further analysis , with a response rate of 96.9% .
duration of chd ranged from 1 to 44 ( median 3 , 2575 percentiles 27 ) years .
the mean score of eq-5d index was 0.889 0.172 , eq - vas score 71.56 17.65 . among the five domains of hrqol , anxiety / depression problem occurred in the lowest proportion of 7.9% patients , whereas pain / discomfort problem took the largest proportion of 24.3% .
study variables and the hrqol scores of chd subjects were presented and compared as shown in table 1 . although sex , comorbidity of hypertension , and compliance with drug treatment had no association with either eq-5d index or eq - vas scores ( p > 0.05 ) , significant associations were observed among other demographic and related variables ( p < 0.05 ) .
relationship between study variables and hrqol of chd patients * p<0.05 ; p<0.01 ; p<0.001 .
bmi : body mass index ; hrqol : health - related quality of life ; chd : coronary heart disease ; eq-5d : european quality of life 5-dimensions ; sd : standard deviation ; eq - vas : european quality of life visual analog scale .
multiple linear regression results in table 2 show that older age and stroke were negatively associated with a low eq-5d index .
physical activity , household income per month , alcohol drinking , and family 's population were positively related to high eq-5d index .
being married , physical activity , alcohol drinking , and family 's population were positively relevant with improving eq - vas scores .
stepwise multiple linear regression analysis for the determinants of hrqol in chd patients * p<0.05 ; p<0.01 ; p<0.001 .
b : standard error of regression coefficient ; hrqol : health - related quality of life ; chd : coronary heart disease ; eq - vas : european quality of life visual analog scale ; eq-5d : european quality of life 5-dimensions .
logistic regression was performed for the five dimensions of eq-5d to determine dimension - specific factors related to hrqol .
ors , 95% ci and p values are presented in table 3 . compared to patients of age
< 50 years , patients of age 80 years had more problems in mobility ( or = 3.236 ) , usual activities ( or = 3.440 ) , pain / discomfort ( or = 2.802 ) , and anxiety / depression ( or = 6.935 ) .
patients aged 7079 years met with more problems in usual activities ( or = 2.151 ) , whereas patients of 5059 or 6069 years experienced more problems in anxiety / depression ( or = 2.934 and or = 3.379 , respectively ) .
compared to patients with normal weight , obese patients ( bmi 30 kg / m ) had more problems in mobility ( or = 1.632 ) and pain / discomfort ( or = 1.633 ) , whereas underweight patients ( bmi 18.5 kg / m ) had more problems in pain / discomfort ( or = 2.431 ) .
patients with stroke were more likely to exhibit problems in self - care ( or = 2.121 ) , usual activities ( or = 1.976 ) and mobility ( or = 1.465 ) , whereas patients with diabetes mellitus were more likely to have problems in anxiety / depression ( or = 1.774 ) .
physical activity had positive effects on mobility ( 14 times / week : or = 0.462 ; 5 times / week : or = 0.495 ) , self - care ( 14 times / week : or = 0.457 ; 5 times / week : or = 0.354 ) , usual activities ( 14 times / week : or = 0.332 ; 5 times / week : or = 0.475 ) and pain / discomfort ( 14 times / week : or = 0.517 ; 5 times / week : or = 0.760 ) .
patients living with 2 , 35 or > 6 family members experienced less problems in mobility ( or = 0.505 , or = 0.318 and or = 0.424 , respectively ) .
past smoking had negative effects on mobility ( or = 1.983 ) , self - care ( or = 2.592 ) , usual activities ( or = 2.613 ) and pain / discomfort ( or = 1.971 ) .
low- , medium- , and high - alcohol drinking were associated with less problems in mobility ( or = 0.373 , or = 0.286 and or = 0.097 , respectively ) .
past and medium alcohol drinkers had less problems in self - care ( or = 0.276 and or = 0.193 , respectively ) .
high education level was protective factors for self - care ( or = 0.575 ) . compared to patients with monthly household income < 1500 rmb ,
patients with 20002999 or 3000 rmb reported less problems in usual activities ( or = 0.505 and or = 0.430 , respectively ) , those with 20002999 rmb suffering less pain / discomfort ( or = 0.544 ) . logistic regression analysis for dimension - specific factors related to hrqol in chd patients
hrqol : health - related quality of life ; chd : coronary heart disease ; bmi : body mass index ; or : odds ratio ; ci : confidence interval .
several studies indicated that smoking , increasing age , lower education level , less household income , and comorbid stroke or diabetes mellitus were related to deteriorated hrqol of chd patients , which was similar to our study .
this is inconsistent with previous studies which showed worse hrqol of female chd patients compared to male patients and may be partly due to a skewed sex ratio ( male 29.4% , female 70.6% ) in our study population , as a result of most skilled men working away in other cities , which is a common phenomenon in rural china .
so far , the relationship between bmi and quality of life in patients with chd has not been particularly well - illustrated .
several studies have shown that being overweight or obese ( bmi 25 kg / m ) was associated with greater survival in coronary artery disease patients compared to normal or ideal
kg / m ) had more problems in mobility ( or = 1.632 , p = 0.014 ) and pain / discomfort ( or = 1.633 , p = 0.006 ) , similar to previous reports which suggested that hrqol was impaired in chd patients with obesity compared to patients with a normal bmi .
our results also indicated that underweight patients ( bmi 18.5 kg / m ) reported more problems in pain / discomfort ( or = 2.431 , p = 0.022 ) and exhibited the worst eq-5d index in comparison to normal and overweight patients .
this discrepancy may be attributed to different body composition among the study population , as well as effects of body fat and fat - free mass on hrqol .
previous studies have demonstrated a j- or u - shaped association between alcohol drinking and the risk of chd . however , not all the studies replicated such type of association . in our study , certain alcohol drinking was related to better hrqol , as patients with medium or high drinking had less problems in mobility , self - care and usual activities , consistent with previous reports .
a recent study revealed that moderate alcohol intake related to improved hdl - cholesterol , fibrinogen and markers of glucose metabolism , implicating reduced chd risk of moderate drinkers .
heavy and binge drinking were also associated with favorable levels of chd biomarkers , and this may be a possible explanation for the negative relationship between alcohol drinking and chd risk .
first , the study used a cross - sectional design and could not show the effects of changes in demographic and related factors over time on hrqol and provide causal information .
we focused on the quality of life of chd patients and a control group without chd was not included .
second , because of data availability , we were unable to obtain treatments received for chd , cardiac function , revascularization method and other clinical factors that may influence hrqol .
third , there are more women than men in our study and selection bias may occur since generally men are affected more by chd than women .
the strength of our study lies in its focus on the hrqol of chd patients in china and was carried out in representative residents of the rural northern han chinese .
our data will be useful for future research in this field , and may provide more valuable information on hrqol in patients with chd when combined with other questionnaires , for example , questionnaires of seattle angina questionnaire , social support scale , and self - rating depression scale . in summary
, this study suggests that older age , comorbid diabetes mellitus and stroke , obesity , underweight , less income , living alone , smoking , less physical activity , and lower education level are negative correlates of impairment of hrqol in chd patients . being married , having more physical activity , moderate alcohol drinking and big family are protective factors for hrqol in chd patients .
clinicians could pay more attention to chd patients with these characteristics so as to optimize care and improve quality of life in this special population .
further large - scale cohort studies should be conducted to confirm our results in the future .
Output:
| background : although coronary heart disease ( chd ) is one of the major cardiovascular diseases , risk factors associated with the health - related quality of life ( hrqol ) of chd patients remain unclear .
the present study was designed to determine the profile and significant factors of the hrqol in chd patients.methods:a cross - sectional study was conducted in rural communities of fangshan district , beijing , china . socio - demographic , lifestyle , and comorbidity information of chd patients
were collected by a structured questionnaire and medical records .
hrqol was measured using european quality of life 5-dimensions ( eq-5d ) scale and eq visual analog scale ( eq - vas ) .
multiple linear and logistic regressions were performed to explore the association of potential risk factors with hrqol scores and each eq-5d , respectively.results:totally , 1928 chd patients ( mean age 61.64 9.24 years ; female : male = 2.4:1 ) were enrolled in the study .
the mean score of eq-5d index and eq - vas were 0.889 0.172 and 71.56 17.65 , respectively .
multiple linear regression revealed that marital status , physical activity , moderate alcohol drinking , and family 's population were positive independent correlates of eq - vas , whereas diabetes mellitus and stroke were negative independent correlates ( all p < 0.05 ) .
age and stroke were negatively while physical activity , moderate alcohol drinking , family 's population and household income were positively correlated with eq-5d index ( all p < 0.05 ) independently .
in addition , each of the five hrqol dimensions had various specific determinants , including obesity , underweight , smoking or education.conclusions:findings of the study highlight certain socio - demographic , lifestyle factors , and comorbid stroke or diabetes mellitus as correlates of hrqol in chinese chd patients .
large - scale cohort studies should be carried out to confirm our results in the future . |
PubmedSumm4888 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: infantile hemangiomas ( ihs ) are common , benign vascular tumors of infancy , 5060% of which affect the head and neck area .
although usually innocuous and self - limiting , they can cause serious complications such as airway compromise , visual loss , severe anemia , and high - output cardiac failure . till recently , treatment modalities included steroids , bleomycin , vincristine , etc .
reported the effect of propranolol in ihs , which provoked a paradigm shift in its management .
however , important questions remain unanswered , and doubts exist among clinicians regarding use in neonates and small infants , optimal dose , duration of treatment , monitoring for side effects , resolution rate , and long - term follow - up .
we present a 2-month - old male infant with extensive hemangioma , involving the face , orbit , buccal mucosa , and palate with potential life - threatening complications of airway compromise , aspiration of blood , and loss of vision which we treated with high - dose propranolol under the strict monitoring and had rapid , excellent response with no side effects .
a 2-month - old male infant presented with the complaints of red patch over the entire right side of the face and right side of the palate .
the baby was unable to open the right eye due to the involvement of the right upper eyelid and had difficult in breastfeeding due to the involvement of the upper lip .
there were no other lesions elsewhere on the body and no associated symptoms of bleeding , airway compromise , or cardiovascular complications .
examination revealed a large 10 cm 12 cm bright red hemangioma involving the right hemiface , including the right orbit , the right half of upper lip , [ figure 1 ] and extending intraorally to involve the right buccal mucosa , the right half of uvula and mucosa of right half of hard , and soft palate .
( a and b ) large , bright red hemangioma involving the right hemiface , including the right frontotemporal region , right orbit , right cheek , and right half of the upper lip blood investigations were normal .
magnetic resonance imaging showed a t1-iso , t2-hyperintense 15 mm 15 mm 15 mm lesion in the extraconal , and conal space of the right orbit with postcontrast intense homogenous enhancement suggestive of low - flow vascular malformation .
magnetic resonance - angiogram showed prominent branches of the right middle meningeal and lacrimal branches of the right ophthalmic arteries [ figure 2 ] .
( a ) magnetic resonance imaging showing t1-iso , t2-hyperintense 15 mm 15 mm 15 mm lesion ( white arrow ) in extraconal and conal space of right orbit ( b ) magnetic resonance - angiogram showing prominent branches of the right middle meningeal and right ophthalmic arteries ( yellow arrows ) oral propranolol was planned after explaining risks and benefits to the parents .
pretreatment evaluation involved a thorough personal and familial history for atopy , asthma , recurrent wheezing , and elaborate clinical examination for multiple hemangiomas , electrocardiography , blood pressure , and blood glucose levels .
after hospital admission , propranolol was initiated at 2 mg / kg body - weight / day as a single oral dose with hourly monitoring of heart rate , respiratory rate , and blood pressure . to avoid the potential side effect of hypoglycemia with propranolol ,
it was administered soon after feeding , and blood glucose was measured after 4 h of the first dose and then 12 hourly for 2 days .
rapid response was observed within 48 h evident by the immediate cessation of growth , softening , and fading of erythema [ figure 3 ] .
baby was discharged after 48 h with detailed instructions regarding dose , administration after feeds , warning signs ( wheeze , lethargy , etc .
, ) , and to bring the child immediately if any of the signs noted .
( a ) response at 48 h evident by cessation of growth , softening , and fading of erythema ( b ) 2 weeks : paleness of lesion and decrease in bulkiness of right upper eyelid ( c ) 2 months : facial and orbital lesions decreased more than 30% and able to open right eye with ease ( d ) 7 months : complete disappearance of the orbital hemangioma and normal eye movements ( e ) 8.5 months : near - total ( ~95% ) resolution with excellent cosmesis and no residual scarring the baby was followed up in the outpatient clinic for the 1 month on a 2-weekly basis , then onward at a monthly interval .
significant response was noted at 2 weeks with paleness of the lesion and disappearance of about 25% of the oral lesions .
the baby was also able to open the right eye and even feed easily . by 2 month
, oral ( palatal and buccal ) lesions completely disappeared with no residual scar while the facial and orbital lesions decreased more than 30% . at 4-month follow - up
, there was 50% resolution and at 7-month , there was complete disappearance of the orbital hemangioma and normal eye movements . at 8.5 months , there is near - total ( ~95% ) resolution with 100% parental satisfaction , excellent cosmesis , and no residual scarring [ figure 3 ] .
gradual tapering and stoppage of propranolol is planned over next 2 months with continued monthly surveillance for 6 more months for any relapse .
infantile capillary hemangiomas are benign vascular tumors with typical clinical course , characterized by rapid proliferative phase in early infancy , followed by an involutional phase .
female : male ratio is 3:15:1 with higher incidence in prematurity , low birth - weight , placentary anomalies and multiple pregnancies .
ihs present as small tumors at birth or first 23 months too , proliferate during 1 year ( most prominent growth during first 46 months ) , and involute over 57 years . as a thumb - rule , 50% of ihs involute by 5 years , 70% by 7 years of age , and remaining
even after involution , permanent residues may present as scars , telangiectasia , or redundant skin .
while most are innocuous and spontaneously resolving , some ihs can cause major complications such as airway compromise , serious visual loss through induction of strabismic , deprivational , or anisometropic astigmatism , severe anemia , kasabach meritt syndrome , and high - output cardiac failure .
feeding difficulties due to oral hemangiomas can lead to poor sucking as was noted in our patient or bleeding during sucking resulting in malnutrition and anemia in infants causing extreme parental anxiety .
various pharmacological agents such as steroids ( systemic or intralesional ) , interferon , vincristine , bleomycin , cyclophosphamide , or imiquimod have been used in the treatment of ih with no single uniformly safe and effective treatment .
the report about the impressive effect of propranolol in treating ihs provoked a paradigm shift in their management with several reports since then .
one explanation is the induction of vasoconstriction , which is immediately visible as a change in color , and palpable softening of the hemangioma .
beta - blockers could also influence signal - transduction - pathway of angiogenic factors ( basic fibroblast - growth - factor , vascular - endothelial - growth - factor , thereby effecting the proliferative phase .
propranolol 's ability to trigger apoptosis in capillary endothelial cells in rat lung tissue might also be applicable to hemangioma endothelial cells . in a large systematic review of ihs treated with propranolol , marqueling et al . reported the most common adverse events as changes in sleep and acrocyanosis seen in 11.4% and 5.1% patients and rare incidence of serious adverse events such as symptomatic hypotension in 0.4% , hypoglycemia in 0.3% , and symptomatic bradycardia in 0.08% patients , respectively .
likewise , restless sleep , constipation , and cold extremities were also observed by de graaf et al .
but they concluded that side effects such as symptomatic hypoglycemia , hypotension , and bronchial hyperreactivity that needed intervention and/or close monitoring were infrequent and not dose - dependent .
xu et al . noted that fluctuations from the normal range of cardiovascular parameters occurred frequently with initiating propranolol , but were clinically asymptomatic .
similarly , our patient also did not develop any major or minor side effects despite initiating a relatively higher dose of propranolol .
it has also been suggested quite wisely that as propranolol may blunt clinical features of hypoglycemia , it should be avoided in neonates in their 1 week of life when symptomatic hypoglycemia is more likely to develop .
reviewed ihs of the airway and concluded that while propranolol was effective in 90% of the cases , 8.6% patients were classified as nonresponders .
nearly 9.8% patients relapsed while weaning of propranolol or after discontinuation , and 1.2% cases appeared resistant to re - initiation of therapy . despite several reports since 2008 , , , even now several doubts exist among clinicians regarding use in neonates and small infants , dosing and duration , monitoring for side effects , and parental counseling .
further research should focus on the optimal treatment protocol , optimal dose range , duration of treatment , resolution rate , predictors of relapse , long - term follow - up , and the actual percentage of nonresponders .
nevertheless , only a minority of patients with life - threatening situations or severe functional impairment require active medical intervention .
administering systemic medication to an infant with a benign condition requires careful consideration and should be advised only by experienced clinicians trained in handling neonates and infants .
close monitoring of the babies is required , considering the risk of serious side effects , relapse , and resistance to propranolol .
the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s )
has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal .
the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .
the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s )
has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal .
the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .
Output:
| infantile hemangiomas ( ihs ) are common , benign vascular tumors of infancy , with more than half affecting the head and neck region .
ihs involving the lips and oral cavity can often present to the oral surgeon and the pedodontist . till date ,
several doubts exist among clinicians regarding the use of propranolol to treat infantile hemangiomas in neonates and small infants , appropriate dose , treatment duration , side effects , response , and long - term follow - up .
we present a 2-month - old male infant with extensive hemangioma involving the face , orbit , buccal mucosa and palate with feeding difficulties , and risk of life - threatening complications such as airway compromise , aspiration , and visual loss which showed excellent response with high - dose propranolol and had no side effects .
we also reviewed literature for the mechanism of action of propranolol and possible minor and serious side effects . |
PubmedSumm4889 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: a 15-year - old adolescent ( weight , 46 kg ; height , 162 cm ) had a medical history of hypertension , cyclic headache , and vomiting for 10 years without an awareness of his medical condition .
thereafter , he demonstrated a seizure with subcortical ich in the left frontal area 6 weeks before the surgery .
he was diagnosed with pheochromocytoma as confirmed by excessive catecholamine production in his serum and urine .
the computed tomography scan revealed two masses ( dimension , 4.0 3.5 cm , and 1.6 1.2 cm ) in the left adrenal gland .
preoperative preparation consisted of terazosin 1 mg , losartan 1.25 mg , atenolol 25 mg , and levetiracetam 1 g daily for 2 weeks , which resulted in symptomatic improvement , normotension and prevention of seizure . before entering the operating room , 2 mg of midazolam
was infused and dexmedetomidine was given 1 g / kg over 10 min at the waiting area , followed by a continuous intravenous infusion at 0.5 g / kg / hr . on arrival to the operating room ,
the intraoperative monitoring consisted of electrocardiogram ( lead ii ) , hr , pulse oximeter , end - tidal co2 , bispectral index , esophageal temperature , invasive measurement of bp with cardiac index , central venous pressure , central venous oxygen saturation , and urine output .
arterial blood gases , electrolytes , glucose , and serum catecholamines were planned to check before induction and after intubation , tumor manipulation , and removal of tumors .
general anesthesia was induced with propofol 100 mg , continuous infusion of dexmedetomidine , remifentanil 0.2 g / kg / min and sevoflurane 2.0 vol% by mask .
anesthesia was maintained with a 2.5% end - tidal concentration of sevoflurane in an oxygen - air mixture ( fio2 = 0.50 ) and infusion of remifentanil 0.1 g / kg / min and dexmedetomidine
however , when the surgeon began to manipulate it , bp and hr were abruptly increased ( fig .
those changes were controlled with bolus injection of remifentanil , nicardipine , esmolol , and sodium nitroprusside .
remifentanil , nicardipine , and sodium nitroprusside were also used to put back his vitals to baseline .
after tumor removal , bp decreased rapidly , which responded to ephedrine and phenylephrine to produce an increase in systolic bp of 80 - 100 mmhg .
dexmedetomidine and remifentanil were stopped at closure of peritoneum and at end of skin closure , respectively .
after extubation , the patient was mildly sedated but had good respiration and possible purposeful movement .
the total operation time was 200 min , and the total period of anesthesia was 285 min . estimated blood loss was about 200 ml and the total dose of infused dexmedetomidine was 144 g .
after the surgery , he stayed at the intensive care unit for 1 day and was discharged 10 days after the surgery with no noticeable complications and events .
the anesthetic management for maintaining stable cardiovascular response during the resection of pheochromocytoma is still an unsolved assignment to the anesthetist . during the operation , catecholamine level increase of up to 200,000 - 1,000,000 pg / ml ( normal catecholamine levels under stressful events : 200 - 2,000 pg / ml ) ,
because our patient had an episode of seizure and ich only 6 weeks before the surgery , we had to concentrate on keeping his bp under our control to avoid neurologic complications .
dexmedetomidine is a highly selective alpha-2 adrenoceptor agonist compared with clonidine , especially for the 2a subtype .
they are located on blood vessels , where they mediate vasoconstriction , and on sympathetic terminals , where they inhibit noradrenaline release .
alpha-2 adrenoceptors are also located within the central nervous system , and their activation leads to sedation , a 60 - 80% reduction of tonic levels of sympathetic outflow and catecholamines , and an augmentation of cardiac - vagal activity .
dexmedetomidine attenuates sympathoadrenal responses to tracheal intubation and surgical stimuli and has a significant anesthetic and analgesic sparing effect when used intraoperatively .
additionally , dexmedetomidine has recently been investigated for its potential in many other clinical scenarios , including neuroprotection , cardioprotection and renoprotection , with promising results .
the pharmacokinetics of remifentanil is characterized by small volume of distribution , rapid clearance , and short context - sensitive half - time .
prompt onset and short duration of action make remifentanil a useful selection for the suppression of the transient sympathetic nervous system response to tracheal intubation and noxious stimuli in at risk patients . although remifentanil is effective for blunting the sympathetic response , there were reports that even if remifentanil was being infused in pheochromocytoma excision to control intraoperative hemodynamic instability , the use of vasodilators was required during tumor manipulations . although our anesthetic team assumed that the combination of dexmedetomidine and remifentanil might produce additional hypotensive agents to be unnecessary , we actually infused low dose of esmolol , sodium nitroprusside and nicardipine when bp surges came up during tumor manipulation .
because one of masses was placed difficult to dissect , the surgeon had a hard time manipulating the tumors before ligation of the adrenal vein .
there are some reports on serum plasma catecholamine levels during the resection of pheochromocytoma , which show wide variation depending on what stimuli had been done to the patient . in comparison , our patient 's levels of catecholamine ( table 1 ) represented persistent decreasing trend except with epinephrine , which means that infusion of dexmedetomidine and remifentanil might interrupt the release of norepinephrine effectively during the procedure .
russell et al . , in a retrospective analysis of a group of adult patients , found a significant correlation between intraoperative cardiovascular instability and peak serum catecholamine levels measured at the time .
. also showed a significant correlation between plasma norepinephrine concentration and mean arterial pressure during surgery .
bryskin and weldon reported that the infusion of dexmedetomidine and magnesium sulfate in their case was effective for stable hemodynamics , with the pattern of steadily decreasing catecholamine levels following intubation .
therefore , we presume that the decreasing trend of catecholamine levels could help to diminish sudden fluctuating changes of hemodynamics . in conclusion , the levels of perioperative catecholamines demonstrate that the combination of dexmedetomidine and remifentanil was an effective manner to achieve safe anesthesia in our patient .
the optimal intra - operative dosing and timing of dexmedetomidine and remifentanil remain to be determined , and a further study in this setting is needed .
Output:
| a 15-year - old adolescent with unilateral multiple adrenal pheochromocytoma had an episode of subcortical intracerebral hemorrhage and seizure 6 weeks before the surgery .
he was pretreated with terazosin , losartan , atenolol and levetiracetam for 2 weeks .
dexmedetomidine was started in the preoperative waiting area , and a combination of dexmedetomidine and remifentanil was continuously infused for most of anesthetic time . to control blood pressure , bolus injection of remifentanil and low - dose infusion of sodium nitroprusside , nicardipine , and esmolol were administered during three adrenergic crises .
there was minimal post - resection hypotension , and his trachea was extubated safely 20 min after the surgery .
he was discharged without noticeable complication .
his catecholamine levels showed the steadily decreasing pattern during the operation in this case .
though a combination of dexmedetomidine and remifentanil may not prevent the hemodynamic instability impeccably during the tumor manipulation , this combination seems to be the way of interrupting release of catecholamines and minimizing hemodynamic fluctuations . |
PubmedSumm4890 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: due to its significant ability to up - regulate or acquire resistant determinants , there are serious challenges associated with choosing and monitoring appropriate antibiotic treatments ( 1 ) . although carbapenems are generally considered to be the most promising antibiotic to use against acinetobacter baumannii , the increasing resistance to treatment with carbapenems may lead to limitations od their use and effectiveness in some cases
. the use of unconventional antibiotics , such as the polymyxins , rifampicin , and tetracyclines has been described , but there are little data on in vitro antibiotic susceptibilities of these agents ( 2 ) .
colistin appears to be very effective against multidrug - resistant ( mdr ) a. baumannii isolates in vitro ; however , it is not used extensively in treatment because of side effects , such as neurotoxicity and nephrotoxicity ( 3 ) .
colistin is now considered as the last line of treatment against mdr acinetobacter infections , but there are still reports of these infections being resistant to colistin .
the mechanism of colistin resistance is the modification of the lipid a of the outer lipopolysaccharide ( lps ) membrane .
more recently , it has been identified that mutations in pmra and pmrb and complete loss of lps production may mediate colistin resistance by a. baumannii ( 4 ) .
a new glycycline , tigecycline also was found to have an excellent in - vitro activity against a. baumannii isolates .
tigecycline was licensed for use in the united states and latin america in 2005 , and it was licensed in canada , europe , the asia / pacific region , and the middle east in 2006 and 2007 ( 5 ) .
tigecycline is a substrate for the ade abc efflux pump system , and resistance to it can be mediated by efflux or ribosomal protection ( 6 ) .
tetracycline - resistant bacteria are often sensitive to tigecycline , and a broad spectrum of activity has been demonstrated against gram - negative bacteria , even extended - spectrum b - lactamase ( esbl)producing escherichia coli and klebsiella pneumonia ( 7 ) .
increasing carbapenem resistance among a. baumannii isolates has led clinicians to look for new treatment alternatives .
many carbapenemase - producing a.baumannii isolates are also resistant to all available antibiotics except polymyxins .
tigecycline , which is active against most carbapenemase - producing strains , may be a useful alternative to polymyxins ( 3 ) , but very little data have been published on the anti - microbial resistance among isolates of acinetobacter species to colistin and tigecycline .
the knowledge of changes in the resistance rates of bacteria in our local hospitals will improve empirical therapy .
since the mobility of the population is a risk factor for the distribution of antimicrobial , drug resistant organisms , this study was conducted to evaluate the in vitro activity of tigecycline and colistin against clinical isolates of a. baumannii in hospitals of tehran and bandar - abbas , two cities in iran that have many immigrants .
the study was conducted from march 2009 to november 2010 at hospitals in tehran and bandar - abbas , iran .
the clinical acinetobacter isolates were identified by conventional methods ( 8) , stored in sterile trypticase soy broth with 30% glycerol , and preserved at 70 c .
acinetobacter isolates were collected from affected patients , ( i.e. , sputum , urine , cerebrospinal fluid , ascites , and pleural effusion ) .
all isolates were subjected to pcr to detect the blaoxa-51-like gene that is unique to the acinetobacter baumannii species ( 9 ) .
the pcr assay was conducted using the primer bla
oxa-51-like ( 353bp 5 f- taa tgc ttt gat cgg cct tg-3 and 5 r - tgg att gca ctt cat ctt gg-3 ) .
pcr reactions were conducted in 25-l reaction volumes with 3 l of extracted dna , 10 pmol of each primer , and 0.2 l of 500 u taq dna polymerase in 10x pcr buffer containing 1 mm mgcl2 and 0.5 l of a 25-mm solution of deoxynucleoside triphosphate .
conditions for the pcr were 95 c for 4 min and then 34 cycles at 95 c for 45 s , 34 cycles at 52 c for 45 s , and 34 cycles at 72 c for 30 s. this was followed by a final extension at 72 c for 10 min ( 10 ) .
the susceptibility tests for tigecycline and colistin were performed in the microbiology laboratory at tarbiat modares university using the disk agar diffusion ( dad ) method , as recommended by the clinical and laboratory standards institute ( 11 ) .
since no interpretive criteria have been approved for tigecycline against acinetobacter species , the results were interpreted by the criteria ( s 16 mm ; i = 1315 mm ; r 12 mm ) recommended by jones et al .
fda for enterobacteriaceae , i.e. , s 19 mm ; i = 1518 mm ; r 14 mm ) ( tygacil package insert [ june , 2005 ] , wyeth pharmaceuticals , inc . ,
we collected the data of the antibiogram pattern of the a. baumannii isolates to commonly - used antibiotics , e.g. , imipenem , ciprofloxacin , amikacin , cefepime , ceftazidime , and polymyxin - b .
the susceptibility testing of these antibiotics was performed by the disk diffusion method on mueller - hinton agar plates .
the study was conducted from march 2009 to november 2010 at hospitals in tehran and bandar - abbas , iran .
the clinical acinetobacter isolates were identified by conventional methods ( 8) , stored in sterile trypticase soy broth with 30% glycerol , and preserved at 70 c .
acinetobacter isolates were collected from affected patients , ( i.e. , sputum , urine , cerebrospinal fluid , ascites , and pleural effusion ) .
all isolates were subjected to pcr to detect the blaoxa-51-like gene that is unique to the acinetobacter baumannii species ( 9 ) .
the pcr assay was conducted using the primer bla
oxa-51-like ( 353bp 5 f- taa tgc ttt gat cgg cct tg-3 and 5 r - tgg att gca ctt cat ctt gg-3 ) .
pcr reactions were conducted in 25-l reaction volumes with 3 l of extracted dna , 10 pmol of each primer , and 0.2 l of 500 u taq dna polymerase in 10x pcr buffer containing 1 mm mgcl2 and 0.5 l of a 25-mm solution of deoxynucleoside triphosphate .
conditions for the pcr were 95 c for 4 min and then 34 cycles at 95 c for 45 s , 34 cycles at 52 c for 45 s , and 34 cycles at 72 c for 30 s. this was followed by a final extension at 72 c for 10 min ( 10 ) .
the susceptibility tests for tigecycline and colistin were performed in the microbiology laboratory at tarbiat modares university using the disk agar diffusion ( dad ) method , as recommended by the clinical and laboratory standards institute ( 11 ) .
since no interpretive criteria have been approved for tigecycline against acinetobacter species , the results were interpreted by the criteria ( s 16 mm ; i = 1315 mm ; r 12 mm ) recommended by jones et al .
fda for enterobacteriaceae , i.e. , s 19 mm ; i = 1518 mm ; r 14 mm ) ( tygacil package insert [ june , 2005 ] , wyeth pharmaceuticals , inc . ,
we collected the data of the antibiogram pattern of the a. baumannii isolates to commonly - used antibiotics , e.g. , imipenem , ciprofloxacin , amikacin , cefepime , ceftazidime , and polymyxin - b .
the susceptibility testing of these antibiotics was performed by the disk diffusion method on mueller - hinton agar plates .
this study included 165 acinetobacter isolates that were collected from hospitals in tehran and bandar - abbas .
one hundred and fifty - seven isolates ( 95.15% ) that gave a band for blaoxa-51-like identified as a.baumannii , figure ( 1 ) .
thirty - four isolates were from bandar - abbas , and 123 were from tehran .
nine of the isolates were from sputum ( 5.7% ) , 25 were from pus ( 15.1% ) , 12 were from urine ( 7.64% ) , four were from cerebrospinal fluid ( 2.54% ) , two were from ascites ( 1.27% ) , two were from ears ( 1.27% ) , three were from catheters ( 1.9% ) , 24 were from burn wounds ( 15.28% ) , and 84 were from pleural effusion ( 53.5% ) .
the quantities of isolates related to wards were as follows : among the isolates 114(72.6% ) were from intensive care unit , 26 ( 16.56% ) were from internal ward , 9 ( 5.73% ) were from surgical ward , 3 ( 1.9% ) from neaurosurgery ward , 2 ( 1.27% ) from pediatric ward , 7 ( 4.45% ) from emergency unit , 1 ( 1.9% ) from coronary care unit , and 2 ( 2.27% ) from ear , nose , and throat ward .
for the two cities , table 1 shows the results of susceptibility to tigecycline and compares the susceptibility rates of the isolates to eight antibiotics .
a high prevalence of multi - drug resistance by a. baumannii limits the therapeutic options for the treatment of infections caused by these bacteria .
it is clear that new drugs are needed for the treatment of mdr a. baumannii . in some studies
, tigecycline has been found to be active in about 87 to 93% in of acinetobacter species ( 3 ) . in our study , according to the jones criteria , the susceptibility rate to tigecycline in the hospital in tehran was 66.7% , and it was 76.5% in the hospital bandar - abbas . however , based on the fda criteria , the rates were 24.2% in tehran and 23.5% in bandar - abbas .
all isolates ( 100% ) were susceptible to colistin and polymyxin b. several studies have reported the susceptibility to colistin as 98 to 100% ( 3 ) .
first , the u.s . food and drug administration ( fda ) has not assigned tigecycline breakpoints for acinetobacter species , and no interpretive criteria are currently available ( 7 ) . the u.s .
fda - approved breakpoints of tigecycline were defined against enterobacteriaceae , and the diameter of the inhibition zone is 19 mm and mic 2 mg / l ( 14 ) .
fda - approved breakpoint of tigecycline against enterobacteriaceae was not applicable to tigecycline against a. baumannii .
the breakpoint for an inhibition zone diameter of 13 mm was more accurate in predicting the susceptibility of a. baumannii to tigecycline with a sensitivity of 99% and a specificity of 100% ( 15 ) . in bouchillon
s study , tigecycline was the most active drug against all species of acinetobacter ( 7 ) .
the tigecycline mic90 of 2 g / ml was 16-fold and 64-fold more potent than the b - lactams and carbapenems , respectively , against all tested strains .
tigecycline was 8-fold and 16-fold more potent against acinetobacter species than levofloxacin and doxycycline , respectively ( 7 ) .
a taiwanese study showed that the overall susceptibility rate of a. baumannii to tigecycline was 80.9% .
the rates of susceptible , intermediate , and resistant isolates by the disk diffusion method , using the criteria of jones et al .
, were 88.3 , 9.9 , and 1.8% , whereas they were 44.0 , 51.7 , and 4.3% by the u.s .
fda s criteria . by comparison with their previous report on tigecycline activity against a. baumannii
isolates in taiwan , they observed a seven - fold increase ( from 3% in 2003 to 20% in 2007 ) in the number of a. baumannii isolates that are not susceptible to tigecycline ( 13 ) .
since the most probable resistance mechanism for tigecycline in a. baumannii is the presence of an efflux pump mechanism , exposure to sub - therapeutic levels of tigecycline for even short periods of time may promote the rapid emergence of tigecycline resistance and cause therapeutic failure . in our study ,
a possible explanation for increased tigecycline resistance was the exposure to multiple antibiotics in our hospitals in which the efflux systems of these strains already are highly active .
the disk diffusion method is the most commonly used ( > 90% ) susceptibility method in our hospitals , since automated susceptibility test systems are not available in most microbiology laboratories .
it appeared to be a good option in the treatment of mdr a. baumannii , but adverse reactions limit its extensive use .
however , colistin resistance is rare worldwide at the current time , which likely reflects its very limited use .
colistin - resistant isolates have recently been identified in several gram - negative species , such as a. baumannii , klebsiella pneumoniae , and p. aeruginosa ( 4 )
. only sporadic cases of colistin resistance have been reported in the literature in clinical isolates of patients admitted to the icus of an argentinian university hospital .
the findings of this study showed that colistin and polymyxin - b still show the highest potency against a.baumannii in our hospitals .
however , the resistance of a.baumannii to tigecycline may limit their use in the future . the broad - spectrum in vitro activity of tigecycline and colistin
may make them a suitable candidate for use in the empirical treatment of serious infections .
however , it should be noted that in vitro data do not equate to clinical efficacy , and resistance rates should be monitored continuously .
finding cases of resistance to tigecycline suggests an efflux - based mechanism , and further work is ongoing to elucidate this mechanism .
Output:
| background : the acinetobacter species , particularly a. baumannii , has emerged as one of the main causes of nosocomial infections in recent years . the high prevalence of drug resistance in a. baumannii limits the therapeutic options for treating infections caused by these bacteria .
the objective of this study was to determine the in vitro activity of tigecycline and colistin against clinical isolates of a. baumannii in tehran and bandar abbas , iran.methods:this study was conducted from march 2009 to november 2010 at three hospitals in tehran and bandar abbas , iran , using 165 acinetobacter species isolated from clinical specimens .
all isolates were subjected to pcr to detect blaoxa-51-like genes that are unique to acinetobacter baumannii .
isolates that gave a band for the blaoxa-51-like genes were identified as a. baumannii .
anti - microbial susceptibility tests were performed for tigecycline , colistin , and other antibiotics.results:sensitivity rates to colistin and polymyxin - b were 100% .
resistance rates for tigecycline were 4.2% in tehran and 8.8% in bandar - abbas according to jones criteria , whereas , according to u.s .
fda criteria , the resistance rates were 20.8% and 17.6% , respectively.conclusions:new alternative drugs are needed for the treatment of drug resistant a. baumannii .
although colistin appears to be a good choice , adverse reactions have limited its usage .
tigecycline is effective against a. baumannii isolates , and it shows promise for solving the problem . |
PubmedSumm4891 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: before the introduction of diffusion tensor imaging ( dti ) , accurate evaluation of the ascending reticular activating system ( aras ) in the live human brain was limited .
recently , diffusion tensor tractography ( dtt ) , which is derived from dti , has enabled 3-dimensional reconstruction and estimation of the aras in the human brain . as a result
, a few recent studies using dtt have reported on injury of the aras in patients with severe traumatic brain injury ( tbi ) . however , no study on injury of the aras in patients with mild tbi has been reported .
the pathogenetic mechanism of post - traumatic fatigue and hypersomnia has not been clearly elucidated , although several studies have suggested an injury of the brainstem or aras . in the present study , using dtt , we report on patients with post - traumatic fatigue and hypersomnia who showed injury of the dorsal ( between the pontine reticular formation [ rf ] and the intralaminar thalamic nucleus [ iln ] ) and ventral ( between the pontine rf and the hypothalamus ) lower portion of the aras following mild tbi .
two patients were enrolled according to the following inclusion criteria : ( 1 ) loss of consciousness ( loc ) for 30 min or less , post - traumatic amnesia ( pta ) for < 24 h and glasgow coma scale ( gcs ) score of 13 to 15 recorded 30 min postinjury or later upon presentation for health care , ( 2 ) notify hypersomnia and fatigue since the onset of tbi , ( 3 ) no visible lesion on t1-weighted , t2-weighted , fluid attenuated inversion recovery , and t2-weighted gradient recall echo images , and ( 4 ) no history of previous head trauma .
all patients provided signed , informed consent , and yeungnam university hospital institutional review board approved the study protocol .
patient 1 was a 51-year - old woman who had suffered head trauma resulting from a car accident . while driving her sedan , the driver side of her car collided with a mini - bus ; consequently , her head hit the car seat .
the patient showed loc ( 5 min ) or pta ( 10 min ) at the time of head trauma , and her gcs was 15 when she arrived at the hospital .
at the time of dti scanning ( 11 months after onset ) , she showed abnormalities as 6.9 ( cut off : 3.7 points ) and 18 ( cut off : 10 ) , respectively , on the fatigue severity scale and the epworth sleepiness scale .
patient 2 was a 64-year - old woman who had suffered head trauma resulting from a car accident .
while driving in a passenger seat of a sedan , her car was hit from front by a sedan . as a result ,
her gcs score was 15 when she arrived at the hospital . at the time of dti scanning ( 3 months after onset ) , she showed abnormalities on the fatigue severity scale and the epworth sleepiness scale with 6.8 ( cut off : 3.7 points ) and 19 ( cut off : 10 ) , respectively .
diffusion tensor imaging data were acquired at 11 months ( patient 1 ) and 3 months ( patient 2 ) after onset of head trauma using a 1.5 t with 32 noncollinear diffusion sensitizing gradients by single - shot echo - planar imaging .
imaging parameters were as follows : acquisition matrix = 96 96 ; reconstructed to matrix = 192 192 ; field of view = 240 240 mm ; tr = 10,398 ms ; te = 72 ms ; parallel imaging reduction factor = 2 ; echo - planar imaging factor = 59 ; b = 1000 s / mm ; and a slice thickness of 2.5 mm .
the oxford centre for functional magnetic resonance imaging of the brain ( fmrib ) software library was used for analysis of dti data .
fmrib diffusion software with routines option ( 0.5 mm step lengths , 5000 streamline samples , curvature thresholds = 0.2 ) was used for fiber tracking .
three portions of the aras were reconstructed by selection of fibers passing through region of interest ( roi ) as follows : the dorsal lower aras , between the pontine rf ( roi 1 ) and the iln ( roi 2 ) , the ventral lower aras , between the pontine rf ( roi 1 ) and the hypothalamus ( roi 2 ) , and the upper aras , in which the neural connectivity of the iln ( roi 1 ) to the cerebral cortex was analyzed . the tract volume and the narrowest area of dorsal and ventral lower aras were measured by counting voxels . in both patients , the upper aras in which the neural connectivity of the iln to the cerebral cortex did not show significant abnormalities .
however , we observed the narrowing of the left dorsal lower aras between the pontine rf and the iln in both patients and the tearing ( patient 1 ) and narrowing ( patient 2 ) of the left ventral lower aras between the pontine rf and the hypothalamus .
the tract volume of the dorsal and ventral lower aras were 280/322 ( right ) and 149/172 ( left ) voxels in the patient 1 , and 320/201 ( right ) and 185/49 ( left ) voxels in the patient 2 .
in addition , compared with the right hemisphere ( 100% ) , the narrowest area of left hemisphere in the dorsal and ventral lower aras on an axial slice were as follows the patient 1 : 7 voxels ( 29.2% , right : 24 voxels ) and 11 voxels ( 26.8% , right : 41 voxels ) , and the patient 2 : 15 voxels ( 33.3% ) , right : 45 voxels ) and 3 voxels ( 15% , right:20 voxels ) ( figure 1 ) .
( a ) t2-weighted brain mr images at 11 months ( patient 1 ) and 3 months ( patient 2 ) after onset show no abnormal lesion .
the narrowing ( red arrows ) of the left dorsal lower ascending reticular activating system ( aras ) between the pontine reticular formation and intralaminar thalamic nucleus in both patients , and the tearing ( patient 1 , green arrow ) and narrowing ( patient 2 , green arrows ) of the left ventral lower aras between the pontine reticular formation and the hypothalamus are observed compared with the right side of each patient and both sides of a normal subject ( 45 year - old woman ) .
aras = ascending reticular activating system , dtt = diffusion tensor tractography , iln = intralaminar thalamic nucleus , mr = magnetic resonance , prf = pontine reticular formation .
two patients were enrolled according to the following inclusion criteria : ( 1 ) loss of consciousness ( loc ) for 30 min or less , post - traumatic amnesia ( pta ) for < 24 h and glasgow coma scale ( gcs ) score of 13 to 15 recorded 30 min postinjury or later upon presentation for health care , ( 2 ) notify hypersomnia and fatigue since the onset of tbi , ( 3 ) no visible lesion on t1-weighted , t2-weighted , fluid attenuated inversion recovery , and t2-weighted gradient recall echo images , and ( 4 ) no history of previous head trauma .
all patients provided signed , informed consent , and yeungnam university hospital institutional review board approved the study protocol .
patient 1 was a 51-year - old woman who had suffered head trauma resulting from a car accident . while driving her sedan , the driver side of her car collided with a mini - bus ; consequently , her head hit the car seat .
the patient showed loc ( 5 min ) or pta ( 10 min ) at the time of head trauma , and her gcs was 15 when she arrived at the hospital .
at the time of dti scanning ( 11 months after onset ) , she showed abnormalities as 6.9 ( cut off : 3.7 points ) and 18 ( cut off : 10 ) , respectively , on the fatigue severity scale and the epworth sleepiness scale .
patient 2 was a 64-year - old woman who had suffered head trauma resulting from a car accident .
while driving in a passenger seat of a sedan , her car was hit from front by a sedan . as a result ,
her gcs score was 15 when she arrived at the hospital . at the time of dti scanning ( 3 months after onset )
, she showed abnormalities on the fatigue severity scale and the epworth sleepiness scale with 6.8 ( cut off : 3.7 points ) and 19 ( cut off : 10 ) , respectively .
diffusion tensor imaging data were acquired at 11 months ( patient 1 ) and 3 months ( patient 2 ) after onset of head trauma using a 1.5 t with 32 noncollinear diffusion sensitizing gradients by single - shot echo - planar imaging .
imaging parameters were as follows : acquisition matrix = 96 96 ; reconstructed to matrix = 192 192 ; field of view = 240 240 mm ; tr = 10,398 ms ; te = 72 ms ; parallel imaging reduction factor = 2 ; echo - planar imaging factor = 59 ; b = 1000 s / mm ; and a slice thickness of 2.5 mm .
the oxford centre for functional magnetic resonance imaging of the brain ( fmrib ) software library was used for analysis of dti data .
fmrib diffusion software with routines option ( 0.5 mm step lengths , 5000 streamline samples , curvature thresholds = 0.2 ) was used for fiber tracking .
three portions of the aras were reconstructed by selection of fibers passing through region of interest ( roi ) as follows : the dorsal lower aras , between the pontine rf ( roi 1 ) and the iln ( roi 2 ) , the ventral lower aras , between the pontine rf ( roi 1 ) and the hypothalamus ( roi 2 ) , and the upper aras , in which the neural connectivity of the iln ( roi 1 ) to the cerebral cortex was analyzed .
the tract volume and the narrowest area of dorsal and ventral lower aras were measured by counting voxels . in both patients , the upper aras in which the neural connectivity of the iln to the cerebral cortex did not show significant abnormalities .
however , we observed the narrowing of the left dorsal lower aras between the pontine rf and the iln in both patients and the tearing ( patient 1 ) and narrowing ( patient 2 ) of the left ventral lower aras between the pontine rf and the hypothalamus .
the tract volume of the dorsal and ventral lower aras were 280/322 ( right ) and 149/172 ( left ) voxels in the patient 1 , and 320/201 ( right ) and 185/49 ( left ) voxels in the patient 2 .
in addition , compared with the right hemisphere ( 100% ) , the narrowest area of left hemisphere in the dorsal and ventral lower aras on an axial slice were as follows the patient 1 : 7 voxels ( 29.2% , right : 24 voxels ) and 11 voxels ( 26.8% , right : 41 voxels ) , and the patient 2 : 15 voxels ( 33.3% ) , right : 45 voxels ) and 3 voxels ( 15% , right:20 voxels ) ( figure 1 ) .
( a ) t2-weighted brain mr images at 11 months ( patient 1 ) and 3 months ( patient 2 ) after onset show no abnormal lesion . ( b )
the narrowing ( red arrows ) of the left dorsal lower ascending reticular activating system ( aras ) between the pontine reticular formation and intralaminar thalamic nucleus in both patients , and the tearing ( patient 1 , green arrow ) and narrowing ( patient 2 , green arrows ) of the left ventral lower aras between the pontine reticular formation and the hypothalamus are observed compared with the right side of each patient and both sides of a normal subject ( 45 year - old woman ) .
aras = ascending reticular activating system , dtt = diffusion tensor tractography , iln = intralaminar thalamic nucleus , mr = magnetic resonance , prf = pontine reticular formation .
in the present study , using dtt , we evaluated the 3 portions of the aras : the upper aras in which the neural connectivity of the intralaminar thalamic nucleus to the cerebral cortex , the dorsal lower aras , between the pontine rf and the iln , and the ventral lower aras , between the pontine rf and the hypothalamus .
we found that the dorsal and ventral lower aras was torn or narrowed in both patients .
the post - traumatic fatigue and hypersomnia in these patients might be mainly attributed to the injury of the left dorsal and ventral lower aras . since introduction of dti ,
a few studies have reported on injury of the aras in patients with tbi . in 2013 ,
edlow et al ( 2013 ) reported on a patient with coma following severe tbi who showed complete disruption of white matter pathways connecting brainstem arousal nuclei to the basal forebrain and thalamic nuclei , and partial disruption of the pathways connecting the thalamus and basal forebrain to the cerebral cortex .
jang et al ( 2015 ) recently demonstrated recovery of the injured lower portion of the aras between the pontine rf and the iln in a patient with severe tbi . on the other hand , descending reticular activating system , which is involved in the generation of movement using mediating the spinal motoneurons , could also be related to the state of consciousness . in 2013 , tapia et al suggested that arousal state was related to muscular activation which was mediated by the descending reticular activating system .
therefore , to the best of our knowledge , this is the first study to demonstrate injury of the lower portion of the aras between the pontine rf and the iln in patients with mild tbi .
first , because it is a case report , this study is limited ; therefore , conduct of further studies comprising a large number of patients would be necessary .
second , despite being a powerful anatomic imaging tool , because regions of fiber complexity and crossing can prevent full reflection of the underlying fiber architecture , dti may underestimate or overestimate the fiber tracts . in conclusion , this study demonstrated injuries of the dorsal and ventral lower portions of the aras in patients with fatigue and hypersomnia following mild tbi .
we believe that these injuries of the aras might be a pathogenetic mechanism of fatigue and hypersomnia in patients with tbi .
Output:
| abstractwe report on patients with post - traumatic fatigue and hypersomnia who showed injury of the lower portion of the ascending reticular activating system ( aras ) between the pontine reticular formation ( rf ) and the intralaminar thalamic nucleus ( iln ) following mild traumatic brain injury ( tbi ) , using diffusion tensor tractography ( dtt).two patients with mild tbi resulting from a car accident were enrolled in this study .
patient 1 was a 51-year - old woman showed abnormalities as 6.9 ( cut off : 3.7 points ) and 18 ( cut off : 10 ) on the fatigue severity scale and the epworth sleepiness scale at 11 months after onset .
patient 2 was a 64-year - old woman who revealed abnormalities on the fatigue severity scale and the epworth sleepiness scale with 6.8 and 19 at 3 months after onset.in both patients , the upper aras in which the neural connectivity of the iln to the cerebral cortex did not show significant abnormalities .
however , we observed the narrowing of the left dorsal lower aras between the pontine rf and the iln in both patients and the tearing ( patient 1 ) and narrowing ( patient 2 ) of the left ventral lower aras between the pontine rf and the hypothalamus.injuries of the dorsal and ventral lower aras were demonstrated in patients with fatigue and hypersomnia following mild tbi .
we believe that these injuries of the aras might be a pathogenetic mechanism of fatigue and hypersomnia in patients with tbi . |
PubmedSumm4892 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: sarcoma is a heterogeneous group of cancers of the soft tissue and bone , and some are extremely rare . the rarity and diverse characteristics of sarcomas has impeded the development of new treatments .
doxorubicin and ifosfamide , either alone or in combination , have been the backbone of metastatic soft tissue sarcomas ( sts ) therapy for over 15 years .
few effective chemotherapeutic options for the treatment of metastatic sts beyond 1st line treatment with doxorubicin- and ifosfamide - based regimens exist . because alternative regimens for the effective treatment of metastatic sarcoma are unavailable
, varying combinations , including doxorubicin and/or ifosfamide , are sometimes used to treat patients who either not candidates for use or are resistant to treatment with doxorubicin and/or ifosfamide .
thus , a number of clinical trials have been conducted to explore alternative chemotherapeutic options .
the reported response rate ( rr ) from five phase ii trials of single - agent gemcitabine treatment in patients with soft tissue and bone sarcoma was 3 - 18% ( median rr , 5.5% ) .
docetaxel as a single agent ( 100 mg / m , iv every 3 weeks ) was examined as a second line therapy in a phase ii study conducted by the european organization for research and treatment of cancer ( eortc ) .
however , based on the results of several phase ii trials , the efficacy of single - agent docetaxel treatment in treating sts appears to be quite limited with a reported rr of 0 - 18% ( median rr , 15% ) [ 3 - 6 ] .
although use of gemcitabine or docetaxel as a single agent has limited efficacy , their use in combination has been shown to be effective in patients with sts . a clinical study by hensley et al
. reported an impressive rr of 53% in patients with predominantly uterine leiomyosarcoma using a study regimen consisting of gemcitabine at a dose of 900 mg / m given over a 90-minute iv infusion on days 1 and 8 , and docetaxel at a dose of 100 mg / m given over a 60-minute iv infusion on day 8 , followed by granulocyte - colony stimulation factor ( g - csf ) , during a 21 day period .
in a subsequent retrospective study of 35 patients with a variety of histologic subtypes of adult sarcoma , the patients received a similar regimen but with lower dosages of gemcitabine ( 675 mg / m ) .
these patients had previously received doxorubicin and/or ifosfamide , or were patients for whom use of gemcitabine and docetaxel ( gd ) was preferable for other medical reasons .
the results of the trial demonstrated an overall rr of 43% and the responses included patients with osteosarcoma and ewing 's sarcoma .
the combination of gd also has been evaluated for use in treatment of a variety of malignancies , with activity demonstrated in non - small cell lung cancer ( nsclc ) , breast cancer , esophageal cancer and others .
recently , a multi - institutional , randomized phase ii study in adult metastatic sts patients demonstrated superior progression - free survival ( pfs ) and overall survival ( os ) for use of the combination regimen when compared with use of gemcitabine alone .
however , more than 40% of patients receiving a combination of gd needed to discontinue the treatment within 6 months of therapy due to a variety of toxicities , despite adhering to recommended dose reductions . therefore , to identify the optimum dose and schedule that has both an antitumor effect and acceptable toxicity , we administered weekly gemcitabine - docetaxel treatments to patients with metastatic or recurrent sts who had failed to improve using doxorubicin and ifosfamide combination chemotherapy . here , we report the results of our retrospective analysis of 22 patients with advanced and refractory sts .
from september 2008 to march 2011 , a total of 22 patients with a variety of sts were treated at yonsei cancer center ( table 1 ) , and the medical records of these patients were retrospectively reviewed .
all patients had metastatic or recurrent cancer and had previously received doxorubicin and ifosfamide combination chemotherapy . following a 21 day cycle ,
on days 1 and 8 , patients received 1,000 mg / m gemcitabine intravenously over a 100 minutes duration , followed immediately by 35 mg / m intravenous docetaxel over 60 minutes .
standard prophylactic premedications were provided on day 1 and day 8 of diphenhydramine and ondansetron or its equivalent .
in addition , patients received 8 - 15 mg intravenous dexamethasone , 30 minutes before docetaxel was administered . in almost all patients , radiological evaluation consisted of a computed tomography scan and bone scintigraphy , as indicated .
response was assessed every two to three cycles . when measurements were available , radiographic studies and/or reports were reassessed and responses were classified according to the response evaluation criteria in solid tumors ( recist ) .
toxicities were evaluated using the national cancer institute common terminology criteria for adverse events ( nci ctcae ) version 3.0 .
best overall response was defined as the best response designation recorded from the start of treatment until disease progression .
pfs was defined as the time from first treatment until clinical or radiographic progression , or death .
patients in the study included 12 females and 10 males with a median age of 41.5 years ( range , 22 to 67 years ) .
of the 22 patients , 20 were considered to be resistant to both drugs and 2 were unable to tolerate these drugs due to hematologic toxicity .
weekly gemcitabine - docetaxel was delivered as a second line chemotherapy to 14 patients ( 63.6% ) and as a third line or more for 8 patients ( 36.4% ) .
a median of 3 weekly gemcitabine - docetaxel chemotherapy courses were delivered ( range , 1 to 39 cycles ) with a total of 116 courses .
no major side effects or severe complications that could be attributed to treatment were reported . according to the medical records , only 4 patients ( 18.2% ) needed a dose reduction due to hematological toxicity .
the primary justification for therapy discontinuation was progressive disease ( pd ) in 20 patients .
of the other 2 patients , one withdrew due to grade 2 gastroparesis and one suffered acute renal failure due to tumor - associated obstructive uropathy .
prophylactic g - csf was not used for any patients , while therapeutic g - csf was used for patients with febrile or grade 4 neutropenia .
grade 3 - 4 neutropenia occurred in 18.2% of cases and grade 3 - 4 thrombocytopenia occurred in 13.6% of cases .
only 4 patients ( 18.2% ) required dose reduction , primarily due to myelosuppression ( table 2 ) .
an allergic reaction occurred with 6 patients when docetaxel was administered , and in these cases , the infusion of docetaxel was discontinued until the symptoms improved and then infusion was slowly restarted .
of the 22 patients reviewed , 2 were not evaluated due to untimely death and one patient was transferred to another hospital prior to evaluation . among the 22 treated patients , one patient ( 4.5% ) with uterine leiomyosarcoma had a partial response ( pr ) , 8 patients ( 36.4% ) had the best response of stable disease ( sd ) , and 11 ( 50% ) had pd .
thus , an overall rr of 4.5% was observed while the disease control rate ( dcr ) was 40.9% with a median follow - up of 6.1 months ( dcr : leiomyosarcoma , 66.7% ; non - leiomyosarcoma , 31.3% ) .
the median pfs was 2.7 months ( 95% confidence interval [ ci ] , 2.0 to 3.4 months ) and the 12-week pfs rate was 41.9% ( fig .
we performed univariate analyses and did not observe any statistical association between pfs and clinical parameters including age , sex , initial localization , prior treatment at baseline , eastern cooperative oncology group performance status ( ecog ps ) , histology , or previous lines of chemotherapy before the gd combination ( second line vs. third line or more ) ( fig .
however , pfs was correlated with the justification for the prior chemotherapy regimen change ( toxicities vs. pd ; p=0.027 ) ( fig .
3a ) and the treatment response to weekly gd treatment ( pr and sd vs. pd ; p<0.0001 ) ( fig .
median pfs was 4.0 months ( range , 2.5 to 28.2 months ) in patients achieving disease control ( pr and sd ) , compared with 1.4 months ( range , 1.2 to 2.7 months ) in those not achieving disease control .
the median survival duration was estimated to be 7.8 months ( 95% ci , 0.0 to 20.6 months ) .
the six - month survival rate was 58.7% and the one - year survival rate was estimated to be 45.7% ( fig .
no statistical association was observed between os and clinical parameters including age , sex , initial localization , prior treatment at baseline , ecog ps and justification for the prior chemotherapy regimen change ( fig .
interestingly , there was no significant difference in os between patients receiving weekly gd as a second line of treatment and those who received a third line or more of chemotherapy ( fig .
however , os did correlate with histology , suggesting patients with leiomyosarcoma have a higher survival rate than other histological subtypes ( p=0.026 ) ( fig .
median os was 24.7 months ( range , 6.4 to 28.2 months ) in patients with leiomyosarcoma , compared with 4.9 months ( range , 1.1 to 24.4 months ) in those with other histology subtypes .
treatment response to weekly gd treatment ( pr and sd vs. pd ) ( p=0.009 ) also correlated with os ( fig .
4b ) , and disease control ( pr and sd ) may be predictive of survival .
patients in the study included 12 females and 10 males with a median age of 41.5 years ( range , 22 to 67 years ) .
of the 22 patients , 20 were considered to be resistant to both drugs and 2 were unable to tolerate these drugs due to hematologic toxicity .
weekly gemcitabine - docetaxel was delivered as a second line chemotherapy to 14 patients ( 63.6% ) and as a third line or more for 8 patients ( 36.4% ) .
a median of 3 weekly gemcitabine - docetaxel chemotherapy courses were delivered ( range , 1 to 39 cycles ) with a total of 116 courses .
no major side effects or severe complications that could be attributed to treatment were reported . according to the medical records , only 4 patients ( 18.2% ) needed a dose reduction due to hematological toxicity .
the primary justification for therapy discontinuation was progressive disease ( pd ) in 20 patients .
of the other 2 patients , one withdrew due to grade 2 gastroparesis and one suffered acute renal failure due to tumor - associated obstructive uropathy .
prophylactic g - csf was not used for any patients , while therapeutic g - csf was used for patients with febrile or grade 4 neutropenia .
grade 3 - 4 neutropenia occurred in 18.2% of cases and grade 3 - 4 thrombocytopenia occurred in 13.6% of cases .
only 4 patients ( 18.2% ) required dose reduction , primarily due to myelosuppression ( table 2 ) .
an allergic reaction occurred with 6 patients when docetaxel was administered , and in these cases , the infusion of docetaxel was discontinued until the symptoms improved and then infusion was slowly restarted .
of the 22 patients reviewed , 2 were not evaluated due to untimely death and one patient was transferred to another hospital prior to evaluation . among the 22 treated patients , one patient ( 4.5% ) with uterine leiomyosarcoma had a partial response ( pr ) , 8 patients ( 36.4% ) had the best response of stable disease ( sd ) , and 11 ( 50% ) had pd .
thus , an overall rr of 4.5% was observed while the disease control rate ( dcr ) was 40.9% with a median follow - up of 6.1 months ( dcr : leiomyosarcoma , 66.7% ; non - leiomyosarcoma , 31.3% ) .
the median pfs was 2.7 months ( 95% confidence interval [ ci ] , 2.0 to 3.4 months ) and the 12-week pfs rate was 41.9% ( fig .
we performed univariate analyses and did not observe any statistical association between pfs and clinical parameters including age , sex , initial localization , prior treatment at baseline , eastern cooperative oncology group performance status ( ecog ps ) , histology , or previous lines of chemotherapy before the gd combination ( second line vs. third line or more ) ( fig .
however , pfs was correlated with the justification for the prior chemotherapy regimen change ( toxicities vs. pd ; p=0.027 ) ( fig .
3a ) and the treatment response to weekly gd treatment ( pr and sd vs. pd ; p<0.0001 ) ( fig .
median pfs was 4.0 months ( range , 2.5 to 28.2 months ) in patients achieving disease control ( pr and sd ) , compared with 1.4 months ( range , 1.2 to 2.7 months ) in those not achieving disease control .
the median survival duration was estimated to be 7.8 months ( 95% ci , 0.0 to 20.6 months ) .
the six - month survival rate was 58.7% and the one - year survival rate was estimated to be 45.7% ( fig .
no statistical association was observed between os and clinical parameters including age , sex , initial localization , prior treatment at baseline , ecog ps and justification for the prior chemotherapy regimen change ( fig .
interestingly , there was no significant difference in os between patients receiving weekly gd as a second line of treatment and those who received a third line or more of chemotherapy ( fig .
however , os did correlate with histology , suggesting patients with leiomyosarcoma have a higher survival rate than other histological subtypes ( p=0.026 ) ( fig .
median os was 24.7 months ( range , 6.4 to 28.2 months ) in patients with leiomyosarcoma , compared with 4.9 months ( range , 1.1 to 24.4 months ) in those with other histology subtypes .
treatment response to weekly gd treatment ( pr and sd vs. pd ) ( p=0.009 ) also correlated with os ( fig .
4b ) , and disease control ( pr and sd ) may be predictive of survival .
currently , the combination of doxorubicin and ifosfamide is a standard chemotherapeutic regimen for soft tissue sarcoma patients with a good performance status .
however , some patients are not candidates for this therapy for reasons such as underlying cardiac dysfunction , renal insufficiency or poor performance status .
furthermore , effective chemotherapeutic options for the treatment of metastatic sarcoma , beyond 1st line treatment with doxorubicin- and ifosfamide - based regimens , remain limited .
the active form , obtained by phosphorylation , inhibits ribonucleotide reductase as a diphosphate , while the triphosphate is incorporated into dna and blocks dna synthesis [ 13 - 16 ] .
therefore , combination of gd may provide synergistic effects due to their complementary mechanisms of action whereby gemcitabine induces cell cycle arrest and docetaxel promotes cell death .
the combination of gd has been shown in recent studies to be effective in patients with sts . in these studies , iv infusion of docetaxel at a dose of 100 mg
generally , the docetaxel dose was used to treat patients with nsclc , breast cancer and others as a one hour iv infusion administered once every 3 weeks ( 3-weekly ) at a dose ranging from 60 - 100 mg / m . in asia , conventional 3-weekly doses of 60 - 75 mg / m have typically been administered due to decreased tolerability compared to non - asian patients . however , in the 3-weekly docetaxel schedule , neutropenia occurs in virtually all patients , and grade 3/4 neutropenia occurs in 65 - 75% of patients given 60 - 75 mg / m .
hence , several clinical trials have examined docetaxel administered as weekly doses of 35 - 40 mg / m , which demonstrated significantly lower toxicity profiles , especially for hematologic toxicity , as well as efficacy similar to the 3-weekly schedule [ 22 - 25 ] .
our patients were heavily treated , and we administered docetaxel at a weekly dose of 35 mg / m . in a phase ii trial including 29 patients with unresectable uterine leiomyosarcoma and 5 patients with sts of other primary sites , an overall rr of 53% ( 95% ci , 35 to 70% ) with acceptable toxicity results was very encouraging .
this study was impressive in its demonstration of leiomyosarcoma as a subtype that is relatively sensitive to this chemotherapy combination .
several subsequent studies have observed antitumor activity using combinations of gd in patients with leiomyosarcoma .
therefore , the efficacy of gd depends on histology . while the os was superior in patients with leiomyosarcoma compared to those with other histological subtypes in our study ( p=0.026 ) ( fig .
4b ) , it is not known why leiomyosarcoma and malignant fibrous histiocytoma / high - grade undifferentiated pleomorphic sarcoma respond better to this combination .
we anticipated the response or survival of patients who received weekly gd as a second line to be superior than those who received it as third line or more .
interestingly , there was no significant difference in the os between the two groups ( fig .
we suspect many patients who received gd as a third line or more had leiomyosarcoma .
but , almost all patient who received it as a third line or more had non - leiomyosarcoma ( 87.5% ) , and only one patient had leiomyoma ( 12.5% ) .
in other studies , the overall rr or os was similar both for patients who had received prior treatments and for those who were treated with gd as a first line therapy .
the reason of this point is not clear , but we suppose it 's because the combination of gd have antitumor effect in a different way than other chemotherapeutic agents ( doxorubicin and ifosfamide ) , and the patents with relatively good performance received third line treatment .
our weekly gd treatment was well tolerated , and grade 3 - 4 neutropenia and thrombocytopenia occurred in only 18.2% and 13.6% of cases . in previous trials ,
the rate of grade 3 - 4 neutropenia and thrombocytopenia were 20 - 40% , though those who were treated with gd as a 1st line therapy were included . in comparison
also , no major side effects or severe complications that could be attributed to weekly gd administration were reported .
in addition , there may be a possibility of increasing dose intensity with proper g - csf support .
weekly infusions of gd were very well tolerated and showed moderate efficacy as second and third line treatments , indicating that this could be a reasonable salvage treatment option for metastatic sts , refractory to doxorubicin and ifosfamide .
the fact that the weekly gd treatment in this study resulted in better survival for patients with leiomyosarcoma highlights the importance of selecting histology subtype - specific treatment .
the fact that there was no significant difference in os between the patients receiving second or third line treatment or more , illustrated the possibility for use of weekly gd as an effective salvage treatment for heavily treated metastatic sts patients .
however , fewer patents were enrolled in this study than in the other studies , and our patients were selected based on good performance and organ function for this salvage treatment , criteria which could become the basis for a prospective validation study . with the result of our study in mind , future salvage treatment studies should be conducted for third line or greater patients , including a higher prophylactic g - csf treatment dose in patients with proper host status .
Output:
| purposethe combination of gemcitabine and docetaxel ( gd ) is used to effectively treat patients with soft tissue sarcoma ( sts ) .
it is widely considered that the conventional doses used are too high for long term use and many patients must discontinue gd treatment due to its toxicity .
therefore , to determine the appropriate dose meeting acceptable efficacy results , while minimizing toxic side effects , we treated patients with a weekly infusion of gd ( weekly gd).materials and methodsa total of 22 patients presenting a variety of stss were treated at yonsei cancer center .
all patients had metastatic or recurrent cancer and had previously received doxorubicin and ifosfamide combination chemotherapy . in all cases , gemcitabine ( 1,000 mg / m2 ) and docetaxel ( 35 mg / m2 ) were administered intravenously on days 1 and 8 of a 21-day cycle .
we retrospectively reviewed the medical records of these patients.resultsthe response rate was 4.5% , with one patient diagnosed with leiomyosarcoma having a partial response , and the disease control rate was 40.9% .
the median progression - free survival ( pfs ) duration was 2.7 months and the pfs was correlated with the treatment response to a weekly gd .
the median overall survival ( os ) duration was 7.8 months and the os was correlated with histology .
there was no significant difference in os between patients who received weekly gd as a 2nd line chemotherapy and those who received 3rd line or more .
treatment was generally well tolerated.conclusionweekly gd was well tolerated and showed moderate efficacy , indicating that this could be a reasonable option as a salvage treatment for metastatic sts . |
PubmedSumm4893 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: adolescents constitute 20% of the world population and are estimated to be 1.13 billion by the year 2025 .
adolescence is a period of rapid growth and development by which up to 45% of skeletal growth takes place and 15 to 25% of adult height is achieved [ 1 , 3 ] .
in addition to the increased nutritional requirements during adolescence period , poor dietary diversity and dietary inadequacies are more likely threats among adolescents due to their erratic eating pattern and having specific psychosocial factors [ 1 , 4 , 5 ] .
malnutrition passes from generation to generation , because adolescent girls that enter pregnancy with poor nutrient store are more likely to give birth to low birth weight or intrauterine growth restricted baby that is more vulnerable to metabolic disorders later in life .
so adolescence period is a unique opportunity to break a range of vicious cycles of structural problems that are passed from one generation to the next , such as poverty , gender discrimination , violence , poor health , and nutrition [ 1 , 4 ] .
study done in khagrachari district , bangladesh , shows that 13.67% of adolescent girls were severely stunted and 20.33% were moderately stunted .
another study done in rural areas of bangladesh shows that 32% of the adolescent girls were stunted .
according to different studies done in india the prevalence of stunting ranges from 11.7% to 34.2% [ 912 ] .
studies done in asembo and mumias , kenya , and tunisia reported that the prevalence of thinness was 15.6% and 1.3% , respectively [ 13 , 14 ] . according to the study done on the rural communities of tigray , ethiopia ,
age , family size , mother education status , wealth index , lack of latrine were the commonly mentioned factors that influence the nutritional status of the adolescents .
despite the fact that adolescents are future mothers and need critical attention , they are the most neglected age groups [ 1 , 4 ] .
the intergenerational cycle of malnutrition has to be broken by strategies to improve nutrition of adolescents .
there is limited information about the nutritional status and associated factors in adolescent girls in ethiopia especially including pubertal landmarks which is critical for creating strategies and interventions on these target groups .
therefore , this study will address the gap by assessing the nutritional status and associated factors of adolescent school girls in adwa town .
this study was conducted from march to april 2015 to assess prevalence of thinness , stunting , and associated factors among adolescent school girls in adwa town , ethiopia .
adwa town is in central tigray zone , northern ethiopia , which is 935 km from addis ababa , ethiopia . in the academic year 2014/2015
the total number of adolescent girls from grade 4 to grade 12 was 5974 of which 5603 were from government schools and the remaining 371 are from nongovernment schools ( adwa town education office ) .
the study utilized institution - based cross - sectional study design with quantitative data collection method and anthropometric measurements .
the study population included all regular adolescent girls attending grades 412 who were randomly selected by computer generated method in the randomly selected schools .
adolescent school girls who were seriously ill and unable to stand by themselves were excluded from the study .
the sample size was calculated using single population proportion formula with the assumptions of prevalence of thinness 58.3% , which was obtained from research conducted among rural adolescent girls of rural community of tigray , ethiopia . using 5% margin of error , 95% confidence level , 10% nonresponse rate , and the design effect of two the calculated sample size was 823 , but due to the 1.09% nonresponse rate information was collected from 814 students , by which 732 were from government schools and 82 from private schools . the sample was obtained using multistage sampling technique . during the first stage , schools were stratified into government and private schools . in the second stage from government schools
2 primary schools , 1 high school , and one preparatory school were selected by using lottery method out of 10 primary schools , 3 high schools , 2 preparatory schools , and 1 private school , which was included purposively since it was the only school from grade 4 to grade 12 .
finally , the total sample size was distributed proportionally to the selected schools based on the total number of students in each school .
individual students from each school were selected by using simple random sampling technique using computer generated random numbers .
the questionnaire was pretested on 5% ( 41 ) adolescent girls in a school other than those included in the sample .
data collectors and supervisors were trained for one day to have consensus and same understanding of what is intended to be measured by each question in the questionnaire .
all the interviewers and supervisors were able to communicate in the local language , tigrigna .
the study was reviewed and approved by institution research review boards , institute of public health at the university of gondar .
individual assent was obtained by explaining the purpose and the importance of the study to the adolescent girls .
parental consent from the parents was obtained by sending consent form with the students the day prior to the data collection .
moreover , confidentiality of the information was assured by using anonymous questionnaires and by keeping the data in a secured place .
family income of the adolescent girls was assessed by using wealth index which is a good method of assessing economic status of a family .
stadiometers with a sliding headpiece attached to digital weight scale were used to measure height and weight , respectively .
height was measured to the nearest 0.1 cm and weight to the nearest 0.1 kg in standing position .
the scales were carefully handled and periodically calibrated by placing standard calibration weights of 2 kg iron bars on the scale .
if the scale weight did not match the calibration weight , the scale was calibrated by adjusting its calibration screw while the calibration weight was on the scale . to avoid variability among the data collectors ,
anthropometric measurements were converted to height - for - age and bmi - for - age z scores by using antro plus software .
girls with height - for - age below 2z scores and bmi - for - age below 2z scores of the 2007 who reference population were classified as stunted and thin , respectively .
the definitions of terms are as follows : thinness : bmi - for - age < 2z scores of the 2007 who reference ; stunting : height - for - age < 2z scores of the 2007 who reference ; adolescents : individuals in the age group of 1019 years of age : early adolescents : adolescents in the age group of 1013 years of age ; middle adolescents : adolescents in the age group of 1416 years of age ; late adolescents : adolescents in the age group of 1719 years of age ; poor dietary diversity : adolescent girls with dietary diversity score below the median value ( < 4 food groups ) ; good dietary diversity : adolescent girls with dietary diversity score of the median and above the median values ( 4 food groups ) ; high mass media exposure : adolescent girls who had listened to radio or watched television or read newspaper / magazines at least once a week ; low mass media exposure : adolescent girls who had not listened to radio or watched television or read newspaper / magazines at least once a week ; improved source of water : including tap water , public tap , and protected well ; nonimproved source of water : including unprotected spring and unprotected well.the dependent variables were thinness and stunting while the following factors were included in the model as independent variables : sociodemographic characteristics ( age , wealth index , family size , mother education , father education , place of residence , and type of school ) , menstruation status , physical activity , meal pattern , dietary diversity , source of drinking water , availability of home latrine , and mass media exposure .
thinness : bmi - for - age < 2z scores of the 2007 who reference ; stunting : height - for - age < 2z scores of the 2007 who reference ; adolescents : individuals in the age group of 1019 years of age : early adolescents : adolescents in the age group of 1013 years of age ; middle adolescents : adolescents in the age group of 1416 years of age ; late adolescents : adolescents in the age group of 1719 years of age ; early adolescents : adolescents in the age group of 1013 years of age ; middle adolescents : adolescents in the age group of 1416 years of age ; late adolescents : adolescents in the age group of 1719 years of age ; poor dietary diversity : adolescent girls with dietary diversity score below the median value ( < 4 food groups ) ; good dietary diversity : adolescent girls with dietary diversity score of the median and above the median values ( 4 food groups ) ; high mass media exposure : adolescent girls who had listened to radio or watched television or read newspaper / magazines at least once a week ; low mass media exposure : adolescent girls who had not listened to radio or watched television or read newspaper / magazines at least once a week ; improved source of water : including tap water , public tap , and protected well ; nonimproved source of water : including unprotected spring and unprotected well .
bivariate analysis was done and variables with p value less than 0.2 were included in the multiple logistic regression analysis .
odds ratio and 95% confidence intervals were also computed along with the corresponding p value .
from the total of 823 adolescent girls , 814 responded to the questionnaire making the response rate 98.9% .
the mean age of the study participants was 15.27 years ( 15.27 2.05 sd ) .
seven hundred thirty - two ( 89.9% ) of the respondents were from government schools and the remaining 82 ( 10.1% ) were from private schools .
three hundred thirty - three ( 40.9% ) of the mothers of the study subjects had no formal education followed by secondary level of education , 181 ( 22.3% ) .
nearly one - quarter , 210 ( 25.8% ) , of respondents were found in the first quintile range of wealth index ( table 1 ) . from the total of 814 respondents , 543 ( 66.7% ) of them usually ate 3 or more meals per day .
four hundred twenty - three ( 52.0% ) of the respondents had good dietary diversity and the remaining 391 ( 48.0% ) had poor dietary diversity score .
from the total respondents , 97 ( 11.9% ) had history of illness in the past two weeks prior to the data collection . regarding physical activity of the respondents , 800 ( 98.3% ) and 561 ( 68.9% ) were involved continuously in walking for > 30 minute per day and moderate intensity sport activities for 10 minutes continuously per day , respectively .
seven hundred fifteen ( 87.8% ) of the respondents used drinking water from improved source .
four hundred fifty ( 55.3% ) and 661 ( 81.2% ) of the study subjects reported that home gardening and home latrine were available in their home , respectively . of the total 814 respondents , 671 ( 82.4% )
had high mass media exposure and the remaining 143 ( 17.6% ) had low mass media exposure .
five hundred sixty - five ( 69.4% ) of the respondents had information about adolescent nutrition and 249 ( 30.6% ) did not have information about adolescent nutrition .
the overall prevalence of thinness and stunting among adolescent school girls of adwa town was 21.4% ( 95% ci = 18.5% , 24.2% ) and 12.2% ( 95% ci = 9.9% , 14.4% ) , respectively .
the odds of thinness were 2.15 times higher among adolescent girls in the early adolescent stage as compared to adolescent girls in the late adolescent stage [ aor ( 95% ci ) = 2.15 ( 1.14,4.03 ) ] .
adolescent girls in government schools were 2.89 times more likely to be thin as compared to adolescent girls from private schools [ aor ( 95% ci ) = 2.89 ( 1.20,6.91 ) ] .
the odds of thinness were 3.27 [ aor ( 95% ci ) = 3.27 ( 1.98,5.40 ) ] times higher among adolescent girls who use water from unimproved source as compared to adolescent girls who use water from improved source ( table 2 ) .
adolescent girls who were from family size of greater than five were 2.05 times more likely to be stunted as compared to adolescent girls from family size of less than or equal to five [ aor ( 95% ci ) = 2.05 ( 1.31,3.23 ) ] .
adolescent girls who did not start menstruation were 2.80 [ aor ( 95% ci ) = 2.80 ( 1.75,4.48 ) ] times more likely to be stunted as compared to adolescent girls who started menstruation ( table 3 ) .
this prevalence is higher when compared to studies done in asembo and mumias , kenya ( 15.6% ) , tunisia ( 1.3% ) , and 10% of tamale metropolis , ghana [ 13 , 14 , 17 ] .
the possible explanation for this difference could be due to difference in the study group since unlike this study which assessed the early , middle , and late stages of adolescent , study done in tunisia considered adolescents in the middle and late stages which are less likely to be thin because of less possibility of height growth than early adolescents .
the variation could also be due to socioeconomic and cultural difference in dietary habit and care practices .
the prevalence in this study is lower than the findings of studies done in bangladesh , tamil nadu and west bengal , india , and tigray , ethiopia , where 26% , 28.2 , 40.94% , and 58.3% of the adolescent girls were thin , respectively [ 8 , 10 , 12 , 15 ] .
this difference might be due to urban rural difference since , unlike this study which included adolescent school girls from both urban and rural setting , the above studies included adolescent girls only from rural settings which are more likely to be involved in activities which need more energy expenditure .
this finding is lower than the findings of studies done in west bengal and tamil nadu , india , urban area of umuahia , nigeria , and tigray , ethiopia , by which 34.2% , 19.2% , 57.8% , and 26.5% of the adolescents were stunted , respectively [ 10 , 12 , 15 , 18 ] .
this difference might be due to the difference in the study setting by which , unlike this study which included urban and rural adolescent girls , the above studies were done in rural areas by which unhealthy household environmental factors are more likely to be common than the urban setting
. the difference could also be due to time gap variation as nowadays knowledge of parents under nutrition and its consequence is improving .
the likelihood of being thin was higher among adolescents in the early and middle stage of adolescence than late stage of adolescence .
adolescent girls in the early stage of adolescence were 2.15 times more likely to be thin as compared to adolescent girls in the late stage of adolescence .
this finding is similar with findings from belgaum and karnataka , india , and tigray , ethiopia [ 15 , 19 ] .
this might be due to the increased growth spurt during the early and middle adolescent stage compared to late adolescent with sudden increase of height in the early and middle adolescents than late adolescents .
adolescent girls enrolled in government school were 2.89 times more likely to be thin as compared to adolescent girls from private school .
this finding is in line with findings from delhi , india , and jimma , ethiopia [ 20 , 21 ] .
this might be due to differing school environment by which government schools environment is less hygienic than the private school predisposing students to infection that leads to poor nutritional status .
other reasons could be that government schools include students who came from rural areas involved in higher energy expenditure activities but private school students are mainly from urban areas .
this finding also could be due to poor economic status of government school adolescent girls ' parents .
adolescent girls who usually eat less than 3 meals per day are 1.66 times more likely to be thin as compared to adolescent girls who usually eat 3 or more meals per day .
this finding is in line with the finding from islamabad city , pakistan , and tamale metropolis , ghana [ 17 , 22 ] .
adolescence period has the fastest growth and the nutritional requirements are increased to promote this growth .
so , in addition to the increased nutritional demand during adolescent period , skipping of meals leads to being thin .
adolescent girls who were from family size of greater than five were about 2.53 times more likely to be thin as compared to adolescent girls from family size of less than or equal to five .
this finding is in line with findings from tamil nadu , delhi , and assam , india , and jimma , ethiopia [ 10 , 11 , 20 , 21 ] .
this might be due to having more family members which could lead to sharing of the available food for the large household members causing inadequate consumption of food leading to being thin .
this finding also could be due to increased family size mostly occurring in uneducated parents who are more likely to accept and practice food taboos affecting mostly females .
adolescent girls whose mothers did not have formal education were 2.34 times more likely to be thin as compared to those whose mothers have completed college and higher education .
this is due to the fact that if the level of education of the mother is low , her decision making and her contribution to the total family income will be low .
adolescents who use drinking water from unimproved source are 3.27 times more likely to be thin as compared to adolescent girls who use drinking water from improved source
. this might be due to the fact that impure water is vehicle for intestinal parasites which leads to loss of appetite leading to poor nutritional status .
adolescent girls who were from family of greater than five individuals were 2.05 times more likely to be stunted as compared to adolescent girls from family of less than or equal to five individuals .
this finding is in line with the findings from tamil nadu and assam , india , and jimma , ethiopia [ 10 , 11 , 21 ]
. this might be due to sharing of the available food for the large household members causing inadequate consumption of food leading to be stunted .
adolescent girls who did not start menstruation were 2.80 times more likely to be stunted as compared to adolescent girls who started menstruation .
this is in line with the findings of studies done in mumias and asembo , kenya , and wannune benue state , nigeria [ 13 , 23 ] .
this might be explained by the fact that starting menstruation coincides with the adolescent growth spurt .
delay in menstruation in stunted adolescents shows the opportunity for catch - up growth as stunting delay menarche .
the odds of stunting were 3.82 times higher among adolescent girls who use water from unimproved source as compared to adolescent girls who use water from improved source .
this might be due to repeated infection causing depressed immunity and making the severity and duration of disease more sever contributing to poor nutritional status of the adolescents .
thinness and stunting are prevalent problems in the study area . age of the respondent , type of school enrolled , meals eaten per day , education status of mother , source of drinking water , and family size were significantly associated with thinness among the respondents .
menstruation status , family size , and source of drinking water were significantly associated with stunting among respondents .
the result of this study helps in understanding of the magnitude of the problem in the area .
as results from different study show micronutrient supplementation for adolescent girls should be provided to improve their nutritional status .
a major strength of this study was the random selection of the schools and adolescents .
generalization may be made to adolescent girls in the study areas as an attempt was made to identify randomized schools and adolescents from the study area .
another strength of this study was the use of dietary diversity as a proxy measure of micronutrient adequacy .
the major limitation of this study was the failure to collect information on variables like food taboos and carrying food to schools .
another limitation of the study was the use of cross - sectional study design which makes any inference of growth pattern over time difficult .
the cross - sectional nature of the study could only generate a hypothesis about the possible role of certain independent variables on the nutritional status of these adolescent girls but not their causal relationships .
Output:
| introduction . despite the fact that adolescence is a window of opportunity to break the intergenerational cycle of malnutrition , adolescents are the neglected age groups .
hence information regarding the nutritional status of adolescents is lacking making creating and implementing intervention programs difficult .
objective . to assess the prevalence of thinness , stunting , and associated factors among adolescent school girls in adwa town , northern ethiopia
. methods . data on 814 adolescent female students were collected from march to april 2015 using interviewer administered pretested semistructured questionnaire and anthropometric measurements .
data were entered using epi info version 3.5.3 and analyzed using spss version 20 and who anthroplus software .
results .
the prevalence of thinness and stunting was 21.4% and 12.2% , respectively .
age of adolescent [ aor = 2.15 ( 1.14,4.03 ) ] , mother 's educational status [ aor = 2.34 ( 1.14,4.80 ) ] , eating less than 3 meals per day [ aor = 1.66 ( 1.12,2.46 ) ] , having family size > 5 [ aor = 2.53 ( 1.66,3.86 ) ] were significantly associated with thinness among the adolescent girls .
family size > 5 [ aor = 2.05 ( 1.31,3.23 ) ] and unimproved source of drinking water [ aor = 3.82 ( 2.20,6.62 ) ] were significantly associated with stunting .
conclusion and recommendation .
thinness and stunting are prevalent problems in the study area . strategies to improve the nutritional status of girls should be given much attention . |
PubmedSumm4894 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: anaplastic thyroid cancer ( atc ) is one of the most aggressive tumours known in medicine .
even though a multimodal approach is used in treating these patients , average survival rate is expressed in months , and one - year survival is 15% [ 1 , 2 ] .
fortunately , atc is a very rare malignancy with an incidence of roughly 2 per 1,000,000 residents .
although atc represents only 2% of all thyroid cancers , it is the cause of death in half of patients whose definitive cause of death is thyroid malignancy . given that atc is a very rare malignancy , it has not been extensively researched .
risk factors for atc have not been sufficiently studied , and its aetiology essentially remains unknown .
there have been numerous case - control studies for all histopathological types of thyroid cancer , even medullary thyroid cancer [ 4 , 5 ] .
apart from our previous study , we did not encounter in the literature other case - control studies of atc ; even though being such an aggressive tumour , it attracts great attention in oncology and endocrinology . probably , one of the possible reasons for this is that a long period of observation is required to gather a significant number of cases , given that atc is quite rare .
we published the first part of our research , with a smaller number of cases and one control group , ten years ago . following that study ,
this research was continued and we published our results with a greater number of cases and two control groups .
the first control group consisted of patients with papillary thyroid cancer , while the second control group was formed from patients with goitre [ 7 , 8 ] . in this paper
we will briefly recapitulate the results of our previous studies and present our new results where the control group was formed from examinees from the general population .
this paper gives the final results of our long - time research that aimed to identify potential risk factors for the development of atc .
the diagnosis of atc was based on the definite histopathological findings for operated patients ( 55 ) and on the basis of the results of fine needle aspiration biopsy for patients that were not operated on ( 71 ) .
all patients were diagnosed at the clinic where the study was carried out , from 1993 to 2005 .
the control group was formed from the general population with the same place of residence as the patients from the studied group .
there were twice as many examinees in the control group , which amounts to 252 .
examinees that were included in the control group were chosen from neighbours of patients from the studied group in the exact same manner .
they were individually matched by place of abode , gender , and age ( 2 years ) .
all examinees ( cases and controls ) were interviewed by the same doctor . before the interview ,
all examinees were made familiar with the aim of the study and voluntarily decided whether they would take part in the research .
it consisted of questions regarding sociodemographic characteristics , habits , life in endemic goitre areas , exposure to radiation , and professional exposure to chemicals .
the next batch of questions consisted of questions about personal history in regard to previous thyroid diseases and thyroid function , other endocrine disorders , other malignancies , various health disorders , diagnostic and therapeutic procedures , previous operations , and use of medicaments .
another group of questions examined family history in regard to thyroid diseases , other diseases of endocrine glands , malignant tumours , and hereditary diseases .
also , detailed data was gathered for menstrual , hormonal , and reproductive characteristics of female examinees .
if a significant health disorder was reported , it was double checked in available medical documentation ; or , if not available , it was double checked with the closest siblings . in statistical analysis
all variables that were statistically related to atc , at a level of significance of p 0.10 , were included in a multivariate conditional logistic regression analysis model ( mlr ) , to identify independent risk factors for atc .
in table 1 basic sociodemographic characteristics , blood type groups , and habits of examinees are shown .
most of the cases were female with a ratio of 1.5 : 1 .
in the cases group , age ranged from 37 to 88 years , with an average age of 67 years .
only 10% of cases were younger than 50 years , and only one case was younger than 40 years .
more patients resided in an urban area ( 69.8% ) than in a rural area ( 30.2% ) .
most cases and even controls had completed only primary school ( 52.4% and 44.0% , resp . ) or had not completed primary school ( 30.2% and 24.6% ) . in general , cases had a lower education level ( only partial or full primary school ) compared to the controls , and this was statistically significant according to ulr .
a statistical significant difference was observed in the number of examinees with blood group type b. this blood group was present in 10.3% of cases and 4.4% of controls .
of the 13 cases with type b blood group , twelve had b+ , while one had b blood group .
we did not find any statistically significant associations within the habits of the examinees ( cigarette smoking , alcohol , and coffee consumption ) .
life in an endemic goitre area did not prove to be statistically significant . among the cases ,
30.2% had a previously diagnosed goitre or thyroid nodules , on average for 18 years ( ranging from 1 to 50 years ) .
six cases had a previous thyroid operation ( three for well - differentiated thyroid cancer and three for benign thyroid diseases ) . on average ,
the time between the operation and atc presentation was a bit longer than five years .
there was not a single examinee with goitre in the control group , except for one with hyperthyroidism and one with hashimoto thyroiditis .
one of the cases , who had been previously operated for well - differentiated thyroid cancer , received i131 therapy , before the anaplastic transformation occurred .
five patients in the cases group were on substitution or suppressive therapy with l - thyroxine .
we found that examinees from the cases group had twice as many nonthyroid malignancies ( 8.7% versus 4.4% ) than the examinees from the control group .
the most common malignancy was cervical cancer ( three cases ) and skin cancer ( basocellular cancer ) in three cases .
this was followed by breast cancer ( two cases ) , lung cancer ( one case ) , colorectal cancer ( one case ) , and prostatic cancer ( one case ) .
professional exposure to chemicals was not statistically significant . in comparison to the control group ,
there were twice as many examinees in the cases group with diabetes , and according to ulr this difference was statistically significant . even though cases were exposed to radiotherapy more often than controls ( 1.6% versus 0.4% as it is in table 2 ) , according to ulr this difference was not statistically significant . a family history of thyroid diseases or other malignancies did not show statistical significance .
menarche was more common in both of the groups ( cases and controls ) , before the age of 15 years .
the number of female examinees who had menarche at the age of 15 years or later was much greater in the cases group ( 20.8% versus 9.1% ) .
a statistical difference was not observed , according to ulr , in relation to normal menstruations , pregnancy , number of children , number of miscarriages , and deliberate terminations of pregnancy .
the same applied to the use of oral contraceptives and menopause estrogens . in the cases group ,
19.2% of examinees were pregnant before the age of 19 , while in the control group there were 9.2% , and this proved to be a statistically significant difference .
variables that were , according to ulr , statistically significantly related to atc were included in a mlr model .
these are education level , type b blood group , goitre , personal history of nonthyroid malignancies , diabetes , late menarche , and an early first pregnancy .
are independently related to atc and represent independent risk factors for atc : low education level , type b blood group , and goitre .
according to the results of this study , when the control group was formed from the general population , independent risk factors for atc were low education level ( or = 1.42 , 95% ci = 1.091.86 ) , type b blood group ( or = 2.41 , 95% ci = 1.035.66 ) , and goitre or thyroid nodules ( or = 25.33 , 95% ci = 5.66126.65 ) .
people with a lower level of education have generally lower health awareness , and they rarely and/or much later seek medical attention . also , adequate health care is less frequently available .
gaitan et al . point out that a lower education and a lower socioeconomic status are associated with a higher incidence of atc and that other thyroid cancers are usually discovered in a more advanced stage [ 9 , 10 ] .
the importance of education is also observed in the paper of memon et al . , where they find that twelve or more years of education significantly decreases the risk of thyroid cancer ( or = 0.6 , 95% ci = 0.30.9 ) .
searching the available literature , we did not encounter any papers that associate type of blood group with atc or any other histopathological type of thyroid cancer . on the other hand ,
find that type b blood group increases the risk of oesophageal cancer , especially in men .
type a blood group is associated with a risk for cancer for various localisations , such as gastric cancer ( especially in patients with a positive family history ) , cancer of the larynx and hypopharynx , pancreatic cancer , breast cancer , and rectal cancer [ 1318 ] . according to the study of marinaccio
et al . , type a blood group , apart from increasing the risk for cervical and ovarian cancer , is a bad prognostic factor for these types of cancer .
we will now compare the results of this study with the results of our previous studies that also researched risk factors for atc , but with different control groups .
our first case - control study of risk factors for atc had a slightly smaller number of cases ( 110 ) and one hospital control group . according to that study , independent risk factors for atc were goitre ( or = 37.55 , 95% ci = 4.86290.11 ) , life in an endemic goitre area ( or = 2.56 , 95% ci = 1.056.22 ) , a personal history of other nonthyroid malignancies ( or = 5.51 , 95% ci = 1.0429.25 ) , diabetes ( or = 4.06 , 95% ci = 1.2912.81 ) , and a lower level of education ( or = 2.44 , 95% ci = 1.175.06 ) .
our present study identified three independent risk factors for atc , compared to our previous study where we identified five .
two of these risk factors are the same in both studies , and those are a lower level of education and goitre .
our present study could not identify life in an endemic area as a risk factor , since the control group was matched by place of abode . practically , the main differences between these two studies are that one found diabetes and a personal history of other nonthyroid malignancies as independent risk factors , while the other identified type b blood group as an independent risk factor for atc .
similar results were obtained when we conducted a case - control study with the same 126 cases of atc that were included in the present study , but the control group was formed from 252 patients with goitre . in fact , the development of atc is preceded by long - term goitre in nearly half of patients .
this is one of the main reasons that we decided to form the control group from patients operated for goitre whose definite pathohistological findings confirmed a benign disease .
this allowed us to establish potential risk factors for the development of atc in patients with goitre .
these risk factors could further help us , as additional criteria , when deciding which patients with benign goitre should undergo operative treatment .
when patients operated for goitre were used as the control group , there were five variables independently related to the development of atc . among these were a lower level of education ( or = 1.85 , 95% ci = 1.212.82 ) and type b blood group ( or = 3.69 , 95% ci = 1.1012.49 ) , which were identified in our present study as well , using a different control group . apart from these two factors ,
the other three factors were a personal history of other nonthyroid malignancies ( or = 4.37 , 95% ci = 1.1117.31 ) , late menarche , at the age of 15 or later ( or = 2.63 .
95% ci = 1.155.88 ) , and an early pregnancy , before the age of 19 ( or = 2.96 , 95% ci = 1.266.96 ) .
these two reproductive factors , as found in our present study , were also statistically significantly associated with atc , according to ulr , but were not found to be independent risk factors .
a late menarche and an early pregnancy have been identified as a risk factor for thyroid cancer in women , where its incidence is several times higher than in men [ 2123 ] .
significantly different results were found when the control group consisted of the same number of cases with atc ( 126 ) but where the controls were formed from examinees with papillary thyroid cancer .
atc can develop from preexistent well - differentiated thyroid cancer , which is found in 1871% of cases with atc [ 2426 ] .
since , in a significant number of cases with atc , well - differentiated thyroid cancer has been proven to coexist , on definitive histopathological findings , we decided to form the control group from patients with papillary thyroid cancer , to try and identify which factors could be responsible for the dedifferentiation , that is , anaplastic transformation of well - differentiated thyroid cancer .
based on the results of mlr , when the control group consisted of patients with papillary thyroid cancer , age proved to be the only independent risk factor for the development of atc ( or = 1.11 , 95% ci = 1.051.15 ) . therefore , in comparison to other observed variables , there were no statistically significant differences between patients with atc and patients with papillary thyroid cancer .
at the end , we would like to point out that in our case - control research of risk factors for atc we tried to surpass one of the greatest problems in the design of case - control studies and that is the choice of the control group .
we overcame this problem by forming several control groups with different criteria and with a bigger number of controls than cases .
however , one of the greatest problems of these studies is the fact that they consist of a relatively small number of cases with atc ; but , on the other hand , there are just a few centres in the world that published papers with more than 100 cases of atc , and unfortunately they have not conducted any case - control studies for risk factors for atc .
therefore , the results of our study should be tested in a study with a higher number of cases , which could only be achieved by a multicentric study with several high volume centres in the world .
Output:
| background . anaplastic thyroid cancer ( atc ) is a form of thyroid cancer with very poor prognosis , but is fortunately quite rare .
its aetiology is unknown and not well researched .
aim .
the aim of this study was to identify potential risk factors for atc .
material and method .
case - control study of 126 atc patients ( 77 females and 49 males ) and 252 controls individually matched by gender , age , and place of abode . in statistical analysis
we used a cox regression model .
results .
univariate logistic regression showed that the risk factors for atc are low education level , type b blood group , goitre , other nonthyroid malignancies , diabetes , late menarche , and an early first pregnancy .
multivariate logistic regression analysis showed that independent risk factors for atc are low education level ( or = 1.42 , 95% ci = 1.091.86 ) , type b blood group ( or = 2.41 , 95% ci = 1.035.66 ) , and goitre ( or = 2533 , 95% ci = 5.66126.65 ) .
conclusion .
independent risk factors for atc are : low education level , type b blood group , and goitre . |
PubmedSumm4895 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: expansion and proliferation of insulin - secreting beta cells in pancreatic islets is a key highly regulated mechanism for establishing , maintaining , and adapting islet function to meet organism physiological demands .
understanding how the pieces of this mechanism fit together could improve development of islet replacement approaches ; given that both type 1 and type 2 diabetes result from reduced beta cell mass and impaired beta cell functions .
islet beta cells expand in neonatal humans , mice , and other species , but this proliferation decays thereafter , which may promote pandemic ( type 2 ) forms of diabetes mellitus .
beta cell mass can be expanded by increasing beta cell replication , enlarging beta cell size , decreasing beta cell death , and promoting beta cell neogenesis .
murine beta cells proliferate slowly after birth , but this process can be accelerated under various conditions , including obesity , pregnancy , and stimulation by different beta cell mitogens , such as glucose , amino acids , insulin , prolactin , placental lactogen , and glucagon - like peptide-1 .
in addition to differentiation from pre - existing adult beta cell progenitors or transdifferentiation from another cell lineage , beta cell self - replication is considered to be the primary source for new beta cell generation in adult animals .
one of the approaches in diabetes research is investigating the function of beta cell cycle activators and inhibitors to elucidate the network by which beta cell replication could be increased to enhance beta cell mass and function .
for the understanding of beta cell replication machinery it is important to focus on the cell cycle phases and checkpoints : the g1-s transition , s phase checkpoint , g2 to m transition and the mitotic checkpoint ( figure 1 ) . checkpoint regulation mechanisms act through negative intracellular signals that arrest the cell cycle , rather than through the removal of positive signals that stimulate cell - cycle progression .
negative signals prevent cycle transition at the initiation of proliferation , replication and mitosis until the cellular conditions are the adequate for cell cycle progression .
sequential activation / inactivation of cyclin - dependent kinases ( cdks ) is the primary means of cell cycle regulation .
cyclins confer substrate specificity and regulation to cdk / cyclin complexes . according to that , in early g1 phase cdk4 and/or cdk6
are activated by d - type cyclins and initiate phosphorylation of the retinoblastoma protein ( rb ) family .
this triggers the release of e2f transcription factors and the subsequent activation and transcription of e2f responsive genes ( including e- and a - type cyclins ) required for cell - cycle progression . in the late g1 phase , cdk2 binds to cyclin e and completes the phosphorylation of rb , reinforcing the activation of e2f mediated transcription .
these events lead to transition from the g1/s boundary point to s phase initiation . through
s phase progression cdk2 binds to cyclin a that contributes to dna replication . during the g2/m transition , cdk1/cyclin a complex is required for the initiation of prophase .
the negative regulation of cdk / cyclin complexes relies on two families of cdk inhibitors ; the ink4 family ( p16 , p15 , p18 , p19 ) specifically bind to cdk4 and cdk6 and prevent d - type cyclin activity and the cip / kip family ( p21/waf1/sdi1 , p27 , p57 ) inhibits cdk2/cyclin e , cdk2/cyclin a , cdk1/cyclin a , as well as cdk1/cyclin b activity ( for review see ) .
the p53 gene product is another key cell cycle check - point regulator at both the g1/s and g2/m and it has been shown to activate transcription of number of cell cycle genes and its essential role is to arrest cells in g1 after genotoxic damage allowing dna repair prior to dna replication and cell division . in response to massive dna damage , p53 triggers the apoptotic cell death pathway . here
we give an overview about the regulation points of arf / ink4a locus transcription in beta cell , specifically in proliferation processes that give rise to cellular senescence and the development of diabetes .
we state the more striking studies that shed a light in the approach of pancreatic beta cell proliferation and regeneration .
candidate gene and genome - wide association studies ( gwas ) have identified several loci associated with type 2 diabetes and related traits .
specifically , genetic variants at cdkn2a / b locus have been associated with type 2 diabetes in many ethnic populations .
a number of publications in the last five years confirm and validate that cdkn2a / b is a locus associated with genetic risk of type 2 diabetes development [ 58 ] . among the strongest linked variants
is rs10811661 , located 125 kb upstream of the cdkn2a and cdkn2b genes ( for review , ) .
this polymorphism appears to be associated to type 2 diabetes in almost all the ethnic cohorts studies [ 1018 ] and people carrying the tt genotype of this variant showed impaired insulin release and impaired glucose tolerance .
the arf / ink4a ( cdkn2a ) locus spans around 35 kilobases on human chromosome 9p21.25 that includes the linked tumor suppressor genes p16 and p14 ( p19 in mice ) that trigger the anti - proliferative activities of both rb and p53 .
while p14 is transcribed from exon 1b and exon 2 , p16 is transcribed from exon 1a localized 20 kb downstream of 1b and exons 2 and 3 . as described in more detail below and shown in figure 2 , p16 binds to cdk4/6 inhibiting its kinase activity thereby preventing rb phosphorylation ( prb ) , while p14 inhibits the ubiquitin ligase activity of mdm2 , thereby stabilizing p53 .
rb remains associated with transcription factor e2f1 localizing it to the cytoplasm and thus preventing transcription of e2f1 target genes that , as mentioned above , are crucial for the g1/s transition .
beta cells express most of the known cell cycle inhibitors , including p16 , p18 , p21 , p27 , p53 , and rb .
in contrast , and according to the negative regulation model explained in the introduction , there is much less redundancy of cell cycle activators in the beta cell .
for example , rodent beta cells express only cdk4 and not cdk6 , whereas most other cell types express both of these proteins .
mouse beta cells express all three d cyclins , d1 , d2 , d3 , but the mrna expression of d2 is significantly higher than both d1 and d3 with only d2 detectable by immunohistochemistry . in order to establish another regulation point of this pathway in beta cells ,
fiaschi - taesch and colleagues [ 21 , 22 ] have delineated the repertoire of g1/s regulatory proteins present in the adult human islet and have used this information to develop what they call the human islet g1/s proteome .
these studies state that although the g1/s molecules are mainly considered to be nuclear proteins , they are present principally in the cytoplasm , where possibly they would not be able to regulate cell cycle progression . furthermore , the only nuclear g1/s molecules are the cell cycle inhibitors , prb , p57 , and p21 .
cell cycle activators as cyclins or cdks , necessary to drive -cell proliferation are present in the cytoplasm , not in the nuclear compartment .
regarding the role of e2f in beta cells , it is well known that the increased expression of e2f contributes to the uncontrolled proliferation of cancer cells , but there is increasing evidence for a cdk4e2f1prb - specific role in metabolism .
to that extent , there is the finding that some specific polymorphisms in the cdk4 gene could contribute to type 2 diabetes - associated obesity . in that sense , studies e2f1 mice show impaired postnatal pancreatic growth that triggers a reduction in pancreatic size with the subsequent impaired glucose homeostasis .
moreover , the cdk4-prb - e2f1 pathway is activated by glucose through the insulin pathway in beta cells , leading to increased kir6.2 expression that induces insulin secretion [ 2527 ] .
emerging evidence indicates that proliferation of pancreatic beta cells is an important mechanism not only to maintain homeostasis in the endocrine pancreas but also for adapting islet function to changes in metabolic demands [ 9 , 28 , 29 ] . the inability of the beta cells to expand and compensate for the changing insulin demand can contribute to the pathogenesis of diabetes .
several studies suggest that beta cell proliferation declines with age [ 30 , 31 ] and this age - dependent decline in the beta cell proliferation could curtail the ability of the endocrine pancreas to respond to metabolic changes .
furthermore , the cell - intrinsic genetic and epigenetic mechanisms regulating the age - dependent decline of beta cell proliferation . on their review , gunasekaran and cols compile contradictory studies on the age - related effects on the beta cell . while some of them found that insulin sensitivity decreases with age , others shown that plasma glucose clearance was found to be dependent on the waist - to - hip ratio and not age , with the exception of older people with pre - existing impaired glucose tolerance or type 2 diabetes .
even if these studies come into contradiction , there is evidence that with age , beta cells show decreased expression of cell cycle activators with simultaneous increases in expression of cell cycle inhibitors .
controversial findings and opinions regarding the balance of cell cycle inhibitors and activators have been found .
gunasekaran 's compendium describes several studies showing that loss of a single cell cycle inhibitor does not accelerate beta cell cycle progression , whereas loss of multiple inhibitors enhances beta cell proliferation . in the opposite sense ,
other groups describe that p16 and p19 expression ( mrna ) was increased significantly with aging in pancreatic islets , but not other cdk inhibitors examined , including p15 , p18 , p21 , p27 .
this up regulation has been linked to reduction in the proliferative capacity of aged beta cells [ 32 , 33 ] .
aging is associated with replicative senescence and p16 levels increase with aging in most mammalian tissues .
the levels of p16 in an individual can be predicted by stochastic model that takes into consideration the subjects ' age . according to this model
, p16 levels exponentially increase with age in a p16-dependent manner and reach a plateau .
increased p16 levels in the pancreas during aging ( independent of telomere shortening ) inhibit the proliferation of beta cells and decrease their ability to respond to injury . while the beta cells of the p16 knockout mice were able to proliferate in response to injury ,
beta cells with ectopic expression of p16 showed reduced proliferative response confirming the association between p16 and beta cell senescence .
in addition , overexpression of p16 in transgenic mice caused a reduction of islet proliferation in younger more than in older animals .
expression of p16 and p14 are regulated by promoter hypermethylation through proteins of the prc1 and prc2 complexes of the polycomb group ( pcg ) of transcriptional repressor proteins .
mll1 and pcg directly control the ink4a / arf locus through chromatin epigenetic modifications and the loss of these repressive epigenetic marks leads to a shift of the replication timing of the locus , both in senescent and polycomb mutant cells .
bmi-1 is a transcription factor , member of the pcg repression complex 1 ( prc1 ) that inhibits senescence by inhibiting transcription of p16 .
ezh2 ( enhancer of zeste homolog 2 ) belongs to the prc2 complex , it is a histone methyltransferase which represses ink4a / arf in islet beta cells , with activity specific for histone h3 k27 [ 35 , 36 ] .
the ability of bmi-1 to decrease transcription from the ink4a locus depends on the presence of ezh2 and other components of the prc2 complex .
kotake et al . showed that the removal of prb from cells resulted in the loss of histone h3 k27 trimethylation leading to the loss of bmi-1 recruitment to the ink4a / arf locus .
moreover , prb is also shown to be necessary for bmi-1 function in the transcription repression of ink4a / arf .
there is a feedback loop between p16 and rb : phosphorylation which results in increased p16 expression and inhibition of cdk4/6 .
other regulatory feedback loop of the locus relays on histone deacetylases ( hdac ) , p53 is required for both hdac and pcg to repress p14 expression , at the same time hdac1 is involved in the release of e2f1 which in turn could up - regulate p14 , leading to an inhibition of mdm2 activity , the subsequent activation of p53 and induction of senescence through p21 [ 20 , 39 ] .
previously described by wang and colleagues , hbp1 induces premature senescence through upregulating p16 expression in primary cells by targeting the p16 promoter , by interacting and recruiting p300/cbp , whereas hdac4 represses hbp1-induced p16 expression , thus represses hbp1-induced premature senescence .
the factors explained below are well known to have a specific role in regulation of beta cell proliferation under physiological and pathological conditions .
however , the molecular pathways in which they are involved are not fully studied , but they could be promising targets for expanding functional pancreatic islets in diabetes .
long non - coding rnas ( lncrnas ) are a new class of regulatory rnas that are defined as transcribed rna molecules ranging in length from 200 to 100,000 nucleotides and lacking protein - coding capacity .
islet lncrnas show a marked cell - type specific expression pattern , morn and colleagues have integrated transcriptional and chromatin maps to systematically annotate lncrna genes in human pancreatic islet cells and they state that some lncrnas are dysregulated in type 2 diabetes or map to susceptibility loci .
furthermore , orthologous transcripts in mice are dynamically regulated in a similar manner as human islet lncrnas . in the case of cdkn2a , a long non - coding rna , anril ( antisense non - coding rna ) , also transcribed from the locus ,
is involved in the epigenetic regulation of the cdkn2a locus by direct binding to the p16 transcript and recruiting the prc complexes to repress the transcription of genes at this locus .
anril is targeted by prc2 to the ink4a / arf / ink4b locus . another regulation point regarding anril and cell cycle
inhibition is that anril is induced by e2f1 transcription factor after dna damage , and thus the elevated anril levels suppress the expression of p14 and p16 at the late - stage of dna damage response ( ddr ) , forming a negative feedback loop to the ddr .
recent studies showed that single nucleotide polymorphisms mapped in the anril as well as in cdkn2a locus sequences are linked to several pathologic conditions , including type 2 diabetes .
yi et al . have described a peptide whose overexpression in mouse liver produces a secreted protein that significantly and specifically promotes pancreatic beta cell proliferation and beta cell mass expansion and , consequently , improves glucose tolerance .
hence , this peptide has been called betatrophin . expression levels of cyclins ( cyclins a1 , a2 , b1 , b2 , d1 , d2 , and f ) , cdks ( cdk1 and cdk2 ) , and e2fs ( e2f1 and e2f2 ) increase , whereas cell cycle inhibitors ( cdkn1a and cdkn2a ) decrease in islets of betatrophin - injected mice compared to control - injected mice . the mechanism of action for betatrophin still remains unknown , if it acts directly or not on the beta cells for controlling their proliferation .
betatrophin is not a novel protein , it is also known as angptl8 , td26 , rifl and lipasin .
previously to the study of yi and colleagues , it has been shown that betatrophin is expressed at the highest levels in liver and adipose tissue , and is up - regulated by feeding and suppressed by fasting [ 45 , 46 ] .
to date the betatrophin receptor has not been identified , and maybe other cofactors are acting in the specificity of the betatrophin effect on beta cell mass
. however , promising opportunities are open with regard to betatrophin and beta cell mass regeneration .
type 1 and 2 diabetes can be reversed by replacement of beta cell mass , as demonstrated by pancreas and islet transplantation .
however , it has limited applicability , given the shortage of organ donors and the need for chronic immunosuppression .
regeneration of beta cell mass is one promising approach to replace the deficit in beta cell mass in diabetic patients .
the results stated in this review support that modulation of the ink4a / arf locus plays a critical role in regulating pancreatic beta cell proliferation during aging and regeneration .
a strategy of beta cell proliferation improvement based in ink4a / arf genes inhibition could help to develop new regeneration approaches
. one of the main concerns about inhibiting the action of these genes is that they are anti - oncogenes , and could trigger tumour development . to date
recently , the direct derepression of p21 and p16 caused by loss of ap4 gene ( a c - myc transcription factor ) in fibroblasts has been shown to be sufficient to mediate cellular senescence . in beta cells
, a recent and promising study shows that a bioavailable hnf4 ( a nuclear receptor transcription factor ) antagonist induced -cell replication in rabbits and mice .
moreover , this compound promotes alpha , beta and delta cell replication in beta cell ablated mice , and repressed the expression of multiple cyclin - dependent kinase inhibitors , including p16 . understanding
the regulation of ink4a / arf locus could reveal the molecular basis of reduced beta cell proliferation with aging and also be extremely useful in devising strategies for beta cell regeneration .
Output:
| the arf / ink4a ( cdkn2a ) locus includes the linked tumour suppressor genes p16ink4a and p14arf ( p19arf in mice ) that trigger the antiproliferative activities of both rb and p53 .
with beta cell self - replication being the primary source for new beta cell generation in adult animals , the network by which beta cell replication could be increased to enhance beta cell mass and function is one of the approaches in diabetes research . in this review ,
we show a general view of the regulation points at transcriptional and posttranslational levels of cdkn2a locus .
we describe the molecular pathways and functions of cdkn2a in beta cell cycle regulation . given that aging reveals increased p16ink4a levels in the pancreas that inhibit the proliferation of beta cells and decrease their ability to respond to injury , we show the state of the art about the role of this locus in beta cell senescence and diabetes development .
additionally , we focus on two approaches in beta cell regeneration strategies that rely on cdkn2a locus negative regulation : long noncoding rnas and betatrophin . |
PubmedSumm4896 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: lupus mastitis presents as single or multiple subcutaneous or deep breast masses , clinically mimicking malignancy [ figure 1 ] .
lupus mastitis presenting as the initial manifestation of lupus erythematosus ( le ) is very rare .
later , she developed discoid le ( dle ) lesions on breast and other sites without any systemic symptoms of le [ figure 2 ] .
evolution of one connective tissue disease to other remains a perplexing event , though there are reports .
literature search shows only a single case of dle progressing to systemic pan even though many cases of systemic le evolving to systemic pan has been reported .
right breast shows atrophy , discoid lupus erythematosus lesions on surface discoid lupus erythematosus lesion in ear
a 35-year - old female presented with hyperpigmented papules on right breast , face and limbs , and weakness of right little finger of 2 weeks duration .
there was no history of tuberculosis , joint pain , photosensitivity , or raynauds phenomenon .
cutaneous examination revealed multiple hyperpigmented discrete and confluent atrophic plaques with adherent scales over the right breast .
breast tissue also showed induration with multiple discrete nodules of size 1 cm 2 cm .
multiple discrete hyperpigmented scaly papules and plaques were present on the upper arms , face and ear concha ( schuster sign ) [ figures 1 and 2 ] .
we had the differential diagnosis of papulonecrotic tuberculid and disseminated dle ( ddle ) ; for the breast nodules , we considered tuberculous mastitis and lupus mastitis .
renal function test , antinuclear antibody ( ana ) , ana profile , and c3 , c4 levels were normal .
mantoux test , perinuclear anti - neutrophil cytoplasmic antibody , and viral markers were negative .
magnetic resonance imaging aortogram revealed luminal irregularity and beaded appearance of left renal artery near the hilum .
skin biopsy from breast lesion shows atrophy of epidermis , follicular plugging , and basal cell degeneration deep biopsy from breast showed features of dle with mixed panniculitis and lymphocytic vasculitis with mucin deposition in dermis , suggestive of lupus mastitis [ figures 4 and 5 ] .
deeper biopsy from breast tissue shows lymphocytic vasculitis and lymphoid aggregates alcian blue stain shows mucin deposition in dermis usg breast showed ill - defined hypoechoic mass with atrophy of fat and large calcifications in fat and breast tissue [ figure 6 ] .
ultrasound picture of breast shows atrophy of breast tissue , large masses of calcification hence , the final diagnosis was lupus mastitis evolving to ddle and systemic pan .
lupus mastitis affects women with a mean age at diagnosis of 40 years and can occur in males also .
the condition leads to fat necrosis , calcification , fibrosis , scarring , and breast atrophy .
most commonly , lupus mastitis is seen in patients with a previous diagnosis of systemic or discoid lupus .
however , in our patient , lupus mastitis was the initial presentation . in the absence of skin lesions and background of le
, it poses a diagnostic challenge and the differential diagnosis involves carcinoma , tuberculosis , idiopathic granulomatous mastitis , lymphoma , and involvement of breast in medium vessel vasculitis .
traumatic procedures such as biopsy may worsen the condition , and it is advisable to avoid biopsy if the diagnosis can be established with the clinical and radiological features .
fine - needle aspiration cytology shows degenerated fat cells with scattered foci of calcification and lymphocytic predominance .
histological findings in lupus panniculitis are hyaline fat necrosis , lymphocytic infiltration surrounding the necrosis , periseptal or lobular panniculitis , and microcalcifications .
other findings include changes of dle in the overlying skin , lymphocytic vasculitis , mucin deposition , and hyalinization of the subepidermal papillary zones .
typical mammographical appearance include segmental heterogeneous calcifications , some curvilinear and coarse due to fat necrosis .
ultrasound shows an ill - defined , isoechoic , or hyperechoic mass , but our patient had hypoechoic lesion , large calcifications , and lipoatrophy .
she also satisfied the criteria for systemic pan . in 1990 , the american college of rheumatology established criteria for pan .
at least 3 of the 10 criteria should be present :
weight loss > 4 kglivedo reticularistesticular painmyalgiamononeuropathy or polyneuropathydiastolic blood pressure > 90 mm / hgelevated blood urea nitrogen or creatinine levelpresence of hepatitis b surface antigenarteriogram demonstrating aneurysmsbiopsy of small- or medium - sized artery containing neutrophils .
mononeuropathy or polyneuropathy diastolic blood pressure > 90 mm / hg elevated blood urea nitrogen or creatinine level presence of hepatitis b surface antigen arteriogram demonstrating aneurysms biopsy of small- or medium - sized artery containing neutrophils .
our patient satisfied this criteria , and literature search showed few reports of systemic lupus erythematosus ( sle ) progressing to pan , but only a single report of dle going for pan . in this case , we faced two questions , is the breast swelling lupus mastitis or pan of breast tissue and whether the patient has a single connective tissue disease or both le and pan .
we report this case as lupus mastitis is a rare entity , and its presence as the initial manifestation of le is still rare .
lupus mastitis presented as initial manifestation of le , so it remained undiagnosed for many years . even though there are reports of sle evolving to pan , a case of dle going to pan is rare .
lupus mastitis presented as initial manifestation of le , so it remained undiagnosed for many years .
even though there are reports of sle evolving to pan , a case of dle going to pan is rare .
lupus mastitis presented as initial manifestation of le , so it remained undiagnosed for many years .
even though there are reports of sle evolving to pan , a case of dle going to pan is rare .
Output:
| lupus mastitis is an uncommon presentation of lupus erythematosus profundus ( le profundus ) , characterized by inflammation of the subcutaneous fat .
le profundus occurring as initial manifestation of le is rare .
we report a case where the patient presented with lupus mastitis and years later , she developed disseminated discoid le ( dle ) and polyarteritis nodosa ( pan ) .
pan and dle are connective tissue diseases with different etiologies , clinical , immunological , and histopathological features .
one connective tissue disease evolving into another is rare , and the reasons remain unexplained .
this woman had histopathologically proven dle and lupus mastitis with a negative antinuclear antibody profile .
she satisfied the american college of rheumatology criteria for pan . |
PubmedSumm4897 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: human multipotent mesenchymal stromal cells ( msc ) , known for their multilineage differentiation potential , possess pleiotropic immunosuppressive functions that are partly mediated by expression of the tryptophan - catabolizing enzyme indoleamine-2,3-dioxygenase ( ido ) [ 14 ] . upon stimulation with inflammatory cytokines ,
msc exhibit broad - spectrum antimicrobial effector functions directed against various clinically relevant pathogens , and these effects are dependent on ido and/or the antimicrobial peptide ll-37 [ 5 , 6 ] .
these dual immunosuppressive and antimicrobial properties render msc a promising novel cellular immunosuppressant which is currently under intensive clinical investigation for various auto- and alloimmune diseases such as steroid - refractory graft versus host disease ( gvhd ) after allogeneic hematopoietic stem cell transplantation ( hsct ) , crohn 's disease , and multiple sclerosis [ 710 ] .
emerging data indicate that signals from the microenvironment including those induced by hypoxia [ 11 , 12 ] or derived from microbes may critically affect ido and consequently msc effector functions [ 1315 ] . as the cytomegalovirus ( cmv ) represents a prominent pathogen in immunocompromised hosts in particular in patients suffering from gvhd after hsct , we initiated studies investigating the impact of cmv infection on msc - mediated effects . during coevolution with its specific host ,
for example , cmv has been reported to inhibit the upregulation of mhc class ii antigens .
furthermore , it was found that cmv generally inhibits signalling via the ifn- receptor and that this is mediated via a reduced phosphorylation of stat1 and an enhanced degradation of jak1 [ 1921 ] .
mesenchymal stromal cells and embryonic stem cells are able to inhibit t - cell responses and several mechanisms including the production of prostaglandins , of immunosuppressive cytokines , of arginase i , or of adenosine [ 23 , 24 ] appear to be involved in this effect .
in addition , we and others reported that the immunoregulatory effects of mesenchymal stromal cells are , at least in part , brought about by the induction of the tryptophan degrading enzyme indoleamine 2,3-dioxygenase .
we report here that cmv is a major negative regulator of ido activity in human msc , dramatically reducing their immunosuppressive and antimicrobial properties , thereby implicating that active cmv infections may undermine the clinical efficacy of msc treatment .
human bone marrow - derived msc were prepared , propagated , and characterized as previously described .
bone marrow aspirates for the generation of msc were obtained from healthy volunteer donors who had provided written informed consent ; the study was conducted according to the declaration of helsinki principles and approved by the ethics committee of the medical faculty of the heinrich - heine - university , dsseldorf , germany .
okt3 producing hybridoma cells were obtained from the american type culture collection ( rockville , usa ) .
l - tryptophan , l - kynurenine , 1-l - methyl - tryptophan ( 1-mt ) , and ehrlich 's reagent were ordered from sigma - aldrich ( deisenhofen , germany ) .
cmv strains ad169 and tb40e were kindly provided by c. sinzger ( institute for medical virology , ulm , germany ) and a. zimmermann ( institute for virology , dsseldorf , germany ) . before infection of msc ,
the virus - containing solution was thawed and diluted in tryptophan - free rpmi 1640 medium to reach a multiplicity of infection ( moi ) of 0.110 . in some experiments
the enzymatic activity of ido directly correlates with the concentration of kynurenine in supernatants of tissue culture cells and therefore , the measurement of kynurenine can be used to determine ido activity .
msc ( 2 10 per well ) were plated in 96-well flat - bottomed microtiter plates in imdm containing 5% fcs and 0.6 mm l - tryptophan .
the plates were incubated at 37c and after 72 h 160 l were removed from each well and transferred to a 96-well v - bottomed plate .
after the addition of 10 l 30% trichloroacetic acid to each well , the plates were incubated at 50c for 30 minutes to hydrolyze n - formyl - kynurenine to kynurenine .
after centrifugation for 10 min at 600 g , 100 l supernatant was transferred to 96-well flat - bottomed plates and 100 l 1.2% ( w / v ) 4-(dimethylamino ) benzaldehyde ( ehrlich 's reagent ) in glacial acetic acid was added .
after 10 minutes at room temperature , the extinction was determined at 492 nm with a microplate reader ( tecan , crailsheim , germany ) .
in some experiments ido was induced by coculturing msc with okt3-stimulated peripheral blood lymphocytes for three days . as a control 1-l - mt ( 1.5 mm ) or a neutralizing anti - ifn- antibody ( 10 ng / ml ) was added at the time point of msc stimulation .
in addition , ido protein was detected in stimulated msc using western blot analysis as described .
1 10 peripheral blood lymphocytes ( pbl ) , obtained from heparinised blood of healthy donors after ficoll purification , were stimulated with a monoclonal anti - cd3 antibody ( okt3 , american type culture collection , rockville , usa ) in the presence of different amounts of msc as described . in some experiments
msc ( 0.52 10 per well ) were infected with cmv and/or stimulated with ifn- at the start of the culture .
after three days the cultures were pulsed with 0.2 ci [ h ] thymidine for 24 hours .
t - cell proliferation was measured by [ h ] thymidine incorporation using liquid scintillation spectrometry ( 1205 betaplate , perkinelmer , jugesheim , germany ) .
bacterial growth was monitored after further incubation of 16 h by measuring optical density at 620 nm . all data are given as mean sem of at least 3 independent experiments and each experiment was performed in triplicate .
data of representative experiments , also performed in triplicate , were given as mean sd . for the comparison of different data student 's t - test for unpaired groups was used and the p value was calculated using graphpad prism software .
the profound t - cell inhibitory capacity of human multipotent mesenchymal stromal cells has raised much interest promting studies investigating msc as a novel cellular immunosuppressant , in particular in steroid - refractory gvhd after hsct . to explore the potential impact of cmv infections on the therapeutic efficacy of msc in this setting
, we set up a three - party cell culture system , in which okt3-induced t - cell proliferation was assessed in the presence or absence of human msc that were infected with cmv at a multiplicity of infection 5 ( moi 5 ) or left untreated .
as shown in figure 1 we found a profound t - cell inhibitory effect of msc , which was partially but significantly reversed in the presence of cmv .
this effect , however , did not rely on cmv - directed t - cell responses as cmv - infected msc did not induce any t - cell proliferation in the absence of okt3 stimulation ( figure 1 ) .
in addition , t cells from our donors did not proliferate in the presence of cmv and cmv did not significantly alter the t - cell response after stimulation with anti - cd3 antibodies as shown in figure 2(a ) .
we have previously shown that the induction of ido is , at least in part , responsible for the reduced t - cell proliferation induced by msc . to prove this finding we used the ido inhibitor 1-l - methyl - tryptophan ( 1mt ) .
as shown in figure 2(b ) human mscs inhibited t - cell responses and this inhibitory effect could be abrogated by the addition of cmv or of 1-mt . to substantiate these experimental findings
, we performed a series of 15 subsequent experiments employing various numbers of cmv - infected msc .
we found that 2 10 msc provided substantial suppression of t - cell proliferation and the addition of cmv consistently antagonizes this t - cell inhibitory effect . in all 15 experiments performed an inhibitory effect of cmv on msc - mediated t - cell suppression was observed ; however , the magnitude of this effect varied ( figure 3(a ) ) .
in contrast , 5 10 msc were unable to restrict t - cell proliferation and , under these conditions , the same amount of cmv that was employed in the experiments shown in figure 3(b ) did not have any impact on t cells , thus ruling out an unspecific effect of cmv .
taken together , this data demonstrates that cmv infection of human msc substantially impedes their t - cell inhibitory effector function . in previous studies
we and others have identified a significant role of the ifn--inducible tryptophan - catabolizing enzyme indoleamine-2,3-dioxygenase ( ido ) in msc - mediated t - cell inhibition [ 4 , 28 ] . in additional studies ,
the role of ido in tolerance induction was demonstrated in in vivo studies using ido deficient animals .
based on these findings we went on to assess the impact of cmv infection on cytokine - induced ido activity of human mcs . as shown in figure 4(a ) , we observed a substantial ido - mediated kynurenine production when msc were cultured in the presence of okt3-activated t cells . as expected , ido activity induced in msc by activated t cells could be blocked by neutralising antibodies directed against ifn- as well as by the ido - specific inhibitor 1-l - methyl - tryptophan .
however , it is of particular interest that cmv - infected msc were unable to express ido activity in the presence of activated t cells , while uv - inactivated cmv preparations had no impact on ido activity .
thus , an infection with replication - competent cmv substantially impairs ifn--induced ido expression in human msc .
in addition to their immunosuppressive capacity , msc have recently been shown to possess cell - autonomous antimicrobial effects directed against various clinically relevant pathogens [ 5 , 6 , 15 ] .
we therefore proceeded to analyse the potential impact of cmv on msc - mediated antibacterial effects induced by cytokines released from okt3-stimulated t cells .
as shown in figure 4(b ) , msc cocultured with activated t cells are able to restrict bacterial growth and cmv infection of msc abrogated their antimicrobial effect against staphylococcus aureus .
the functional relevance of ido - mediated antibacterial effects was confirmed by demonstrating that addition of excess amounts of tryptophan completely abolished the antimicrobial effector function of msc ( figure 4(b ) ) . in additional experiments we analysed cmv - mediated inhibition of
we found that cmv infection impairs cytokine - induced ido activity of human msc in a dose - dependent manner with significant inhibition observed at cmv doses as low as a moi of 0.6 and with a maximum effect at a moi of 5 ( figure 5(a ) ) .
furthermore , western blot analysis , depicted in figure 5(b ) , showed that cmv infection of msc results in a reduced expression of ido protein . in our present work
we describe for the first time that a cmv infection critically impairs the immunosuppressive and antimicrobial effector functions of human msc possibly via an interaction with the ifn--induced ido pathway .
we demonstrate that this interaction between cmv and ido - mediated effector functions of stromal cells critically depends on intact virus as well as the number of host cells and virus employed .
we have recently reported that human fibroblasts lose their immunosuppressive capacity after a cmv infection and that this finding might be relevant for host - versus - graft reaction disease triggered by cmv infection / reactivation after solid organ transplantation . here
we show that a similar cmv - mediated effect on msc might influence the clinical effectivity of these cells as immunosuppressant .
we are aware of the fact that our observations are derived from in vitro cell culture experiments . in the in vivo situation an immunosuppressive therapy , necessary in transplant patients , might result in an inhibition of ifn- production and therefore inhibit ido induction .
immunosuppressive substances such as glucocorticoides at high concentrations are able to enhance ido activity [ 31 , 32 ] .
furthermore the broad organ tropism , different cell types , and differences in cell tropism might have an impact on cmv - mediated inhibition of ido activation .
however , based on the species specificity of cmv infection as well as ido expression [ 5 , 34 ] , murine in vivo experiments including humanized xenograft models will unfortunately not be informative with regard to the in vivo impact of a cmv infection on msc - mediated immunosuppressive and antimicrobial effects .
we put a particular focus on msc in our study as these cells represent a promising novel therapeutic approach for a variety of clinical applications ranging from tissue engineering and regenerative medicine to the treatment of auto- and alloimmune diseases refractory to conventional pharmacologic immunosuppression [ 35 , 36 ] .
one might speculate that the inhibitory interaction of cmv with ido - mediated immunosuppressive effects may explain the consistent clinical observation that cmv infection frequently triggers gvhd following hematopoietic stem cell transplantation .
the findings presented here may have implications for transplantation medicine and the future clinical use of msc .
we found that msc and fibroblasts are permissive for cmv infection and are able to inhibit viral growth due to ido - dependent mechanisms .
we suggest that the balance between ifn- dose - dependent ido induction and cmv dose - dependent ido inhibition might influence the clinical outcome of organ or stem cell transplantation in cmv - infected patients .
we are aware that the magnitude of virus load and of ifn- concentrations in virus plaques within infected human tissues is unknown .
however we recommend that patients scheduled for msc therapy should undergo thorough evaluation for an active cmv infection and receive cmv - directed antiviral therapy prior to administration of msc , if appropriate , since overt cmv infection of msc recipients may undermine the clinical efficacy of the msc treatment .
thus , strategies that aim at restoring ido expression in cmv - infected msc may prove beneficial in certain clinical scenarios .
further studies characterizing the distinct signalling pathways that are targeted by cmv and result in modulation of ido expression in msc are necessary to identify molecular targets for therapeutic intervention .
Output:
| human mesenchymal stromal cells ( msc ) possess immunosuppressive and antimicrobial effects that are partly mediated by the tryptophan - catabolizing enzyme indoleamine-2,3-dioxygenase ( ido ) .
therefore msc represent a promising novel cellular immunosuppressant which has the potential to control steroid - refractory acute graft versus host disease ( gvhd ) .
in addition , msc are capable of reducing the risk of infection in patients after haematopoietic stem cell transplantation ( hst ) .
recent data indicate that signals from the microenvironment including those from microbes may modulate msc effector functions . as cytomegalovirus ( cmv ) represents a prominent pathogen in immunocompromised hosts , especially in patients following hst , we investigated the impact of cmv infection on msc - mediated effects on the immune system . we demonstrate that cmv - infected msc lose their cytokine - induced immunosuppressive capacity and are no longer able to restrict microbial growth .
ido expression is substantially impaired following cmv infection of msc and this interaction critically depends on intact virus and the number of msc as well as the viral load . since overt cmv infection may undermine the clinical efficacy of msc in the treatment of gvhd in transplant patients , we recommend that patients scheduled for msc therapy should undergo thorough evaluation for an active cmv infection and receive cmv - directed antiviral therapy prior to the administration of msc . |
PubmedSumm4898 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: bilateral hearing loss represents a great disability for patients with neurofibromatosis type 2 ( nf2 ) and patients with vestibular schwannoma ( vs ) in the only hearing ear .
the treatment for vs patients ( unilateral and bilateral ) is diverse , including observation , surgery , and radiotherapy .
treatment of the worst hearing ear in nf2 patients could leave an only hearing ear with tumor and the risk of further hearing loss .
moreover , treatment of vs in an only hearing ear can also lead to deafness .
, auditory brainstem implant ( abi ) has been the only auditory rehabilitation option in patients with no serviceable hearing and previous schwannoma resection .
abi was designed to restore hearing in patients with nonfunctional cochlear nerves who were not candidates for cochlear implantation .
although abi provides environmental sound and significant lip reading assistance , they have not reached consistent results in speech discrimination [ 37 ] .
initially patients should undergo schwannoma resection with preservation of the cochlear nerve as the main goal .
subsequently ci is done in a standard fashion through a cochleostomy or directly through the round window .
results of ci in nf2 patients and vs in an only hearing ear are quite promising [ 810 ] and may provide outcomes comparable to those of postlingually implanted nontumor patients . in this study we reviewed cochlear implantation as hearing rehabilitation in patients with nf2 and in patients with vs in the only hearing ear .
bilateral vestibular schwannomas in a nf2 patient can invade and grow within the cochlear nerve , while unilateral sporadic vestibular schwannoma ( vs ) only compresses it .
also , identification of the surgical plane between the tumor and the cochlear nerve is more demanding on an nf2 patient than on sporadic vs [ 11 , 12 ] . despite the difficulty implied in schwannoma resection , there are reports that demonstrate cochlear nerve preservation after surgery .
different approaches used for tumor removal are retrosigmoid , middle fossa and translabyrinthine [ 810 , 12 ] .
cochlear nerve function is not always preserved in spite of anatomic preservation of the cochlear nerve .
cochlear nerve can be injured during surgery , causing intraneural hemorrhage , disruption of axons , especially in the obersteiner - redlich zone .
a moderate injury can cause hearing loss but still allows electrical transmission of the stimulus .
spiral ganglion cells are the neural structure stimulated by the cochlear implant , therefore crucial for cochlear implantation . with deafness
stated that in contrast with animal studies spiral ganglion cells can survive even in the absence of hair cells .
they demonstrated that 16 of 33 ears had peripheral processes despite the total absence of hair cells .
nadol found in 93 temporal bones of profoundly deaf people a diminished main spiral ganglion population .
the loss of spiral ganglion cells was greater in older patients , with longer duration of hearing loss and located in the basal turn .
patients with aminoglycoside toxicity and sudden idiopathic deafness had the highest spiral ganglion cell counts , whereas patients with the lowest counts were diagnosed with postnatal viral labyrinthitis , congenital deafness , or bacterial meningitis .
the authors described 27,304 4,203 spiral ganglion count in the normal hearing group and 15,463 7,838 in patients with hearing loss ( p = 0.0008 ) .
useful auditory sensation could result from 10% of the total number of ganglion cells .
there is controversy on the role spiral ganglion cells have on speech perception [ 15 , 19 ] .
fayad et al . in 1991 compared the speech results in single channel implanted patients .
blamey also found no evidence of strong association between speech perception and ganglion cell number .
the authors assumed that the minimum number of cells required for speech perception is quite low .
a histopathological study demonstrated a poor correlation between speech performance and number of ganglion cells .
histological studies in temporal bones with labyrinthectomy have demonstrated that enough ganglion cells may survive , proving the feasibility of cochlear implants [ 20 , 21 ] .
another temporal bone study examined 8 specimens from patients who underwent acoustic tumor removal through a translabyrinthine approach . because of different histological cochlear modifications after surgery ( e.g. : ossification , fibrosis ) , they recommended simultaneous cochlear implantation for better results .
coco et al . showed a significant increase in the soma area of ganglion cells adjacent to the stimulating electrodes in cats with profound hearing loss and chronic electrical stimulation .
a significant rescue of ganglion cells in middle and apical turns of stimulated cochlea in animals with partial hearing was also found .
. demonstrated no modification in spiral ganglion cell population with prolonged electrical stimulation ( up to 14 years ) . in the evaluation of trauma to the inner ear by cochlear implantation , nadol found damage to the lateral cochlear wall and basilar membrane in the upper basal turn .
hearing preservation approaches include middle fossa and retrosigmoid . in spite of preservation of the cochlear nerve during surgery ,
theories that explain this finding are direct neuronal disruption of the cochlear nerve and vascular injury to the cochlea . as stated before , promontory electrical stimulation can be used to assess ganglion cell survival .
a possible explanation of anacusis in this case was vascular compromise of the cochlea .
neff et al . also reported cases with postoperative hearing loss with hearing preservation techniques in spite of anatomically preserved cochlear nerve .
they suggested cochlear implantation in these patients even if blood supply is interrupted as long as electrical promontory stimulation ( eps ) is positive .
failure of hearing preservation after surgery has also been described by lustig et al . who included 5 cases with this situation .
patients with good performance with cochlear implantation were supposed to have vascular injury and those with poor performance a significant neuronal injury due to tumor growth or surgical removal .
all patients in this series had some functional improvement with cochlear implantation , emphasizing that even limited electrical stimulation can offer benefit in these patients .
mckenna et al . did a long - term followup ( 3.4 to 10.4 years ) of patients with vs removal via rs approach .
four patients ( 22% ) experienced a decline in pta or sds , probably related to vascular compromise or microscopic recurrence .
this group reported the largest followup in patients with cochlear implantation and vs resection available in the literature .
with a mean followup of 7.9 years , in all but one case , hearing results did not deteriorate over time .
we performed a literature review from 1992 to 2010 by using a comprehensive search strategy in cochrane library , medline , and pubmed databases .
the following search terms were used : neurofibromatosis type 2 , vestibular schwannoma , acoustic neuroma , bilateral hearing loss , deafness , auditory rehabilitation , auditory brainstem implants , radiosurgery , and mri .
the identified articles were assessed for eligibility and only the articles that explored cochlear implantation in nf2 patients and vs in the only hearing ear were selected . only retrospective case series or case reports were available for review .
various centers have reported their outcomes in cochlear implantation and vestibular schwannoma resection [ 810 , 12 , 2836 ] .
twenty - seven patients were treated with vs surgery and cochlear implantation and 6 cases with radiosurgery and cochlear implantation .
only two studies reported two cases with unilateral vestibular schwannoma in the only hearing ear .
a slight better hearing performance could be observed in a unilateral vestibular schwannoma patient compared to the performance of an nf2 patient of the same institution ( vowel identification 100% , bisyllable word recognition 95% versus vowel identification 80% , bisyllable word recognition 90% , resp . ) .
another case with vs in the only hearing ear was published by arriaga and marks .
this patient presented with a postoperative pta of 25 db , the best reported in the literature .
lip reading with the implant was 50% better than without the implant with markedly improved recognition of environmental sounds and communication at home .
regardless of the time of cochlear implantation or approach used , the speech perception outcome through the studies is diverse .
some studies focus on open - set speech perception whereas others report on closed - set tests .
we detail the results in subsequent tables , to be analyzed separately ( tables 1 and 2 ) .
three patients who underwent vs resection and cochlear implantation had 0% in all the speech tests . however , all patients had environmental sound awareness , sound localization , and improved performance .
the variability of the performance was explained by the authors , by variations in the status of the cochlear nerve .
patients were assumed to have difficulty in integrating input from a cochlear implant from the deaf ear with contralateral serviceable hearing .
it is assumed that as patients lose hearing in the better ear they should rely more on the implanted side . in the whole series
only one patient ( 1/6 ) was described as a telephone user in the radiosurgery group
. this may be due to the lack of reported data in the radiosurgery patients .
the daily use of the cochlear implant was reported in 16 patients ( 48% ) .
theoretically , a prompt implantation will reduce cochlear fibrosis or ossification and avoid multiple interventions .
overall , the authors reported good results compared to their counterparts ( delayed surgery ) .
this was the only case of postponed cochlear implantation in tl surgery . in another case from another institution , cochlear implantation was attempted one year after tl surgery .
the authors found total ossification and implantation could not be performed . due to bilateral hearing loss secondary to nf2
, they decided to resect the contralateral vs with simultaneous ci in that side , which was performed uneventfully .
the longest period between surgery and implantation was 84 months following a retrosigmoid approach , with reported hearing gain .
, with an average of 7.9 years after ci . to assess the status of the cochlear nerve , electrical promontory stimulation
is recommended before implanting patients with vs. promontory or round window stimulation evaluates the neurons in the cochlear spiral ganglion .
however , false negative stimulations have been described if eps is performed too close to the surgical event . it is recommended to repeat measurements 68 weeks postoperatively , even after a previous negative measurement . in the literature review we found four cases with promontory stimulations initially negative and subsequently positive ( tables 1 and 2 ) .
the possible mechanism of this phenomenon is described by the authors [ 8 , 12 , 34 ] .
one theory states possible surgical damage to the cochlear nerve with postoperative inflammation that subsequently subsides .
reported a case in which the eps was negative , and because cochlear nerve integrity was certain , they proceeded with the cochlear implant .
another case with negative eps was published by trotter and briggs after radiosurgery , the results showing improved outcome with 72% in cuny sentences in quiet and 45% in cnc words .
only one patient had postoperative positive eps suggesting vascular compromise to the cochlea ( especially stria vascularis ) with a partially intact cochlear nerve . the majority of the studies reviewed ( table 1 ) reported positive electrophysiological studies consisting of electrical promontory stimulation ( eps ) or compound action potential ( cnap ) .
authors considered the performance of electrophysiological tests an important examination prior to implantation , although not crucial .
thirteen cases of the present review did not have data on electrophysiological tests and were nonetheless submitted to cochlear implantation .
arstegui and denia reported one case with 100% in daily words and 100% in cid .
other cases had no reported eps or speech tests but authors reported subjective auditory benefit .
in addition to two cases with negative eps , a total of 15 cases underwent ci without objective evidence of cochlear nerve function .
the speech tests results in conventional postlingually deaf adults undergoing conventional ci are similar with all devices manufactured .
good results in speech discrimination achieved by these patients are published through the literature [ 3742 ] , in general : 80 to 90% in vowel recognition , 5060% in bisyllable identification , 70 to 100% in word recognition , 65% to 80% in correct sentence recognition scores [ 3739 ] , 85% hint in quiet score , and 65% in hint in noise score .
two factors implied in good performance were age at implantation and duration of deafness .
the house clinic reported that up to one - third of postlingual adults undergoing implantation achieve open - set speech recognition .
highlight the similarity of speech tests results between ci patients after vs resection compared with conventional postlingually implanted patients .
neff et al . described hint results ranged from 83 to 96% , cid between 22100% .
on the other hand , arstegui and denia found 100% daily words recognition and 100% in cid in two postimplanted patients with vs resection .
described the results of open sentences recognition test without lip reading from 8197% , although lustig et al .
reported more variable results when 3 of their patients performed 0% in all speech tests .
the best results in speech discrimination achieved by postimplanted patients with nf2 or patients with vs in the only hearing ear are comparable with the results obtained by conventional postlingually deaf adults .
( 2009 ) , compared open - set speech perception in tumor and nontumor patients treated with abi .
they found 10100% on open - set speech perception scores in nontumor patients , compared with 531% in tumor patients .
the authors conclude that abi is an effective tool for hearing rehabilitation in patients with profound hearing loss who can not be fitted with cochlear implants ( ci ) .
grayeli et al . reported open set dyssyllabic word recognition of 36% for vision only mode , 3% for sound only mode , and 65% for vision plus sound mode in nf2 patients with abi .
combined with lip reading cues , 93% of patients improved sentence understanding in 3 to 6 months .
most patients had environmental sound awareness and understanding of closed set words , consonants , and vowels , while open set speech discrimination was difficult to achieve .
in contrast , lenarz et al . reported better results with 2 out of 11 patients achieving some kind of telephone conversation .
in general open set speech recognition in the auditory mode alone is not common among patients implanted with abi [ 5 , 6 ] .
the only study found to compare abi versus ci after vs resection from the same institution was performed by vincenti et al . .
they included 9 patients , 4 with ci and 5 with abi . at 1-year followup ,
mean common phrases comprehension score was 60% in the ci group and 29% in the abi group .
mean sentence recognition score was 55% in the ci group and 27% in the abi patients .
moreover , mean bisyllabic word recognition score was 53% in the ci group and 32% in the abi group .
the authors concluded that when possible the ci should be the preferred hearing rehabilitation device for patients with vs , not only because of the better hearing results , but also because of the reduction of the surgical risks and lesser extent of the operation .
as poor speech reception results are prevalent in the abi literature , it is recommended to preserve the cochlear nerve during vs resection in order to achieve better hearing results with a cochlear implant .
radiosurgery is an alternative to surgery for patients with vs. this treatment consists in the delivery of ionizing radiation to the intracranial target with the use of a stereotactic technique [ 43 , 44 ] .
irradiation of head and neck tumors without ear involvement has shown to affect ganglion cell population in a temporal bone study .
marked spiral ganglion loss in the basal turn of the cochlea was found in the irradiated group compared with the same area in controls .
guinea pigs also showed damaged to outer and inner hair cells after fast neutron irradiation greater than 15 gy . in relation to gamma knife surgery , linskey et al . described the radiation exposure of normal temporal bone structures during gamma knife surgery .
a mean of 5.5 gy absorption was found at the inferior portion of the basal turn of the cochlea and 8.9 gy absorption at the modiolus of the basal turn .
although doses greater than 12 gy are described as potentially toxic to the inner ear , the basal turn of the cochlea absorbed doses greater than 12 gy in 10 to 14% of cases . additionally a change in pta was significantly poorer at 12 months for patients whose cochlea received 4.75 gy or more .
examined 59 patients and found a hearing loss pattern consistent with stria vascularis devascularization after gamma knife surgery , that is , hearing loss across all frequencies and relative preservation of speech discrimination ability .
based on this data , direct cochlear damage could be the sole cause of post radiotherapy hearing loss .
furthermore , they did not find a correlation between change in tumor size after radiotherapy and hearing loss , making tumor edema a less likely cause . in order to confirm this ,
more studies are required , including temporal bone histopathology examination . among series describing cases with cochlear implantation after radiation
are those of lustig , tran ba huy et al . , and trotter and briggs .
lustig et al . reported 2 cases treated with radiosurgery and then cochlear implantation .
these 2 cases had the best speech test results at that same institution ( one patient mtsr 46% , the other sds 46% , hint 98% ) .
and trotter and briggs [ 13 , 30 ] reported good results in speech score tests after cochlear implantation and radiosurgery in 3 more patients .
mean followup was 32 months with no sign of malignancy until the end of followup ( table 3 ) .
an important issue in nf2 patients and patients with resected vs is the necessity of followup with mri . to perform mri , there are basically 3 options : removal of the magnet before mri , implantation of magnetless device , and implementation of low tesla 's mri .
the risks of mri imaging in patients with the magnet device in place include potential device displacement , overheating of the surrounding tissues , demagnetization of the device , and cochlear implant malfunction .
ci magnets described to be removable by a surgical procedure are cochlear corporation ci24 m , ci24r , nucleus freedom , ci24abi devices , and advanced bionics hires90k .
this option requires two minor surgical procedures , one to remove the magnet and another to replace it .
current us fda guidelines have approved the use of 0.2 to 1.5 teslas with the magnet in place in pulsar and sonata med - el corp .
unfortunately , 0.2 or lower than 1.0 tesla mri is not available in most hospitals , while 1.5 tesla is becoming more universally used .
ex vivo and in vivo studies recommend the use of 1.5 teslas for a safe mri scan in patients with cochlear implant [ 52 , 53 ] .
baumgartner et al . published the results of 30 cochlear implants undergoing 1.0 tesla mri examination .
they recommended scanning med el combi 40 and nucleus mini 22 series at 1 tesla as a safe procedure , magnet removal being not necessary . during a 1.5 tesla mri scan ,
the force described with the magnet removed is 0.03 n in a 1.5 tesla mri . on the other hand , with the magnet in place
the force is 0.42 n. however , the force described to fracture the ci receiver bed was much higher than that generated by a 1.5 tesla mri .
deneuve et al . reported a case of magnet displacement during 1.5 t mri .
interestingly , the authors took all precautions and had an external fixation dressing at the time of the mri .
other authors suggest that previous surgery to remove and replace the magnet in this patient may have weakened the pocket .
heating of the ci during 1.5 tesla mri is reported to be lower than 0.1c and the electrical stimulation is less than the intensity required for auditory stimulation . in an ex vivo study ,
a maximum temperature of 2.0c is set by the industry standard as the temperature that can damage the tissues and cause patient discomfort .
reported that demagnetization depends on the angle between the magnetic field of the ci magnet and the mri .
another issue to consider is the image quality obtained from the mri scan . while in the contralateral side of the cranium and remainder of the body
, the image has no distortion ; ipsilateral soft tissues within 7 to 8 cm from the magnet are poorly visualized .
some authors recommend combining mri with high resolution ct with contrast to counterweigh the area of image distortion .
an ex vivo study performed mri tests ( 1.5 tesla and 0.3 tesla ) to a clarion 1.2 magnet - containing cochlear implant .
the area of distortion had a radius of 60 mm in the 1.5 tesla mri group and 100 mm in the 0.3 tesla group .
furthermore , a retrospective study by the john hopkins university included 16 patients with ci from 3 major manufactures .
they reported an artifact on brain mri with a maximal anterior - posterior dimension of 6.6 cm and a lateral dimension of 4.8 cm around the magnet device with no difference among the 3 ci manufacturers .
the contralateral internal auditory canal was seen in all patients and the ipsilateral internal auditory canal was at least partly visible in all but one patient . no magnet displacement was observed .
they recommended the use of 1.5 teslas mri in ci patients . on the other hand ,
in a 1.0 tesla mri setting reported minimal artifact although they provided no artifact area measurements and it was not clear whether the ipsilateral iac was evident on mri . see figure 2 for an example of mri followup in an implanted patient .
a safe use of 1.5 t mri is recommended for cochlear implant patients . in patients with nf2 and vs , ipsilateral mri control can be accomplished with adjuvant ct with contrast , and an artifact around 5 cm should be expected .
cochlear implantation in patients with neurofibromatosis type 2 and patients with vestibular schwannoma in the only hearing ear is a reasonable hearing rehabilitation option .
auditory benefit can be expected in most patients , and in good candidates excellent benefit with good speech discrimination and telephone use may be achieved .
although not crucial , promontory stimulation for evaluating the integrity of the cochlear nerve is recommended .
mri up to 1.5 teslas with external head fixation can be done safely in cochlear implanted patients .
Output:
| cochlear implants are a new surgical option in the hearing rehabilitation of patients with neurofibromatosis type 2 ( nf2 ) and patients with vestibular schwannoma ( vs ) in the only hearing ear .
auditory brainstem implant ( abi ) has been the standard surgical treatment for these patients .
we performed a literature review of patients with nf2 and patients with vs in the only hearing ear .
cochlear implantation ( ci ) provided some auditory benefit in all patients .
preservation of cochlear nerve integrity is crucial after vs resection .
results ranged from environmental sound awareness to excellent benefit with telephone use .
promontory stimulation is recommended although not crucial .
mri can be performed safely in cochlear implanted patients . |
PubmedSumm4899 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: regular home oral care and a yearly dental check - up are the best means for saving one s own teeth , but it appears that in spite of the information on adequate dental care provided by the dental professional and the mass media many people fail to take these precautions . although social factors are included in several models explaining the use made of health services or health behavior , individual factors are also emphasized presenting thorough discussion of subjective and environmental constraints regarding the adoption of ideas arising from health education . in order to take care of his teeth in a regular manner , a person has to introduce an innovation into his life - a new attitude to dental health .
the reasons which prevent the change to the desired dental behavior are viewed as various forms of rejection of the innovation .
epidemiological studies have shown high prevalence of dental diseases . despite the pervasive need for treatment , less than half the adult population visit the dentist in a year .
the interest in developing models explaining the utilization of dental services has increased ; issues like dental anxiety , price , income , the distance a person had to travel to get care and preference for preservation of teeth are treated as barriers in regular dental care . according to schuurs et al , three factors ; namely , dental anxiety , preference for preservation of the teeth and the family dental health problem were found to be associated with regular and irregular dental attendance .
nowjack - raymer and gift reports four major groups of factors influencing the use of dental services which comprises demographic factors , attitude towards dentists and dentistry , access to care and health services .
andersen defines three main concepts explaining the use of health services ; namely , predisposing factors , enabling factors and the need for use of services .
predisposing factors are an individual s characteristics which reflect the propensity to use health services .
andersen s predisposing factors include three subcategories such as health attitudes , social structure and social demographic factors .
india is one of the largest democracies in the world , with a population of one billion .
it is a rapidly developing nation and is making great progress in it , finance and living standard . in spite of these
, it is very sad to know that very few people believe in regular dental care .
the inverse care law states that about 80 percent of the indian population resides in the rural areas , most without health care access , while only 20 percent of india s dentists serve the large population of rural residents .
it is believed that 80 percent of dentists are serving in cities where only 20 percent of the population resides .
although dentist ratio is high in cities or urban areas , people still do not show regular dental care or dental attendance .
use of dental services is more discretionary than use of either physician or hospital services because oral conditions are not life threatening .
data collected over the past few years have shown that about 36% of the general population visit dentists during any one year period . a smaller percentage of them visit twice yearly .
it was analyzed that the most important factor influencing dental visits was the cost . in an attempt to ascertain the factors associated with irregular dental care
, this study was carried out to determine the barriers that prevent regular dental care or attendance for dental check - ups and to assess their association with age , sex , education , income and dental behavior .
the study was carried out in debari village situated twenty kilometers from udaipur city , rajasthan .
simple random sampling was done to obtain a sample size of 427 young and middle aged individuals from debari .
young and middle aged individuals were preferred in order to obtain a homogeneous population and to minimize the number of patients with full dentures .
the age distribution of the participants was as follows : 2535 years and 2645 years .
educational background of the individuals was as follows ; basic education : primary , middle and higher school education and further educational group included the graduate and postgraduate education .
the data were collected by means of a questionnaire usually filled in the presence of the investigators , who gave additional information whenever needed . prior to the data collection
the questions were pre - tested among a group of 50 individuals revealing no need for any corrections .
kappa value was 0.85 for the questionnaire . a structured questionnaire designed in the local language consists of 14 questions
among which four were included in reasons preventing daily home care and 10 in reasons preventing yearly dental check - ups .
each respondent was asked a series of questions about his health beliefs , attitude and his last dental visit .
the answer very much was scored as one , to some degree as two , and not at all as three .
responses to the questionnaire were analyzed using chi - square test to assess the association between demographic characteristics .
a significant relationship was assumed to exist between the groups if the p value was found to be less than 0.05 ( p<0.05 ) .
logistic regression was performed using age , sex and education as independent variables and dental visits as dependent variables .
the study was carried out in debari village situated twenty kilometers from udaipur city , rajasthan .
simple random sampling was done to obtain a sample size of 427 young and middle aged individuals from debari .
young and middle aged individuals were preferred in order to obtain a homogeneous population and to minimize the number of patients with full dentures .
the age distribution of the participants was as follows : 2535 years and 2645 years .
educational background of the individuals was as follows ; basic education : primary , middle and higher school education and further educational group included the graduate and postgraduate education .
the data were collected by means of a questionnaire usually filled in the presence of the investigators , who gave additional information whenever needed .
prior to the data collection the questions were pre - tested among a group of 50 individuals revealing no need for any corrections .
a structured questionnaire designed in the local language consists of 14 questions among which four were included in reasons preventing daily home care and 10 in reasons preventing yearly dental check - ups .
each respondent was asked a series of questions about his health beliefs , attitude and his last dental visit .
the answer very much was scored as one , to some degree as two , and not at all as three .
data were analyzed using spss version 11.5 software ( spss inc . , chicago , il , usa ) .
responses to the questionnaire were analyzed using chi - square test to assess the association between demographic characteristics .
a significant relationship was assumed to exist between the groups if the p value was found to be less than 0.05 ( p<0.05 ) .
logistic regression was performed using age , sex and education as independent variables and dental visits as dependent variables .
a total population of 427 comprising of 248 males ( 58.1% ) and 179 females ( 41.9% ) in the age group of 2545 years with a mean age of 35.25 were included in the study ( table 1 ) . among the study population ,
78.2% of the study population had average knowledge of dental care , 52.9% agreed on having better oral health after brushing .
34.4% of the population had fear of the painful dental procedures , 49.9% to some extent believed that dental care is expensive .
laziness and unpleasant experiences did not have any association and were not considered as a barrier in regular dental care .
but the majority of the study population ( 50.1% ) believed in felt need and was not aware of the prevention ( table 2 ) .
the majority of the study population ( 38.4% ) belonged to the lower income group , 28.6% to middle income group and very few ( 1.6% ) belonged to the higher income group ( table 1 ) . in this study
, 50% of the population who had higher education did not find any difficulty in arranging an appointment with the dentist in comparison to those who had basic education ( 42.42% ) with a highly significant p value of less than 0.05 .
in addition , it was found that the expense of dental care was less restrictive among the higher education group ( p<0.05 ) and the younger age group ( p<0.05 ) .
the association between the expense of dental care and gender was not statistically significant ( p>0.05 ) ( table 2 ) .
dental fear was highly significant among females ( 17.3% ) in comparison to males ( 14.56% ) , with a p value less than 0.05 .
65.32% of the males had unpleasant dental experiences compared to 45.81% of the females with a significant p value ( p<0.05 ) . among the study population ,
subjects of 2535 years age group ( 13.79% ) had significant better knowledge of dental health care in comparison to 9.23% of the 3645 years age group ( p<0.05 ) .
it was also seen that laziness was of no much concern among the younger age group ( 65.94% ) in comparison to the other age group ( 50.25% ) with a p value < 0.05 ( table 3 ) .
logistic regression showed that the younger age group had 4.553 times more visits within one year than the other age group with ( p<0.05 ) .
besides , males had 0.411 times higher dental visits than females which was not statistically significant ( p>0.05 ) .
education had a significant association ; higher education group showed 0.088 times higher dental visits than the lower education group ( p<0.05 ) ( table 4 ) .
the higher income group in the study population had better access , affordability for dental procedures compared to the lower income group .
but in spite of this , income had a negative correlation with dental visits ( table 5 ) .
social factors are important as shown in various models , but here we concentrated on subjective reasons which act as barriers in regular dental care , because the individual himself is mainly responsible for his regular dental care and dental attendance .
the finding of this study was based on sex , age , education and income in association with the last dental visit .
this study showed that the younger age group visited the dentist more regularly in comparison to the older age group ( table 3 ) , which was found to be similar to a study by syrjala et al .
this may be due to the fact that the younger age group had more knowledge and fewer barriers .
it was also found that the older age group did not think that oral health was important .
previous studies by fukai et al , meng et al , liddell and locker , brukiene et al , heft et al and skaret et al found that dental fear is related to dental attendance .
meng et al assessed the effect of fear on a number of dental utilization behaviors and oral health outcome in a sample of adult from floridians .
they found that dental fear and fear of dental pain have independent negative effects on dental utilization behaviors and oral health outcome after controlling for other sociodemographic and general health factors .
similar findings were found in a study by liddell and locker , where the thoughts , feelings and behavior regarding dental treatment was assessed in a group of subjects of metropolitan toronto .
this study demonstrated that attitudes to dental pain and dental control have some gender and age specifications and the most important contributor of dental anxiety for both male and female subjects was fear of dental pain . in the present study , females showed higher dental fear which was also seen in other studies by fukai et al and liddell and locker .
this may be one of the reasons of dental visit being lower in females in the present study in comparison with the male population .
unlike other studies by heloe et al and pizarro et al , where even though dental fear was more common in females , they utilized dental services more frequently than males possibly due to the fact that females have greater tendency to expect good outcome from dental attendance . on the other hand ,
brukiene et al and quteish taani said that anxiety itself may make an appointment unpleasant .
according to quteish taani , dental anxiety constitutes a major problem for patients and dental care providers alike .
he conducted a study to examine the association between dental anxiety and regularity of dental attendance among young adults .
the results showed that only 20.9% were regular dental attendees while the majorities ( 79.1% ) were irregular attendees .
the reasons given for irregular attendance were lack of time ( 36% ) , treatment not needed ( 34.1% ) , fear from dentist ( 13.3% ) and cost ( 16.6% ) . the sight and sensation of the injection and sight , sound and sensation of the drill were the most common fear eliciting stimuli .
females had higher mean ratings , therefore tended to be more anxious than males . dental anxiety , represented by the mean responses to the items ,
there can be no doubt that patient charges affect the use of dental services as found in previous studies by syrjala et al , reisine and yule et al .
petersen et al said that dental visits may be influenced by dental health status , expectations about the value of dental care , income and the price of dental care . in the association between cost of dental care and education
, it was found that the higher education group found the expense of treatment less restrictive than the lower education group , which was in accordance with previous studies by syrjala et al and kegeles .
socio - economic constraints were one of the reasons for irregular dental visits in a study by kegeles and muirhead et al .
kegeles made an attempt to understand what motivates people to seek dental care and what keeps people from making dental visits .
interviews with the employees of endicott - johnson corporation established that among the motives promoting people to seek preventive dental care is the belief that one is susceptible to dental disease , a belief that dental treatment is beneficial , a belief in natural causality , an esthetic concern for one s teeth , a lack of anxiety about dental treatment , no fear of pain and a positive appraisal of the dentist .
according to kegeles the distance a person had to travel to get dental care was found to influence the visits , but in the present study there was no significant relationship between distance and dental visits which was in accordance with a similar study by petersen et al .
muirhead et al used the gelberg - andersen behavioral model for vulnerable populations to identify predictors of dental care utilization among working poor canadians .
this study identified predisposing and enabling vulnerabilities that jeopardize the dental care seeking practices of working poor persons .
dental care utilization was associated with relinquishing spending on other goods and services , which suggests that dental care utilization is a competing financial demand for economically constrained adults . in this study
, income seemed to have a negative and significant correlation with the dental visits ( table 5 ) , which was also found in the study by petersen et al . on the other hand , in contrast to this finding a positive correlation
this negative correlation may be due to the social and cultural beliefs of the people .
in previous studies by reisine , afonso - souza et al , schuurs et al , al - shammari et al , lopez and baelum , and poudyal et al , patient dental need was found to be the predictor of regular dental visits .
afonso - souza et al investigated the association between routine visits for dental check - up and self - perceived oral health .
data were obtained from 3252 participants . when compared with individuals who reported self - perceived oral health as good ,
individuals who reported self - perceived oral health as bad were significantly more likely to be older , male , less educated , poorer ; they also reported losing teeth more frequently and not visiting the dentist for routine dental check - up. in a study by al - shammari et al , conducted to assess the prevalence of preventive dental visits and to identify self - reported barriers for this practice among kuwaiti adults , it was found that the most common reasons for the last dental visits were pain or a dental emergency , need for restorative treatment and an examination / prophylaxis . besides , older respondents , female gender and those having only high school education or less were less likely to visit a dentist for preventive reasons .
lopez and baelum demonstrated that socioeconomic and behavioral factors are independently associated with the frequency of and reasons for dental visits in this adolescent population and that self - perceived poor oral health status is strongly associated with infrequent dental visits and symptoms .
poudyal et al conducted a study to assess the factors related to the utilization of dental services in a field practice area in mangalore . in this study , the reported reason for not visiting the dentist in the past was
i havent had any problems with my teeth followed by lack of time and fear of painful dental procedures .
similarly this study also revealed the patient s perceived need that people visited the dentist only if they had symptoms which may be due to their belief that dental conditions are not serious or life threatening .
many factors revealed aspects which have been shown to restrict regular dental care . given recent controversy about the desirability of six monthly dental check - ups , it could be argued that some reduction in the frequency of dental visits would not be injurious to health , but in order to promote health and prevent illness , having regular dental visits would be a better response . to improve the regular dental attendance , the barriers have to be controlled by appropriate education and intervention .
the results support the idea that in order to motivate people successfully , one not only has to give them information but also has to pay attention to the individual reasons which restrict their behavior
. the limitations of the present study were namely the small sample size and localization of the study to a particular area ; therefore , to determine the relative effects of socioeconomic factors and the barriers , further investigation should be conducted .
if we want to gain a better understanding of how adults use dental services and why , a more sophisticated indicator of use , is needed to determine who the regular attendees are and what structural and oral health variables are important predictors of attendance .
utilization of oral health care has long been used as an indicator of oral health related behavior . the highly reported reason for not visiting a dentist in this study was
i havent had any problems in my teeth indicating the low felt need of the people which calls for improving their awareness and motivating them to use the services available for them so that they lead a socially and economically productive life .
many other factors revealed aspects which have shown to restrict regular dental care such as knowledge about dental care , dental fear , expense of dental care , unpleasant dental experiences and socioeconomic factors .
Output:
| objective : regular home care and yearly dental check - ups are the best means of dental care . in spite of the information on dental care , many people fail to take these precautions .
the objective of this study was to determine the barriers in regular dental care and home care and to assess their association with age , sex , education and income.materials and methods : a cross - sectional survey was conducted among 427 randomly selected individuals , 248 males and 179 females .
data were collected by a pre - tested , self - administered 14 question questionnaire .
the answer very much was scored as one , to some degree as two and not at all as three .
the data was described and analyzed by frequency distribution and chi square test with p<0.05 level of significance .
logistic regression was used to investigate the association between dental visits with age , sex and education .
correlation between income and dental visits was determined by spearman s correlation coefficient.results:the male group had more dental visits ( p>0.05 ) , but females experienced higher dental fear ( p<0.001 ) .
the younger age group had more visits within one year in comparison to the older .
increase in education , decreases the barriers for regular dental care .
income had a significantly negative correlation with dental visit ( p=0.02).conclusion : our findings suggest that males believed in having regular dental care .
cost of the treatment also affected the dental visits , but the distance they had to travel to get the dental treatment was not much significant .
above all , felt need had a major impact on the dental visits . |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.