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PubmedSumm118500 | ***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: acne is a very common dermatological problem , especially in teenagers and also quite frequently in adults .
scarring and postinflammatory hyperpigmentation ( pih ) are the two main complications of acne and are also the prominent reasons , which principally bring patients to a dermatologist .
pih occurs with higher frequency in fitzpatrick skin types iii - vi and though not life - threatening , it may cause significant distress to the patient .
dermal hyperpigmentation can take years to fade to normal , while the epidermal variant can take up to 6 - 9 months .
pih is generally clinically apparent a few weeks after erythema from acne subsides . in severe cases ,
the patient may withdraw from group settings owing to the social stigma attached to this cosmetically displeasing condition .
many topical medications have been used for pih , including keratolytics , retinoids , corticosteroids , and depigmenting agents .
although individual agents can be used with some success , the most significant improvement may be achieved with a combination therapy of topical medications and adjunctive dermatosurgical or cosmetological procedures .
a few of the procedures available are chemical peeling with glycolic acid , salicylic acid , and trichloroacetic acid and laser modalities such as q - switched ( qs ) ruby laser , q - switched alexandrite laser , and q - switched neodymium - doped yttrium aluminum garnet ( qsny ) laser .
we wish to share our experience with the 1,064-nm qsny laser in the treatment of acne - induced pih .
seventy - eight patients , 65 females and 13 males aged between 18 years and 27 years and with fitzpatrick skin types iv - vi were considered for the study .
inclusion criteria were all cases of persistent ( unresponsive to various topical medications and lasting for 3 months or more ) acne - induced pih who were willing to undergo the procedure .
patients with pregnancy or planning for pregnancy , those with systemic diseases or other facial skin disorders , those who were lactating , had active acne lesions , on topical medications for the preceding 2 weeks , and on oral isotretinoin for the preceding 6 months were excluded from the study .
a pretreatment history of the onset , duration of the condition , and response to previous medications was elicited .
written consent was taken from all patients and they were explained about the risks , benefits , and potential complications of the laser therapy . topical anesthetic ( lidocaine 2.5% and prilocaine 2.5% )
six treatments at two weekly intervals were administered to all patients using 1,064 q - switched mode with 1.5-mm spot size , 2-hz repetition rate , pulse width of 6 ns , and a fluence of 450 mj in all sessions ( coherent medical system portable model , 2012 , ( precise co ; shanghai ; supplied by coherent , mumbai , india ) ) .
prilesional erythema with whitening of fine hair was considered as the end point . immediately after the procedure
, a combination of betamethasone and fucidic acid cream was applied to the irradiated areas for up to 3 days .
patients were advised to avoid direct sunlight and use sunscreen at least thrice a day .
the immediate transient effects observed were stinging , erythema , edema , and punctate bleeding , which settled down in 1 - 2 days .
in very few cases , mild crusting was noticed after 2 - 5 days , which cleared without any sequelae .
a blinded evaluator assessed the changes in the severity of pigmentation and the same evaluator was used at each session for a given patient .
improvement of pih was graded on the following scale : score 1 : none ( 0% improvement ) score 2 : poor ( 1 - 24% improvement ) score 3 : fair ( 25 - 49% improvement ) score 4 : good ( 50 - 74% improvement ) score 5 : excellent ( 75 - 100% improvement ) one and 3 months after the last treatment , participants and physicians were asked to rate the improvement in the same categories using the same scale .
the student 's t - test ( paired samples ) was used to analyze the data .
there were 13 male ( 17% ) and 65 female ( 83% ) patients , with a mean age of 23 years ( age range of 18 - 27 years ) .
out of 78 patients , five patients dropped out of the study after four sessions and the remaining completed all six sessions done twice weekly .
only one female patient exhibited transient confetti - like hypopigmentation , which recovered spontaneously within 10 days without any active intervention .
the immediate cutaneous response was mild to moderate erythema and edema in all of the patients , which subsided in a couple of hours .
serial follow up photographs of a few patients are depicted in the pictures [ figures 13 ] .
( a ) before treatment of hyperpigmentation on the forehead of a male patient ( b ) treatment with qsny laser ( c ) edema and erythema after 10 min ( d ) significant lightening of pigmentation after three sittings ( e ) complete resolution after six sittings ( a ) before treatment of hyperpigmentation on the forehead of a female patient ( b ) treatment with qsny laser ( c ) good reduction of pigmentation after three sittings ( d ) significant lightening after six sittings ( a ) before treatment of hyperpigmentation on the left malar area of a male patient ( b ) immediately after treatment ( c ) good reduction in pigmentation after three sittings assessment of blinded evaluator and pre- and postphotography revealed significant improvement in pih [ tables 1 and 2 ] .
patient satisfaction score for treatment physician scores for treatment patient satisfaction scores revealed that 56/73 ( 76.7% ) patients had noticed good to excellent improvement .
only 3/73 ( 4.1% ) patients felt that there was hardly any or poor improvement .
the blinded evaluator scores revealed that 63/73 ( 86.7% ) patients had good to excellent improvement while only 3/73 ( 4.1% ) patients had hardly any or poor improvement .
these values were found to be highly significant by paired t - test ( p < 0.001 ) .
pih is a very common sequela of various inflammatory dermatoses and tends to affect darker skinned patients with greater frequency and severity .
the first is pigment incontinence , which occurs after the basal cell layer in the inflamed skin is destroyed leading to accumulation of melanophages containing a large amount of melanin in the upper dermis .
the other process involves an epidermal inflammatory response , resulting in the release and oxidation of arachidonic acid to prostaglandins and leukotrienes .
these mediators stimulate increase in the synthesis of melanin in melanocytes and transfer of pigment to the surrounding keratinocytes .
epidermal hypermelanosis usually appears as tan , brown , or dark brown while dermal pigmentation has a blue - gray appearance .
most cases improve spontaneously ; some take months or years to resolve and some remain permanent .
treatment may be prolonged , lasting for 6 - 12 months or longer for adequate restoration of normal pigmentation .
photoprotection , including sunscreens , sun - protective clothing and hats , and sun avoidance , also helps to prevent any further increase in melanin production .
effective treatment strategies for acne pih include using topical depigmenting agents for 3 months as first - line treatment .
this can be followed by laser treatments such as 595-nm long - pulsed dye laser ( lpdl ) that targets any vascular inflammatory component . for recalcitrant dermal pigmentation ,
first - line management of pih includes topical tyrosinase inhibitors such as hydroquinone , kojic acid , azelaic acid , arbutin , licorice extracts , and others such as retinoid , ascorbic acid , niacinamide , and soy , along with a number of emerging therapies .
the role of laser treatment in pih is usually reserved for lesions that remain refractory after several months of topical therapy .
lasers that have been mainly tried in pih include q - switched ruby laser , pulse dye laser , fractional co2 , qsny , and the intense pulsed light .
the green ( 510-nm , 532-nm ) , red ( 694-nm ) , or near - infrared ( 755-nm , 1,064-nm ) lasers are those which are pigment - specific and can selectively target intracellular melanosomes .
the problem with the pigmentary laser is that due to the wide absorption spectrum of melanin ( 250 - 1200 nm ) , laser energy that is intended for deeper targets can also be absorbed by the pigment in the pigmented epidermis , which can lead to complications such as dyschromia , blistering , and scars .
the 595-nm lpdl has been previously used in the treatment of acne - induced pih .
a previous study demonstrated transepidermal elimination of dermal component through incorporation into microscopic epidermal necrotic debris .
the expulsion of dermal pigment in conjunction with the affected microthermal zones ( mtzs ) is the most likely mechanism of action when treating pih .
traditionally , the qsny laser delivers pulses with durations in the nanosecond range , which are thought to generate acoustic waves within the biological tissue . with a longer wavelength ,
the 1,064-nm qsny is used to target any dermal pigment , which may be too deep for topical agents to penetrate .
cho et al . reported a good improvement in three patients of pih treated with 1,064-nm qsny laser at fluences of 1.9 - 2.6 j / cm and five sessions .
ho et al . found good results with 1,064-nm qsny ( medlite c3 or c6 ) where energy was 13 - 2.5 j / cm , frequency was 10-hz , and spot size was 6 - 8 mm in nine patients .
laser toning using low fluence , large spot size , multiple passes of 1,064-nm qsny laser has also recently gained popularity in the treatment of pih . here
, multiple passes of low - fluence ( 1.6 - 3.5 j /cm ) are delivered through a large spot size ( 6 - 8 mm ) to optimize energy delivery and achieve mild erythema as the clinical endpoint .
daily usage or treatments at weekly , twice in a week , or monthly intervals with a wide variation in the total number of treatment is recommended . in our study , we used 1,064 mode with 1.5-mm spot size , 2-hz repetition rate , pulse width of 6 ns , and a fluence of 450 mj in all sessions .
it was been proposed that 1064-nm qsny laser can be used in pih treatment at a low - fluence setting .
kim and cho demonstrated effective treatment by full - face low - fluence 1,064-nm qsny laser in acne pih in skin photo types , fitzpatrick ( spts ) iv - vi patients . in this study 1,064-nm qsny laser treatment was found to be effective at treating pih with statistical significance .
our study is one of the initial studies , which have demonstrated the efficacy of qsny laser in acne pih in a larger number of patients . in our study
, 76% patients felt that they had good to excellent improvement while physician evaluation revealed that 86% patients had good to excellent improvement .
these values suggest a significant improvement in pih by using qsny laser both statistically and clinically .
confetti - like or spotty hypopigmented macules or punctate leukoderma and rebound hyperpigmentation are common side effects associated with low - fluence 1,064-nm qsny laser . in our study , we did come across only one patient of transient hypopigmentation after sessions with qsny laser , which recovered without any active treatment within 10 days .
therefore , further studies involving the control subjects are required to study the efficacy and safety of qsny laser in pih .
therefore , further studies involving the control subjects are required to study the efficacy and safety of qsny laser in pih .
management of long - lasting pih due to acne is a psychological and cosmetic morbidity and it remains a challenge , especially in dark - skinned individuals .
although many treatment options are available for pih , it takes months for pih to resolve , even with an adequate therapy .
the advantages of qsny are minimal downtime and absence of adverse effects such as bleeding and crust formation .
also , 1,064 nm being a longer wavelength penetrates deeper , thus leading to less paradoxical pih with the treatment itself .
more randomized controlled clinical studies in large numbers of pih patients would be helpful in providing standardized measurable outcomes for this indication . there is a sparse data in the indian literature for treatment of acne pih with qsny laser and we did not find any recent literature in the indian published reports .
the authors found the qsny laser to be a feasible , economic modality of treatment , which can be used optimally for the darker skin type with minimal adverse effects .
we believe that qsny may be considered as a viable option in cases of persistent pih due to acne .
Output:
| background : postinflammatory hyperpigmentation ( pih ) is a common sequela seen in the indian population following affliction by acne .
it is psychologically extremely disturbing for the patients and can severely affect the quality of life .
very few therapeutic modalities have proved to be really efficacious in this condition.aims:the aim was to review our experience with 1,064-nm q - switched neodymium - doped yttrium aluminum garnet ( qsny ) laser in the treatment of pih.materials and methods : seventy - eight patients with postacne hyperpigmentation were included in the study .
they were treated with six sessions at two weekly intervals using a 1,064-nm qsny laser .
patient and physician scores were assessed at 1 month and 3 months after the last treatment .
clinical photographs also were reviewed to determine the efficacy .
adverse effects were noted.results:seventy percent of the patients reported significant improvement in hyperpigmentation as compared to the baseline .
the majority of the adverse events were limited to mild , brief erythema.conclusion:the 1,064-nm qsny laser is an effective modality for the treatment of pih caused by acne . |
PubmedSumm118501 | ***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 total of 947 independent cancer cell lines were profiled at the genomic level ( data available at www.broadinstitute.org/ccle and gene expression omnibus ( geo ) using accession numbers gse36139 ) and compound sensitivity data was obtained for 479 lines ( supplementary table 11 ) .
mutation information was obtained both by using massively parallel sequencing of > 1,600 genes ( supplementary table 12 ) and by mass spectrometric genotyping ( oncomap ) , which interrogated 492 mutations in 33 known oncogenes and tumor suppressors .
genotyping / copy number analysis was performed using affymetrix genome - wide human snp array 6.0 and expression analysis using the genechip human genome u133 plus 2.0 array .
8-point dose response curves were generated for 24 anticancer drugs using an automated compound - screening platform .
compound sensitivity data were used for two types of predictive models that utilized the naive bayes classifier or the elastic net regression algorithm .
the effects of ahr expression silencing on cell viability were assessed by stable expression of shrna lentiviral vectors targeting either this gene or luciferase as control .
the effect of compound treatment on ahr target gene expression was assessed by quantitative rt - pcr . a full description of the methods is included in the supplementary information .
Output:
| the systematic translation of cancer genomic data into knowledge of tumor biology and therapeutic avenues remains challenging .
such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacologic annotation is available1 . here
we describe the cancer cell line encyclopedia ( ccle ) : a compilation of gene expression , chromosomal copy number , and massively parallel sequencing data from 947 human cancer cell lines . when coupled with pharmacologic profiles for 24 anticancer drugs across 479 of the lines , this collection allowed identification of genetic , lineage , and gene expression - based predictors of drug sensitivity .
in addition to known predictors , we found that plasma cell lineage correlated with sensitivity to igf1 receptor inhibitors ; ahr expression was associated with mek inhibitor efficacy in nras - mutant lines ; and slfn11 expression predicted sensitivity to topoisomerase inhibitors .
altogether , our results suggest that large , annotated cell line collections may help to enable preclinical stratification schemata for anticancer agents .
the generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of personalized therapeutic regimens2 . |
PubmedSumm118502 | ***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: pheochromocytoma of urinary bladder accounts for less than 0.05% of all bladder tumors and less than 1% of all the pheochromocytomas . various imaging studies
metaiodobenzylguanidine ( mibg ) scan is considered specific but has limited utility because of cost and restricted availability .
pheochromocytomas are usually hypervascular , so biphasic ct play an important role in its diagnosis even in the patients where bladder phaeochromocytoma is not considered as clinical diagnosis .
a 37-year - old female presented with vague abdominal discomfort for 2 years . on examination , she was found to be hypertensive .
ultrasound showed a lobulated 6.55 cm heterogeneously hyperechoic mass at right para - aortic region at level of renal hilum and a 3.52 cm lesion along posterior wall of the bladder .
in addition , the bladder lesion showed small central speck of calcification . with the possibility of multifocal pheochromocytoma ,
axial sections of ct in arterial ( a , b ) showing hyper enhancing lesions at right para - aortic region ( black arrow ) and along posterior wall of the urinary bladder ( white arrow ) .
in addition , bladder lesion showed small central speck of calcification a 40-year - old male presented with recurrent and intermittent hematuria for last 2 years , and was recently detected to have hypertension .
ultrasound showed a 32 cm heterogeneous lesion at the bladder base with enlarged lymph nodes along right iliac vessels and perivesical region .
coronal reformatted ct images in arterial ( a ) and venous phase ( b ) depicting the bladder base lesion ( white arrows ) with enlarged lymph nodes along right iliac vessels and perivesical region ( black arrow ) .
the lesion and the lymph nodes are showing hypervascularity and there is coarse calcification in the bladder lesion
a 37-year - old female presented with vague abdominal discomfort for 2 years . on examination , she was found to be hypertensive .
ultrasound showed a lobulated 6.55 cm heterogeneously hyperechoic mass at right para - aortic region at level of renal hilum and a 3.52 cm lesion along posterior wall of the bladder .
in addition , the bladder lesion showed small central speck of calcification . with the possibility of multifocal pheochromocytoma ,
axial sections of ct in arterial ( a , b ) showing hyper enhancing lesions at right para - aortic region ( black arrow ) and along posterior wall of the urinary bladder ( white arrow ) .
a 40-year - old male presented with recurrent and intermittent hematuria for last 2 years , and was recently detected to have hypertension .
ultrasound showed a 32 cm heterogeneous lesion at the bladder base with enlarged lymph nodes along right iliac vessels and perivesical region .
coronal reformatted ct images in arterial ( a ) and venous phase ( b ) depicting the bladder base lesion ( white arrows ) with enlarged lymph nodes along right iliac vessels and perivesical region ( black arrow ) .
the lesion and the lymph nodes are showing hypervascularity and there is coarse calcification in the bladder lesion
extra - adrenal pheochromocytoma ( eap ) develops in the paraganglion chromaffin cells in the sympathetic nervous system and accounts for 10 - 15% of pheochromocytomas in the adults and 30 - 40% in children .
more than 85% of the tumors occur below the diaphragm with para - aortic region being the commonest site .
other locations for the paragangliomas include gallbladder , urinary bladder , prostate , spermatic cord , uterus and duodenum .
these tumors are malignant in approximately 30 - 40% of patients compared to less than 2% in children .
the first category includes symptoms due to an excess of catecholamine and are similar to their adrenal counterpart .
the second category includes symptoms that are due the specific location of the tumor and may help in its localization .
the bladder pheochromocytoma occurs between the third and fifth decade but may occur at any age .
they are usually submucosal or intramural with intact vesical epithelium , and are common in the region of the trigone .
painless hematuria has been seen in 50 - 60% and hypertension in 65 - 80% patients .
these symptoms may be accompanied by headache , palpitations , hot flushes and sweating which may be aggravated by micturition or overdistension of the bladder .
they are malignant in about 10% and may metastasize to regional lymph nodes or distant site .
imaging studies for the bladder pheochromocytoma include ultrasonography ( usg ) , ct , mri and mibg . on usg ,
the tumors are usually hypointense to isointense on t1-weighted images , hyperintense on t2-weighted images and show avid contrast enhancement .
on cystoscopy , they appear granulated and lobulated , protruding into the bladder as globular yellowish , submucosal tumors . irrigating the mass during cystoscopy can be helpful in confirm the diagnosis preoperatively as the blood pressure fluctuates .
cystoscopic biopsies are usually not advocated because positive rate is very low , bleeds easily and induces the blood pressure fluctuations .
both the patients in our study were in the fourth decade with nonspecific clinical symptoms .
bladder lesions could have been missed if preoperative biphasic imaging had not been performed . in case 2
, patient could have undergone transurethral resection ( tur ) or other surgery without knowing its character leading to inadvertent complications .
the preoperative diagnosis of the bladder pheochromocytoma is important because preoperative preparation ( requires the similar preoperative stabilization of hypertension strategy as other pheochromocytomas ) and intraoperative ( cystoscopic examination prior to the excision to delineate the exact location of the lesion , depth of invasion and the involvement of the ureters ) treatment varies as compared to the other bladder lesions .
in addition , the preferred treatment to the bladder pheochromocytoma is open surgery rather than tur of bladder tumors or laparoscopic partial cystectomy . to conclude , pheochromocytoma ( paragangliomas )
should always be considered as in the differential diagnosis of hypervascular lesions in the bladder .
patients having atypical morphology bladder lesion , abdominal paragangliomas and varied symptoms associated with micturition should undergo biphasic ct . it may help in the diagnosis of bladder pheochromocytoma , even if there is no characteristic clinical history or clinical suspicion , by showing its hypervascularity .
Output:
| pheochromocytoma of urinary bladder are rare tumors .
they present with nonspecific clinical signs and symptoms , so imaging plays an important role in diagnosing and localizing the tumor .
we present two cases of bladder pheochromocytoma , one of them presented with vague abdominal pain and the other with hematuria .
biphasic ct in both the cases showed hypervascular intravesical mass suggestive of bladder pheochromocytoma .
the lesions were confirmed biochemically or on postoperative histopathology .
a brief review of the imaging in bladder pheochromocytoma is also presented . |
PubmedSumm118503 | ***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: natural selection is the process of preservation of genotypes among organisms , which increase chances of survival , procreation and multiplication from generation to generation at the expense of less - advantageous ones .
natural selection may arise from differences in survival , fertility , rate of development , mating success or any other aspect of the life cycle .
all such differences result in natural selection to the extent that they affect the number of progeny an organism leaves .
it was difficult to measure the intensity of natural selection directly in human populations ( homo sapiens sapiens ) .
this index enables the change in fitness to be measured from specific birth and death rates .
thus , natural selection is the relative probability of survival and reproduction of the genotype . only when a certain variability of this fitness is present in a population does natural selection occur . in human populations ,
the relative reproductive success of the different genotypes depends on the total number of offspring that each couple leaves to the next generation .
however , natural selection does not operate only through differential fertility ; the existence of differential survival of descendents up to reproductive age also determines the biological fitness .
crow 's index of opportunity for natural selection merely sets an upper limit on the amount of selective opportunity that can exist in any particular population .
it measures actual selection only if the heritability of fitness were complete and if birth and death rates were totally determined by genetic factors . despite this limitation ,
crow 's index has been widely used in human populations because it allows indirect quantitative estimation of the selection inherent in the evolutionary process simply on the basis of demographic statistics for birth and death rates.[6 - 10 ] fertility and mortality can cause a major disruption of gene frequencies from those predicted by the hardy weinberg theorem .
therefore , the quantum of change of differential genetic transmission becomes a significant indicator of the amount of potential evolutionary change within a group , which is actually the production of reproductive viability expressed in the form of differential fertility and mortality .
studies from all over the world have brought forth evidence in support of the contention that the socioeconomic and sociocultural milieus of a population have a tremendous impact on the fertility and mortality components of that population and , subsequently , on selection.[1511 - 14 ] in india , a few studies have demonstrated the role of natural selection in imposing characteristic fertility and mortality differentials among the different populations.[3715 - 23 ] all these studies reveal a relationship between socioeconomic conditions and the index of total selection .
himalayan populations are widely studied by kapoor et al . , wherein they computed the index of total selection for 24 himalayan populations , revealing that the contribution of fertility component ( if ) in determining total index of selection ( it ) is stronger than the mortality component ( i m ) .
simultaneously , they observed that both if and i m are strongly associated with it , accounting for 76 and 67% variability in it , respectively . but , in their study , highlanders are small in number . therefore , an attempt was made in the present study to generate data on the highland population .
the present study was conducted in district kinnaur , which is among one of the 12 districts of himachal pradesh of the indian republic .
the area lies between 31-05'-55 and 32-05 - 20 north latitude and between 77-45'-0 ' and 79-0'-50 east longitude , being demarcated as district kinnaur .
kinnars are often referred to in hindu religious books . according to mythologies , they are neither god nor human , but are in between these two . in 1960 ,
the northeastern region of himachal pradesh was administratively recognized to form the present - day district of kinnaur .
the total area of the district is 6401 sq km , which is 11.5% of the total area of the state .
the district is a land of scenic beauty and , at the same time , comprises a cold desert zone too .
sangla , kalpa and nichar valleys are enchanting valleys , with lush green forests and apple orchards , whereas the yangthang , pooh and ropa etc .
22 is constructed in place of the old hindustan tibet road , which goes along the river sutlej , the river itself passing through narrow fissures of extremely vertical mountains .
the vertical valleys are blasted toward the river to construct the present national highway . in many places ,
the road looks like a tunnel , the mountain hanging over the road , with the deep furious river flowing underneath .
but , in spite of all these efforts , the road communication network is not very efficient .
it is believed that the district derived its name from its inhabitants who are known as kinner , or kinnaura . according to an indian traveler
sanskritayan , the original name of the district was kimpurus desh , i.e. land of kimpurusa . in the absence of an authentic historical record ,
the early history of kinnaur region is obscure and the reference of the kinnaura or kannaura and their land is by and large confined to legends and mythological accounts .
some of the authors chandra , had associated the term kinnaura with indian religious mythology .
these authors tried to describe the term kinner , as mentioned in the vedas , puranas , epics and other religious books , which means half - god or godly - people or angle - like people .
raha and mahato opined that it was a derogatory term , indicating to kunit and kanya - het .
kunit means one who does not perform his duties as per norms a violator , whereas kanya - het means a father who has a lot affection for his daughter .
kanya is a hindi word , a synonym for daughter , and het meaning liking or affection or love . according to hearsay ,
in the ancient period , there was a custom of female feticide or female infanticide among the rajput , the occupants of the region .
but , some of these rajputs had violated the norms of killing the newly born daughter ; hence , they were called kanet ( the term kanet was possibly derived from hindi words , either kunit or kanya - het or both ) by the daughter killer group of rajputs of the area . it is observed that there are two clear - cut divisions in terms of habitations too . these may be designated as middle - and high - altitude region .
the high altitude can be associated with an area above an altitude of 3,000 m and the middle altitude can be associated with an altitude ranging between 2,000 and 3,000 m. the kalpa , nichar and sangla valleys fall in the middle - altitude zone and their habitant are migrants , largely from shimla and rampur districts . whereas kinnaurs of the high altitude are always struggling for subsistence due to the harsh environment and tough challenging ecological conditions , hardly having large land holdings .
the present study was conducted in district kinnaur , which is among one of the 12 districts of himachal pradesh of the indian republic .
the area lies between 31-05'-55 and 32-05 - 20 north latitude and between 77-45'-0 ' and 79-0'-50 east longitude , being demarcated as district kinnaur .
kinnars are often referred to in hindu religious books . according to mythologies , they are neither god nor human , but are in between these two . in 1960 ,
the northeastern region of himachal pradesh was administratively recognized to form the present - day district of kinnaur .
the total area of the district is 6401 sq km , which is 11.5% of the total area of the state .
the district is a land of scenic beauty and , at the same time , comprises a cold desert zone too .
sangla , kalpa and nichar valleys are enchanting valleys , with lush green forests and apple orchards , whereas the yangthang , pooh and ropa etc .
22 is constructed in place of the old hindustan tibet road , which goes along the river sutlej , the river itself passing through narrow fissures of extremely vertical mountains .
the vertical valleys are blasted toward the river to construct the present national highway . in many places ,
the road looks like a tunnel , the mountain hanging over the road , with the deep furious river flowing underneath .
but , in spite of all these efforts , the road communication network is not very efficient .
it is believed that the district derived its name from its inhabitants who are known as kinner , or kinnaura .
according to an indian traveler sanskritayan , the original name of the district was kimpurus desh , i.e. land of kimpurusa . in the absence of an authentic historical record ,
the early history of kinnaur region is obscure and the reference of the kinnaura or kannaura and their land is by and large confined to legends and mythological accounts .
a majority of them identify themselves as rajputs , the suffixe negi being a common title after their names .
some of the authors chandra , had associated the term kinnaura with indian religious mythology .
these authors tried to describe the term kinner , as mentioned in the vedas , puranas , epics and other religious books , which means half - god or godly - people or angle - like people .
raha and mahato opined that it was a derogatory term , indicating to kunit and kanya - het .
kunit means one who does not perform his duties as per norms a violator , whereas kanya - het means a father who has a lot affection for his daughter .
kanya is a hindi word , a synonym for daughter , and het meaning liking or affection or love . according to hearsay ,
in the ancient period , there was a custom of female feticide or female infanticide among the rajput , the occupants of the region .
but , some of these rajputs had violated the norms of killing the newly born daughter ; hence , they were called kanet ( the term kanet was possibly derived from hindi words , either kunit or kanya - het or both ) by the daughter killer group of rajputs of the area . it is observed that there are two clear - cut divisions in terms of habitations too . these may be designated as middle - and high - altitude region .
the high altitude can be associated with an area above an altitude of 3,000 m and the middle altitude can be associated with an altitude ranging between 2,000 and 3,000 m. the kalpa , nichar and sangla valleys fall in the middle - altitude zone and their habitant are migrants , largely from shimla and rampur districts . whereas kinnaurs of the high altitude are always struggling for subsistence due to the harsh environment and tough challenging ecological conditions , hardly having large land holdings .
for the present investigation , the kinnaura tribe of kinnaur district of himachal pradesh is taken into consideration .
as kinnaura are occupants of two different geoclimatic set - ups , i.e. , middle and high altitudes , the study sample for the present investigation comprises a subsample of a total of 160 post - menopausal mothers belonging to the kinnaura of the himalayan highlands .
village and population - wise distribution of the sample the information was collected using anthropological techniques , viz .
case studies , focus group discussion , in - depth interview , participants ' methods , genealogy and semi - structured schedule .
post - menopausal women are interviewed for different aspects , like age at menarche , menopause , children born , children surviving , child death , etc . and the information given by them is cross - checked through different methods by other members of the family .
data regarding other himalayan and indian populations were collected from 33 different published studies conducted on 70 various endogamous populations of eight himalayan and four non - himalayan ( plain ) states .
the data collected from primary and secondary sources were given essential statistical treatment using ms - excel and spss softwares . among the chief statistical treatments are regression analysis , error bar diagram and scattered plot diagram .
the following formulas are used for computing different indices and indicators : the index of opportunity for natural selection ( it ) is calculated using crow 's index , as cited below : where i m = pdps1 and if = vfx2 here , i m = index of opportunity for natural selection due to pre - reproductive mortality ( mortality from birth to reproductive age below 15 years ) if = index of opportunity for natural selection due to fertility x = average number of live births per women aged 45 years and above who has completed her reproductive life span vf = variance ( average deviation from mean ) of number of live births pd = proportion of pre - reproductive deaths ps1 = proportion of survivors from birth to reproductive ages proportion of pre - reproductive deaths ( pd ) is calculated from children ever born from mothers of age 45 years and above ( who have completed their fertility ) and pre - reproductive deaths , as cited below : proportion of pre - reproductive deaths(pd ) = children ever born from mothers of age of 45 years and above ( with completed fertility)children died before attaining reproductive age ( under 15 years ) born from these mothers proportions of survivors were calculated by subtracting pd from 1 , as given below : the index of opportunity for natural selection ( i2 ) following johnston and kensinger 's index has been calculated as follows : i2 = ime + 1pbime + 1pbps1if where ime = 1pdpb , imc = pdps , if = vfx2 and pb = 1pd pd = total prenatal deaths experienced by the mothers of age of 45 years and above ( with completed fertility)number of pregnancies experienced by the same mothers of age of 45 years and above ( with completed fertility ) here , ime = index of opportunity for natural selection due to embryonic mortality imc= index of opportunity for natural selection due to pre - reproductive mortality ( mortality from birth to reproductive age below 15 years ) if = index of opportunity for natural selection due to fertility x = average number of live births per women aged 45 years and above who have completed their reproductive life span vf = variance ( average deviation from mean ) of number of live births pb = proportion of survivors to birth pd = proportion of pre - reproductive deaths ps = proportion of survivors from birth to reproductive ages
the index of opportunity for natural selection ( it ) is calculated using crow 's index , as cited below : where i m = pdps1 and if = vfx2 here , i m = index of opportunity for natural selection due to pre - reproductive mortality ( mortality from birth to reproductive age below 15 years ) if = index of opportunity for natural selection due to fertility x = average number of live births per women aged 45 years and above who has completed her reproductive life span vf = variance ( average deviation from mean ) of number of live births pd = proportion of pre - reproductive deaths ps1 = proportion of survivors from birth to reproductive ages proportion of pre - reproductive deaths ( pd ) is calculated from children ever born from mothers of age 45 years and above ( who have completed their fertility ) and pre - reproductive deaths , as cited below : proportion of pre - reproductive deaths(pd ) = children ever born from mothers of age of 45 years and above ( with completed fertility)children died before attaining reproductive age ( under 15 years ) born from these mothers proportions of survivors were calculated by subtracting pd from 1 , as given below :
the index of opportunity for natural selection ( i2 ) following johnston and kensinger 's index has been calculated as follows : i2 = ime + 1pbime + 1pbps1if where ime = 1pdpb , imc = pdps , if = vfx2 and pb = 1pd pd = total prenatal deaths experienced by the mothers of age of 45 years and above ( with completed fertility)number of pregnancies experienced by the same mothers of age of 45 years and above ( with completed fertility ) here , ime = index of opportunity for natural selection due to embryonic mortality imc= index of opportunity for natural selection due to pre - reproductive mortality ( mortality from birth to reproductive age below 15 years ) if = index of opportunity for natural selection due to fertility x = average number of live births per women aged 45 years and above who have completed their reproductive life span vf = variance ( average deviation from mean ) of number of live births pb = proportion of survivors to birth pd = proportion of pre - reproductive deaths ps = proportion of survivors from birth to reproductive ages
among the kinnaura , a total of 813 mothers were interviewed , of whom 160 had already completed their fertility ( above 45 years of age ) and constituted the sample size for analysis of natural selection .
these 160 mothers had conceived a total of 809 pregnancies , which resulted in 793 live births . of these 793 live births ,
the mean number of live birth per mother has been found to be 4.89 , with a variance of 3.79 [ table 2 ] .
for further elucidation of facts , box pot and error bar diagrams are constructed [ figures 1 and 2 ] .
it is evident from the error bar diagram that there is a significant difference in the numbers of pregnancy experienced by the mother , children ever born and children surviving .
this indicates that fetal loss and child mortality is significant among kinnaura of middle and high altitude .
clustered box plot diagram showing comparative details of median , quartile and extreme values of number of pregnancies , total live birth and surviving children among the kinnaura of middle - and high - altitude zones error bar diagramme showing comparative details of median , quartile and extreme values of number of pregnancies , total live birth and surviving children among kinnaura of middle and high altitude zones demographic variables utilized in calculating the index of total selection for middle - and high - altitude kinnaura the indices of total selection , based on differential fertility and mortality data , have been computed using the methodologies of crow and johnston and kensinger , presented in tables 3 and 4 . the mean number of live births is slightly higher among middle - altitude kinnaura ( 5.14 ) as compared with high - altitude kinnaura ( 4.49 ) .
the index of total selection intensity ( it ) calculated according to crow is always lower than that of the johnston and kensinger index ( i2 ) , perhaps because of inclusion of embryonic deaths in the latter .
it is also evident that differential mortality contributes more than differential fertility to the total selection intensity .
selection intensities ( based on live births and pre - reproductive mortalities ) among the kinnaura of middle and high altitudes selection intensities ( based on live births and pre - reproductive mortalities ) among the kinnaura of middle and high altitudes the proportions of survivors from birth to reproductive age were found to be slightly higher for high - altitude kinnaura ( 0.842 ) , as compared with middle - altitude kinnaura ( 0.832 ) .
contrary to this , the proportions of pre - reproductive deaths were found to be higher among middle - altitude kinnaura ( 0.168 ) as compared with high - altitude kinnaura ( 0.158 ) . on the whole , the proportion of survivors from birth to reproductive age was found to be 0.837 and the proportion of pre - reproductive deaths was 0.163 . however , the proportion of embryonic ( pre - natal ) deaths varied from 0.007 to 0.033 [ table 4 ] .
it has been noticed that the total index of selection is higher among middle - altitude kinnaura as compared with high - altitude kinnaura , irrespective of the methodology used .
however , all the estimates ( as per crow 's formulation ) were below 1.18 , as reported by sphuler for various populations .
the present findings are compared with other indian tribes as well as non - tribes of the himalayan region and other parts of the country [ table 5 ] .
it reveals that this index among the kinnaura is moderate as compared with the other population groups . among the himalayan population ,
the highest was reported for galong ( it = 1.07 ) of arunachal , whereas the lowest was reported from ahom ( it = 0.218 ) of manipur . in the western himalayas ,
the index was found to be highest for baltis ( it = 1.02 ) of jammu and kashmir and lowest for the bodhs ( it = 0.263 ) of himachal pradesh , whereas for all of kinnaura , the index is computed to be it = 0.384 , which varies from it= 0.370 ( high altitude ) to it = 0.386 ( middle altitude ) .
thus , kinnaura show similarities with muklom ( it = 0.315 ) of arunachal pradesh , khamti ( it = 0.312 ) and sonawal kachari ( it = 0.360 ) of assam , swangal ( it = 0.339 ) of himachal pradesh , ladakhi ( it = 0.34 ) as a whole , dogra rajput ( it = 0.313 ) of jammu and kashmir and halba ( it = 0.388 ) of madhya pradesh .
the overall indian scenario shows that the kota ( it = 1.367 ) have the highest selection intensity while ahom ( it = 0.218 ) have the lowest index of total selection [ table 5 ] .
the correlation and regression analysis [ table 6 ] between total index of selection ( it ) and fertility ( if ) and mortality ( i m ) components for pooled data of populations of indian himalayan states [ figures 3 and 4 ] , showing that if and i m account for 21.6 and 29.1% variability , respectively , in the crow 's total index of selection ( it ) along with a strong association that is significant at the 1% level .
this indicates that mortality plays a greater role in natural selection in comparison with fertility among populations of the indian himalayas .
furthermore , the individual analysis for states [ figures 5 and 6 ] exhibit great variation , the least variability of fertility component ( if ) being noticed in meghalaya ( 3% ) , followed by jammu and kashmir ( 5% ) , whereas the highest was noticed in himachal pradesh ( 76% ) , followed by assam ( 55.3% ) , uttaranchal ( 38.4% ) and arunachal ( 21.1% ) .
similarly , the least variability of the mortality component ( i m ) on crow 's total index of selection ( it ) was found to be in the state of assam ( 2.8% ) , followed by jammu and kashmir ( 40.4% ) , whereas the highest was noticed in uttaranchal ( 93.8% ) , followed by himachal pradesh ( 91.8% ) , meghalaya ( 87% ) and arunachal ( 77.9% ) . in light of the above discussion
, the findings of the present study indicate that kinnaura have a moderate value of component of fertility ( if ) , mortality ( i m ) and mortality playing a greater role in natural selection over fertility , as is true to a majority of the himalayan populations .
the present findings do not show any great variation from the previous one , but more or less support it , the average ( 0.361 ) of total index of selection being present closer to the present findings ( 0.384 ) .
bivariate scattered plot diagram showing regression and correlation between the fertility component and total index of selection among himalayan populations bivariate scattered plot diagram showing regression and correlation between the mortality component and total index of selection among himalayan populations bivariate scattered plot diagram showing regression and correlation between the fertility component and total index of selection among populations of different himalayan states bivariate scattered plot diagram showing regression and correlation between the mortality component and total index of selection among populations of different himalayan states indices of natural selection among different population groups ( tribes and non - tribes ) of the himalayan region and other parts of india hpa = himalyan population with asian affinities ; ha = high altitude ; ma = middle altitude ; sc = schedulded altitude ; up = uttar pradesh regression and correlation of the fertility ( if ) and mortality ( i m ) components with the index of total selection ( it ) among populations of the different himalayan states ( dependent variable , it ) it can be concluded that determinants of mortality among kinnaura should be identified and targeted for reduction .
the department of health and the integrated child development functionaries must pay attention to reduce fetal loss and infant and child mortality .
the improvement in health infrastructure and facilities in the remote areas may change the scenario .
Output:
| the present investigation on fertility and mortality differential among kinnaura of the himalayan highland is based on data collected from 160 post - menopausal women belonging to the middle and high altitude region of kinnaur district of himachal pradesh ( indian himalayas ) .
selection potential based on differential fertility and mortality was computed for middle - and high - altitude women .
irrespective of the methodology , the total index of selection was found to be highest among middle - altitude women ( 0.386 ) as compared with high - altitude ( 0.370 ) women , whereas for the total population it is estimated to be 0.384 .
it was found that the kinnaura of the himalayan highland showing moderate index of total selection and relative contribution of the mortality component ( i m ) to the index of total selection is higher than the corresponding fertility component ( if ) .
the analysis of embryonic and post - natal mortality components shows that the post - natal mortality components are higher in comparison with the embryonic mortality components among highlanders and needs special intervention and health care .
the present findings are compared with other indian tribes as well as non - tribes of the himalayan region and other parts of the country .
it reveals that this index among kinnaura is moderate than the other population groups ; among the himalayan population , the highest was reported for galong ( it = 1.07 ) of arunachal , whereas the lowest was reported from ahom ( it = 0.218 ) of manipur .
the correlation and regression analysis between total index of selection ( it ) and fertility ( if ) and mortality ( i m ) components for pooled data of populations of the indian himalayan states show that if and i m account for 21.6 and 29.1% variability , respectively . in crow 's total index of selection ( it ) along with strong association , which is significant at the 1% level ,
this indicates that mortality plays a greater role in natural selection in comparison with fertility among populations of the indian himalayas . |
PubmedSumm118504 | ***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 dominant theoretical models of health outcomes or the consequence of disease have been the models developed by the world health organisation .
the most recent version , the international classification of functioning , disability and health ( icf ) is based on a biopsychosocial model that integrates medical and social models .
the icf model identifies three main distinct outcomes , impairment ( i ) , activity limitations ( a ) and participation restrictions ( p ) and their respective opposites , body function and structure , activity and participation .
the icf model allows for all causal pathways between the constructs to be explored , with significant paths likely to vary for different conditions . while the relationships between i , a and p have been explored in some conditions , we are unaware of any studies that have explored if the relationships amongst the constructs are the same for different subgroups of a population .
for example , if we were to find that for people who are socially deprived , impairment directly impacts participation restriction , whereas for those who are less deprived there is no direct path , then it might be possible to target interventions more accurately and to gain greater understanding of the process of disablement . in this study
, we explore the icf model by different subgroups in people with osteoarthritis ( oa ) .
there is evidence that for osteoarthritis there are strong relationships between impairment and activity limitation and between activity limitation and participation restriction with a weaker path between impairment and participation restriction [ 35 ] .
first , it has previously been shown that many existing measures do not map onto single icf constructs ( i.e. the items and/or measures are contaminated with other icf constructs ) , for example the item doing household tasks measures both activity limitations and participation restriction , making it impossible to examine relationships between a and p. for this study , we used the method of discriminant content validity ( dcv ) to construct pure measures of impairment , activity limitation and participation restriction that were uncontaminated to enable us to accurately explore if the same model applies for subgroups of the population .
second , it is also possible that different patterns of relationships could be found for different subgroups if there is measurement bias , i.e. items working in a different way for different subgroups .
such items exhibit differential item functioning ( dif ) and dif items have been found in health outcome measures [ 911 ] .
hence , we explored whether items had dif to ensure that differences in models were not simply due to measurement bias .
thus , the aim of the study was to explore if the icf model varies with respect to gender , age and social deprivation for people with osteoarthritis .
statistical techniques were applied to an existing data set to explore if the icf model varies with respect to gender , age and social deprivation .
uncontaminated , dif - free measures of the icf constructs were developed using dcv , classic and modern item analysis .
multigroup structural equation modelling was used to explore if the same pathways exist for subgroups of gender , age and social deprivation .
the sample comprised a community of 763 people who had been diagnosed with osteoarthritis from 1359 people with hip and/or knee symptoms who completed a follow - up assessment ( 20022003 ) of health outcome measures as part of the somerset and avon survey of health survey ( sash ) .
osteoarthritis was diagnosed by a clinician assessing x - rays using the kellgren lawrence classification .
the age sex stratified survey of 28 080 people registered with 40 general practices in avon and somerset yielded 2703 people reporting hip and/or knee symptoms at baseline ( 19941995 ) .
ethics approval was obtained from the south west research ethics committee ( mrec/01/6/51 ) , and the study was conducted in accordance with the helsinki declaration .
statistical techniques were applied to an existing data set to explore if the icf model varies with respect to gender , age and social deprivation .
uncontaminated , dif - free measures of the icf constructs were developed using dcv , classic and modern item analysis .
multigroup structural equation modelling was used to explore if the same pathways exist for subgroups of gender , age and social deprivation .
the sample comprised a community of 763 people who had been diagnosed with osteoarthritis from 1359 people with hip and/or knee symptoms who completed a follow - up assessment ( 20022003 ) of health outcome measures as part of the somerset and avon survey of health survey ( sash ) .
osteoarthritis was diagnosed by a clinician assessing x - rays using the kellgren lawrence classification .
the age sex stratified survey of 28 080 people registered with 40 general practices in avon and somerset yielded 2703 people reporting hip and/or knee symptoms at baseline ( 19941995 ) .
ethics approval was obtained from the south west research ethics committee ( mrec/01/6/51 ) , and the study was conducted in accordance with the helsinki declaration .
these included two standard measures , the western ontario and mcmaster universities osteoarthritis index ( womac ) , which is the most commonly used disease - specific measure of outcome used in oa .
also included was the short form-36 ( sf-36 ) , which is the most commonly used generic measure of outcome used in oa .
however , these measures have been shown to contain items that map onto more than one icf construct and have evidence of dif for the groups investigated here [ 9,11,1820 ] .
discriminant content validity methods were used to classify the pool of 134 items to i , a or p and item analysis was carried out in order to develop i , a and p measures .
where dif items were identified , they were removed for the relevant analysis ( see statistical analysis section ) .
the townsend index was based on the four variables from the 1991 census : unemployment , non - car ownership , non - home ownership and household overcrowding .
the following steps were carried out.dcv was used to classify the 134 self - report items to i , a and p or a combination thereof .
six expert judges provided judgements of whether each item matched the theoretical definition of each icf construct and provided a confidence rating for each judgement .
single sample t - tests were used to assess whether each item significantly tapped one unique construct or a mixture of constructs .
intraclass correlations ( icc ) were used to assess agreement between judges or inter - rater reliability applying a two - way mixed model with measures of consistency.item analysis was carried out on the resultant pool of unique i , a and p items from the dcv .
a combination of classic psychometric methods and the modern methods of item response theory and dif were used to develop the measures.items were removed if there was more than 10% missing data.items were removed that duplicated content.categories were collapsed if there was a less frequency of occurrence in this sample of less than 5%.cronbach s alpha was calculated for i , a and p with items removed if their inclusion decreased cronbach s alpha.item response theory was carried out on the i , a and p measures to reduce items where there was more than 10 items in scale ; in practice , this only applied to the activity limitation scale .
items with information < 2.0 were removed.correlations between the resultant measures and other standard measures ( sf-36 and womac ) were explored to evaluate validity .
cronbach s alpha was calculated to explore reliability.dif was carried out to evaluate if any of the items were biased for the subgroups under study , i.e. age group , gender and social deprivation group .
the swaminathan and rogers ( sr ) ordinal logistic regression method was used with a bonferroni correction applied as this has been suggested to minimise type 1 error due to the multiple testing .
dcv was used to classify the 134 self - report items to i , a and p or a combination thereof .
six expert judges provided judgements of whether each item matched the theoretical definition of each icf construct and provided a confidence rating for each judgement .
single sample t - tests were used to assess whether each item significantly tapped one unique construct or a mixture of constructs .
intraclass correlations ( icc ) were used to assess agreement between judges or inter - rater reliability applying a two - way mixed model with measures of consistency .
item analysis was carried out on the resultant pool of unique i , a and p items from the dcv .
a combination of classic psychometric methods and the modern methods of item response theory and dif were used to develop the measures.items were removed if there was more than 10% missing data.items were removed that duplicated content.categories were collapsed if there was a less frequency of occurrence in this sample of less than 5%.cronbach s alpha was calculated for i , a and p with items removed if their inclusion decreased cronbach s alpha.item response theory was carried out on the i , a and p measures to reduce items where there was more than 10 items in scale ; in practice , this only applied to the activity limitation scale .
items with information < 2.0 were removed.correlations between the resultant measures and other standard measures ( sf-36 and womac ) were explored to evaluate validity .
cronbach s alpha was calculated to explore reliability.dif was carried out to evaluate if any of the items were biased for the subgroups under study , i.e. age group , gender and social deprivation group .
the swaminathan and rogers ( sr ) ordinal logistic regression method was used with a bonferroni correction applied as this has been suggested to minimise type 1 error due to the multiple testing .
categories were collapsed if there was a less frequency of occurrence in this sample of less than 5% .
cronbach s alpha was calculated for i , a and p with items removed if their inclusion decreased cronbach s alpha .
item response theory was carried out on the i , a and p measures to reduce items where there was more than 10 items in scale ; in practice , this only applied to the activity limitation scale .
correlations between the resultant measures and other standard measures ( sf-36 and womac ) were explored to evaluate validity .
dif was carried out to evaluate if any of the items were biased for the subgroups under study , i.e. age group , gender and social deprivation group .
the swaminathan and rogers ( sr ) ordinal logistic regression method was used with a bonferroni correction applied as this has been suggested to minimise type 1 error due to the multiple testing .
structural equation modelling ( sem ) is a statistical method that is mainly used to evaluate if a hypothesised theoretical model is plausible when compared to the observed data .
sem allows for the testing of both a measurement model and a structural model in a single model .
multigroup sem allows for testing if the measurement and structural model are equivalent across groups .
multigroup sem proceeds in hierarchical steps with increasingly restrictive models being tested by constraining sets of model parameters .
constraining models involves forcing the model s parameters to be the same for all groups : this evaluates if the same model holds between groups .
the main focus of this study was to use multigroup ( sem ) to explore if structure equivalence exists by evaluating if there are similar path coefficients between the constructs for each subgroup .
the i , a and p measures were used to explore the icf model for each subgroup .
the subgroups of gender , age , social deprivation were explored for the primary direction , i.e. i to a to p and from i to p. as standard , one indicator factor loading was set to one , and initially correlations between the underlying latent factors were free to be estimated .
as some items did not appear to be normally distributed , robust maximum likelihood estimation was used together with robust fit statistics and robust standard errors .
bentler chi - squared statistic was calculated to assess model fit . as it has been shown that with large samples chi - square - based statistics are often highly significant even if there is good model fit , other fit indices were also explored .
model fit was assessed with emphasis on the robust comparative fit index ( cfi ) , the normed fit index ( nfi ) , the non - normed fit index ( nnfi ) and the robust root mean squared error of approximation ( rmsea ) with the 90% confidence interval .
a rmsea value of less or equal to 0.08 is generally accepted as an upper bound for acceptable fit .
if a small number of items ( < 5 ) prevented the model from converging , then these items were removed .
nested models can be compared by calculating the differences in chi - square as this is also chi - square distributed with the degrees of freedom being the difference in degrees of freedom between the two models . however ,
bentler chi - squared statistic is used , then this does not apply and a correction must be made .
satorra and bentler have developed a method for computing a scaled difference chi - square statistic .
initially , a baseline 3 factor sem model was fitted ( including all the items i.e. without excluding any dif items ) . for each subgrouping factor
the first model that was fitted was a baseline 3 factor ( i , a , p ) sem model with the combined data , but omitting dif items .
thus , model 1 may vary from the initial baseline model if some items were identified from the dif analysis and hence excluded for that particular subgroup analysis .
the second model to be fitted was the baseline 3 factor two group sem model tested simultaneously with no constraints .
good fit of this model would indicate configural equivalence , i.e. the number of factors and pattern of item loadings are similar across the groups
model 3a : 2 group factor constrained model .
thirdly , model 2 was constrained by fixing the factor loadings to be equal across the two groups .
if there is no significant difference between this model and model 2 , then the factor structure would appear to be similar between the two groups as this tests if the two models can be considered as having similar factor loadings .
if there was a significant difference between model 3a and model 2 , then the lagrange multiplier ( lm ) test was used to identify the factor loading constraints that should be released to improve the measurement equivalence .
finally , model 3 ( a or b ) was further constrained by fixing the path coefficients to be equal between the two groups to test the equality of the structural regression paths .
a non - significant difference between this model and the model 3 would indicate that the same model appears appropriate for each subgroup , i.e. the models can be considered as having similar path coefficients , and hence there is structural equivalence of the subgroups .
if the models did appear to significantly differ , then the lm test was used to identify the paths that should be released to improve measurement equivalence , i.e. to identify the paths that were not equivalent .
the first model that was fitted was a baseline 3 factor ( i , a , p ) sem model with the combined data , but omitting dif items .
thus , model 1 may vary from the initial baseline model if some items were identified from the dif analysis and hence excluded for that particular subgroup analysis .
the second model to be fitted was the baseline 3 factor two group sem model tested simultaneously with no constraints .
good fit of this model would indicate configural equivalence , i.e. the number of factors and pattern of item loadings are similar across the groups
model 3a : 2 group factor constrained model .
thirdly , model 2 was constrained by fixing the factor loadings to be equal across the two groups .
if there is no significant difference between this model and model 2 , then the factor structure would appear to be similar between the two groups as this tests if the two models can be considered as having similar factor loadings .
if there was a significant difference between model 3a and model 2 , then the lagrange multiplier ( lm ) test was used to identify the factor loading constraints that should be released to improve the measurement equivalence .
finally , model 3 ( a or b ) was further constrained by fixing the path coefficients to be equal between the two groups to test the equality of the structural regression paths .
a non - significant difference between this model and the model 3 would indicate that the same model appears appropriate for each subgroup , i.e. the models can be considered as having similar path coefficients , and hence there is structural equivalence of the subgroups .
if the models did appear to significantly differ , then the lm test was used to identify the paths that should be released to improve measurement equivalence , i.e. to identify the paths that were not equivalent .
table 1.participant characteristic table ( percents or means and standard deviations and median split values for the grouping variables).gender ( male)43.3%age ( years)69.56 ( 9.84 ) median = 70.88marital status ( married)72%ethnicity ( white)99.1%paid employment ( yes)33.7%social class i5.7% ii33.8% iiinm19.0% iii m23.4% iv14.7% v3.4%townsend quintiles ( lower = most affluent)median = 1.47 20%2.76 40%1.89 60%0.80 80%1.46bmi29.21 ( 5.30)affected joints hip oa487 knee oa612 both hip and knee oa336 hip oa only151 knee oa only276 no of affected joints2.64 ( 1.01)womac physical20.03 ( 14.51)womac pain for hip oa3.70 ( 4.16)womac pain for knee oa5.83 ( 4.34)womac stiffness hip oa1.70 ( 1.82)womac stiffness knee oa2.53 ( 1.92 )
participant characteristic table ( percents or means and standard deviations and median split values for the grouping variables ) . in brief , there was a pool of 134 potential items .
dcv identified that 87 of these items were tapping only a single icf construct ( 37 i items , 34 a items , 16 p items ; icc = 0.86 ) . of the 47 items that were not uniquely classified , 12 items were classified to both a and i , 2 to a and p with the remaining items unable to be classified to i , a or p. the item analysis , using classic test theory and item response theory , reduced the items to 10 i , 16 a and 4 p items .
these items demonstrated good levels of reliability with cronbach s alpha for i = 0.92 , a = 0.96 and p = 0.75 .
there was also evidence of validity ; the new measures were most highly correlated with the appropriate subscales from the established measures of sf-36 and womac .
dif analysis indicated that for activity limitation , 3 items ( limited lifting groceries , problems getting in and out of the bath and maximum distance walk with pain ) were identified as having gender dif and one item was identified as having age dif ( difficulties putting on shoes , stockings , socks by bending forward ) .
hence , for the analysis by gender and age , the respective dif items were removed from the activity limitation measure .
table 2.items in the final i , a and p measures.impairment items how much bodily pain in the past month pain / discomfort pain during day over past year even with tablets / medication pain during the night over past year even with tablets / medication pain on walking over past year even with tablets / medication have you had pain in past month when start to move or walk do you have pain or discomfort during bed rest at night do you experience morning stiffness or pain that decreases after rising pain in last 48 hours at night while in bed how severe is the stiffness after sitting , lying or resting later in the dayactivity limitation items does health limit you doing moderate activities lifting or carrying groceries climbing several flight of stairs climbing one flight of stairs maximum distance can you walk with pain can you stand from sitting from a standard chair with no arms can you walk on uneven ground can you get in and out of a car can you squat down can you put on socks , stockings or socks by bending forward can you pick up an object from the floor are you able to get in and out of the bath difficulty standing difficulty bending to floor walking on the flat rising from bedparticipation restriction items has health limited your social activities do you have problems with usual activities taking part in holidays or outings going shopping
items in the final i , a and p measures .
( a ) baseline overall model ( with all measurement items ) : the overall baseline model showed good fit .
overall significant paths were found between i , a and p with the strongest paths being between a and p ( path coefficient = 0.83 , p < 0.01 ) and i and a ( path coefficient = 0.76 , p < 0.01 ) with a much weaker but significant path , between i and p ( path coefficient = 0.11 , p < 0.05 ) ( figure 1a ) .
figure 1.icf structural paths between i , a and p. ( a ) base one group model ; ( b ) gender ; ( c ) social deprivation .
icf structural paths between i , a and p. ( a ) base one group model ; ( b ) gender ; ( c ) social deprivation . for the exploration of the model by gender ,
the base 1 and 2 group models both showed good fit ( model 1 and model 2 ) ( table 3 ; figure 1b ) . the 2 group base model with factor loadings constrained to be equal ( model 3a ) also showed good fit , but was significantly worse than two group model without the constraints , indicating that not all the equality constraints were appropriate ( table 3 ) .
difficulty standing should be released ( as the factor loading for men appeared to be greater than for women ( standardised path men = 0.83 , women = 0.72 ) .
model 3b was only just significantly different from model 2 , suggesting the measurement model ( with one released constraint ) was reasonable .
the model with constrained structural paths added ( model 4 ) had worse fit and very significant chi - square difference from model 3 , and so was not structurally equivalent .
table 3summary table of the structural equation models for gender.modelchi-squarerobust chi - sqdfcfinfinnfirmseachi square change ( satorra bentler)model 1sem base 1 group3694.81515.72270.9790.9750.9760.092model 2 ( m2)sem base2 group2339.01115.32980.9790.9720.9760.090m2 and m3a = 47.54 ( 16 ) p < 0.0005model 3a ( m3a)factor loadings constrained2405.61166.83140.9780.9700.9760.089model 3b ( m3b)with released factors if needed*2377.21148.43130.9790.9710.9770.089m2 and m3b = 24.97 ( 15 ) p = 0.05model 4 ( m4)factor loadings and paths constrained2433.41185.13160.9780.9700.9760.090m3b and m4 = 179.62 ( 3 ) p < 0.0005cfi : robust comparative fit index , nfi : robust normed fit index , nnfi : robust non - normed fit index , rmsea : robust root mean squared error of approximation.*constraint released 1 item : difficulty standing .
cfi : robust comparative fit index , nfi : robust normed fit index , nnfi : robust non - normed fit index , rmsea : robust root mean squared error of approximation .
the path between i and p was significant for men ( path coefficient = 0.12 , p < 0.05 ) , but not for women ( path coefficient = 0.007 , p < 0.05 ) .
the paths between a and p were similar for men and women ( path coefficients = 0.82 and 0.85 , respectively , p < 0.01 ) .
the lm test indicated that the path coefficients between i to a were significantly different for men and women ( path coefficients = 0.75 ( men ) and 0.62 ( women ) , p = <
( c ) social deprivation ( townsend : 2 groups with median split = 1.47 ) for the exploration of the model by social deprivation group , the base 1 and 2 group models both showed good fit ( model 1 and model 2 ) ( table 4 ; figure 1c ) . the 2 group base model with factor loadings constrained to be equal ( model 3a ) also showed good fit , but was significantly worse than the two group model without the constraints ( table 4 ) .
the lm test indicated that the constraint on the item holidays / outings and the item pain in bed at night should be released ( with the factor loadings for those less deprived being greater than for those more deprived , 0.72 and 0.53 and 0.89 and 0.81 , respectively ) .
the model with these two released constraints ( model 3b ) was now not significantly better than model 2 and so indicated measurement equivalence .
the model with constrained structural paths added ( model 4 ) had worse fit and very significant chi - square difference from model 3b and so was not structurally equivalent .
table 4.summary table of the structural equation models for social deprivation.modelchi-squarerobust chi sqdfcfinfinnfirmseachi square change ( satorra
base 1 group4077.41712.32960.9830.9790.9810.085model 2 ( m2)sem base 2 group2820.41346.34120.9830.9750.9810.083m2 and m3a = 37.34 ( 19 ) p = 0.007model 3a ( m3a)factor loadings constrained2858.31383.74310.9820.9750.9810.082m2 and m3b = 12.0 ( 17 ) p = 0.80model 3b ( m3b)with released factors if needed*2840.71366.44290.9830.9750.9810.081model 4 ( m4)factor loadings and paths constrained2894.81393.84320.9820.9740.9810.082m3b and m4 = 27.41 ( 3 ) p < 0.00005cfi : robust comparative fit index , nfi : robust normed fit index , nnfi : robust non - normed fit index , rmsea : robust root mean squared error of approximation.*constraints released for 2 items = holidays / outings and pain in bed at night .
cfi : robust comparative fit index , nfi : robust normed fit index , nnfi : robust non - normed fit index , rmsea : robust root mean squared error of approximation .
constraints released for 2 items = holidays / outings and pain in bed at night .
the path between i and p was significant for those less deprived ( path coefficient = 0.19 p < 0.05 ) , but was not significant for those more deprived ( path coefficient = 0.07 , p > 0.05 ) .
when the lm test was examined , this path did not quite reach statistical significance for the difference ( p = 0.08 ) .
the paths between i and a appeared similar for those less or more deprived ( path coefficients = 0.63 and 0.67 , respectively , p < 0.01 ) .
the paths between a and p were also both significant for those less or more deprived ( path coefficients = 0.79 and 0.92 , respectively , p < 0.01 ) , but the lm test indicated that they were not significantly different from each other ( figure 1c ) .
( d ) age : 2 groups with median split = 70.88 for the exploration of the model by age group , the base 1 and 2 group models both showed good fit ( model 1 and model 2 , see table 5 ) . the 2 group base model with factor loadings constrained to be equal ( model 3 ) also showed good fit and was not significantly different to the two group model without the constraints ( model 2 ) ,
the model with the added structural path constraints ( model 4 ) was not significantly different from the model without the path constraints , so it appears that there was structural equivalence , i.e. the same model applies for both age groups .
table 5.summary table of the structural equation models for age.modelchi-squarerobust chi - sqdfcfinfinnfirmseachi square change ( satorra
1sem base 1 group3829.91578.82720.9830.9790.9810.085model 2 ( m2)sem base 2 group amend2583.91218.33720.9830.9760.9810.083m2 and m3a = 20.55 ( 18 ) p = 0.30model 3a ( m3a)factor loadings constrained2622.11243.43900.9830.9750.9820.081model 4 ( m4)factor loadings and paths constrained2618.31246.33920.9830.9750.9820.081m3a and m4 = 3.96 ( 3 ) p = 0.27cfi : robust comparative fit index , nfi : robust normed fit index , nnfi : robust non - normed fit index , rmsea : robust root mean squared error of approximation .
cfi : robust comparative fit index , nfi : robust normed fit index , nnfi : robust non - normed fit index , rmsea : robust root mean squared error of approximation . as men and those less deprived
had lower levels of impairment , activity limitation and participation restrictions , a post - hoc regression - based moderation analyses were carried out to explore if this would help explain the different models ( based on median splits of i , a and p ) .
however , these analyses did not offer evidence that the model significantly differed by level of i , a and p ( not shown ) .
these included two standard measures , the western ontario and mcmaster universities osteoarthritis index ( womac ) , which is the most commonly used disease - specific measure of outcome used in oa .
also included was the short form-36 ( sf-36 ) , which is the most commonly used generic measure of outcome used in oa .
however , these measures have been shown to contain items that map onto more than one icf construct and have evidence of dif for the groups investigated here [ 9,11,1820 ] .
discriminant content validity methods were used to classify the pool of 134 items to i , a or p and item analysis was carried out in order to develop i , a and p measures .
where dif items were identified , they were removed for the relevant analysis ( see statistical analysis section ) .
the townsend index was based on the four variables from the 1991 census : unemployment , non - car ownership , non - home ownership and household overcrowding .
the townsend index was based on the four variables from the 1991 census : unemployment , non - car ownership , non - home ownership and household overcrowding .
the following steps were carried out.dcv was used to classify the 134 self - report items to i , a and p or a combination thereof .
six expert judges provided judgements of whether each item matched the theoretical definition of each icf construct and provided a confidence rating for each judgement .
single sample t - tests were used to assess whether each item significantly tapped one unique construct or a mixture of constructs .
intraclass correlations ( icc ) were used to assess agreement between judges or inter - rater reliability applying a two - way mixed model with measures of consistency.item analysis was carried out on the resultant pool of unique i , a and p items from the dcv .
a combination of classic psychometric methods and the modern methods of item response theory and dif were used to develop the measures.items were removed if there was more than 10% missing data.items were removed that duplicated content.categories were collapsed if there was a less frequency of occurrence in this sample of less than 5%.cronbach s alpha was calculated for i , a and p with items removed if their inclusion decreased cronbach s alpha.item response theory was carried out on the i , a and p measures to reduce items where there was more than 10 items in scale ; in practice , this only applied to the activity limitation scale .
items with information < 2.0 were removed.correlations between the resultant measures and other standard measures ( sf-36 and womac ) were explored to evaluate validity .
cronbach s alpha was calculated to explore reliability.dif was carried out to evaluate if any of the items were biased for the subgroups under study , i.e. age group , gender and social deprivation group .
the swaminathan and rogers ( sr ) ordinal logistic regression method was used with a bonferroni correction applied as this has been suggested to minimise type 1 error due to the multiple testing .
dcv was used to classify the 134 self - report items to i , a and p or a combination thereof .
six expert judges provided judgements of whether each item matched the theoretical definition of each icf construct and provided a confidence rating for each judgement .
single sample t - tests were used to assess whether each item significantly tapped one unique construct or a mixture of constructs .
intraclass correlations ( icc ) were used to assess agreement between judges or inter - rater reliability applying a two - way mixed model with measures of consistency .
item analysis was carried out on the resultant pool of unique i , a and p items from the dcv .
a combination of classic psychometric methods and the modern methods of item response theory and dif were used to develop the measures.items were removed if there was more than 10% missing data.items were removed that duplicated content.categories were collapsed if there was a less frequency of occurrence in this sample of less than 5%.cronbach s alpha was calculated for i , a and p with items removed if their inclusion decreased cronbach s alpha.item response theory was carried out on the i , a and p measures to reduce items where there was more than 10 items in scale ; in practice , this only applied to the activity limitation scale .
items with information < 2.0 were removed.correlations between the resultant measures and other standard measures ( sf-36 and womac ) were explored to evaluate validity .
cronbach s alpha was calculated to explore reliability.dif was carried out to evaluate if any of the items were biased for the subgroups under study , i.e. age group , gender and social deprivation group .
the swaminathan and rogers ( sr ) ordinal logistic regression method was used with a bonferroni correction applied as this has been suggested to minimise type 1 error due to the multiple testing .
categories were collapsed if there was a less frequency of occurrence in this sample of less than 5% .
cronbach s alpha was calculated for i , a and p with items removed if their inclusion decreased cronbach s alpha .
item response theory was carried out on the i , a and p measures to reduce items where there was more than 10 items in scale ; in practice , this only applied to the activity limitation scale .
correlations between the resultant measures and other standard measures ( sf-36 and womac ) were explored to evaluate validity .
dif was carried out to evaluate if any of the items were biased for the subgroups under study , i.e. age group , gender and social deprivation group .
the swaminathan and rogers ( sr ) ordinal logistic regression method was used with a bonferroni correction applied as this has been suggested to minimise type 1 error due to the multiple testing .
structural equation modelling ( sem ) is a statistical method that is mainly used to evaluate if a hypothesised theoretical model is plausible when compared to the observed data .
sem allows for the testing of both a measurement model and a structural model in a single model .
multigroup sem allows for testing if the measurement and structural model are equivalent across groups .
multigroup sem proceeds in hierarchical steps with increasingly restrictive models being tested by constraining sets of model parameters .
constraining models involves forcing the model s parameters to be the same for all groups : this evaluates if the same model holds between groups .
the main focus of this study was to use multigroup ( sem ) to explore if structure equivalence exists by evaluating if there are similar path coefficients between the constructs for each subgroup .
the i , a and p measures were used to explore the icf model for each subgroup .
the subgroups of gender , age , social deprivation were explored for the primary direction , i.e. i to a to p and from i to p. as standard , one indicator factor loading was set to one , and initially correlations between the underlying latent factors were free to be estimated . as some items did not appear to be normally distributed , robust maximum likelihood estimation was used together with robust fit statistics and robust standard errors .
bentler chi - squared statistic was calculated to assess model fit . as it has been shown that with large samples chi - square - based statistics are often highly significant even if there is good model fit , other fit indices were also explored .
model fit was assessed with emphasis on the robust comparative fit index ( cfi ) , the normed fit index ( nfi ) , the non - normed fit index ( nnfi ) and the robust root mean squared error of approximation ( rmsea ) with the 90% confidence interval .
a rmsea value of less or equal to 0.08 is generally accepted as an upper bound for acceptable fit .
if a small number of items ( < 5 ) prevented the model from converging , then these items were removed .
nested models can be compared by calculating the differences in chi - square as this is also chi - square distributed with the degrees of freedom being the difference in degrees of freedom between the two models . however , if the non - normal satorra
bentler chi - squared statistic is used , then this does not apply and a correction must be made .
satorra and bentler have developed a method for computing a scaled difference chi - square statistic .
initially , a baseline 3 factor sem model was fitted ( including all the items i.e. without excluding any dif items ) . for each subgrouping factor
the first model that was fitted was a baseline 3 factor ( i , a , p ) sem model with the combined data , but omitting dif items .
thus , model 1 may vary from the initial baseline model if some items were identified from the dif analysis and hence excluded for that particular subgroup analysis .
the second model to be fitted was the baseline 3 factor two group sem model tested simultaneously with no constraints .
good fit of this model would indicate configural equivalence , i.e. the number of factors and pattern of item loadings are similar across the groups
model 3a : 2 group factor constrained model .
thirdly , model 2 was constrained by fixing the factor loadings to be equal across the two groups .
if there is no significant difference between this model and model 2 , then the factor structure would appear to be similar between the two groups as this tests if the two models can be considered as having similar factor loadings .
if there was a significant difference between model 3a and model 2 , then the lagrange multiplier ( lm ) test was used to identify the factor loading constraints that should be released to improve the measurement equivalence .
finally , model 3 ( a or b ) was further constrained by fixing the path coefficients to be equal between the two groups to test the equality of the structural regression paths . a non - significant difference between this model and the model 3
would indicate that the same model appears appropriate for each subgroup , i.e. the models can be considered as having similar path coefficients , and hence there is structural equivalence of the subgroups .
if the models did appear to significantly differ , then the lm test was used to identify the paths that should be released to improve measurement equivalence , i.e. to identify the paths that were not equivalent .
model 1
the first model that was fitted was a baseline 3 factor ( i , a , p ) sem model with the combined data , but omitting dif items .
thus , model 1 may vary from the initial baseline model if some items were identified from the dif analysis and hence excluded for that particular subgroup analysis .
the second model to be fitted was the baseline 3 factor two group sem model tested simultaneously with no constraints .
good fit of this model would indicate configural equivalence , i.e. the number of factors and pattern of item loadings are similar across the groups
model 3a : 2 group factor constrained model .
thirdly , model 2 was constrained by fixing the factor loadings to be equal across the two groups .
if there is no significant difference between this model and model 2 , then the factor structure would appear to be similar between the two groups as this tests if the two models can be considered as having similar factor loadings .
if there was a significant difference between model 3a and model 2 , then the lagrange multiplier ( lm ) test was used to identify the factor loading constraints that should be released to improve the measurement equivalence .
finally , model 3 ( a or b ) was further constrained by fixing the path coefficients to be equal between the two groups to test the equality of the structural regression paths .
a non - significant difference between this model and the model 3 would indicate that the same model appears appropriate for each subgroup , i.e. the models can be considered as having similar path coefficients , and hence there is structural equivalence of the subgroups .
if the models did appear to significantly differ , then the lm test was used to identify the paths that should be released to improve measurement equivalence , i.e. to identify the paths that were not equivalent .
the following steps were carried out.dcv was used to classify the 134 self - report items to i , a and p or a combination thereof .
six expert judges provided judgements of whether each item matched the theoretical definition of each icf construct and provided a confidence rating for each judgement .
single sample t - tests were used to assess whether each item significantly tapped one unique construct or a mixture of constructs .
intraclass correlations ( icc ) were used to assess agreement between judges or inter - rater reliability applying a two - way mixed model with measures of consistency.item analysis was carried out on the resultant pool of unique i , a and p items from the dcv .
a combination of classic psychometric methods and the modern methods of item response theory and dif were used to develop the measures.items were removed if there was more than 10% missing data.items were removed that duplicated content.categories were collapsed if there was a less frequency of occurrence in this sample of less than 5%.cronbach s alpha was calculated for i , a and p with items removed if their inclusion decreased cronbach s alpha.item response theory was carried out on the i , a and p measures to reduce items where there was more than 10 items in scale ; in practice , this only applied to the activity limitation scale .
items with information < 2.0 were removed.correlations between the resultant measures and other standard measures ( sf-36 and womac ) were explored to evaluate validity .
cronbach s alpha was calculated to explore reliability.dif was carried out to evaluate if any of the items were biased for the subgroups under study , i.e. age group , gender and social deprivation group .
the swaminathan and rogers ( sr ) ordinal logistic regression method was used with a bonferroni correction applied as this has been suggested to minimise type 1 error due to the multiple testing .
dcv was used to classify the 134 self - report items to i , a and p or a combination thereof .
six expert judges provided judgements of whether each item matched the theoretical definition of each icf construct and provided a confidence rating for each judgement .
single sample t - tests were used to assess whether each item significantly tapped one unique construct or a mixture of constructs .
intraclass correlations ( icc ) were used to assess agreement between judges or inter - rater reliability applying a two - way mixed model with measures of consistency .
item analysis was carried out on the resultant pool of unique i , a and p items from the dcv .
a combination of classic psychometric methods and the modern methods of item response theory and dif were used to develop the measures.items were removed if there was more than 10% missing data.items were removed that duplicated content.categories were collapsed if there was a less frequency of occurrence in this sample of less than 5%.cronbach s alpha was calculated for i , a and p with items removed if their inclusion decreased cronbach s alpha.item response theory was carried out on the i , a and p measures to reduce items where there was more than 10 items in scale ; in practice , this only applied to the activity limitation scale .
items with information < 2.0 were removed.correlations between the resultant measures and other standard measures ( sf-36 and womac ) were explored to evaluate validity .
cronbach s alpha was calculated to explore reliability.dif was carried out to evaluate if any of the items were biased for the subgroups under study , i.e. age group , gender and social deprivation group .
the swaminathan and rogers ( sr ) ordinal logistic regression method was used with a bonferroni correction applied as this has been suggested to minimise type 1 error due to the multiple testing .
categories were collapsed if there was a less frequency of occurrence in this sample of less than 5% .
cronbach s alpha was calculated for i , a and p with items removed if their inclusion decreased cronbach s alpha .
item response theory was carried out on the i , a and p measures to reduce items where there was more than 10 items in scale ; in practice , this only applied to the activity limitation scale .
correlations between the resultant measures and other standard measures ( sf-36 and womac ) were explored to evaluate validity .
dif was carried out to evaluate if any of the items were biased for the subgroups under study , i.e. age group , gender and social deprivation group .
the swaminathan and rogers ( sr ) ordinal logistic regression method was used with a bonferroni correction applied as this has been suggested to minimise type 1 error due to the multiple testing .
structural equation modelling ( sem ) is a statistical method that is mainly used to evaluate if a hypothesised theoretical model is plausible when compared to the observed data .
sem allows for the testing of both a measurement model and a structural model in a single model .
multigroup sem allows for testing if the measurement and structural model are equivalent across groups .
multigroup sem proceeds in hierarchical steps with increasingly restrictive models being tested by constraining sets of model parameters .
constraining models involves forcing the model s parameters to be the same for all groups : this evaluates if the same model holds between groups .
the main focus of this study was to use multigroup ( sem ) to explore if structure equivalence exists by evaluating if there are similar path coefficients between the constructs for each subgroup .
the i , a and p measures were used to explore the icf model for each subgroup .
the subgroups of gender , age , social deprivation were explored for the primary direction , i.e. i to a to p and from i to p. as standard , one indicator factor loading was set to one , and initially correlations between the underlying latent factors were free to be estimated .
as some items did not appear to be normally distributed , robust maximum likelihood estimation was used together with robust fit statistics and robust standard errors . the satorra
as it has been shown that with large samples chi - square - based statistics are often highly significant even if there is good model fit , other fit indices were also explored .
model fit was assessed with emphasis on the robust comparative fit index ( cfi ) , the normed fit index ( nfi ) , the non - normed fit index ( nnfi ) and the robust root mean squared error of approximation ( rmsea ) with the 90% confidence interval .
a rmsea value of less or equal to 0.08 is generally accepted as an upper bound for acceptable fit .
if a small number of items ( < 5 ) prevented the model from converging , then these items were removed .
nested models can be compared by calculating the differences in chi - square as this is also chi - square distributed with the degrees of freedom being the difference in degrees of freedom between the two models . however , if the non - normal satorra
bentler chi - squared statistic is used , then this does not apply and a correction must be made .
satorra and bentler have developed a method for computing a scaled difference chi - square statistic .
initially , a baseline 3 factor sem model was fitted ( including all the items i.e. without excluding any dif items ) . for each subgrouping factor
the first model that was fitted was a baseline 3 factor ( i , a , p ) sem model with the combined data , but omitting dif items .
thus , model 1 may vary from the initial baseline model if some items were identified from the dif analysis and hence excluded for that particular subgroup analysis .
the second model to be fitted was the baseline 3 factor two group sem model tested simultaneously with no constraints .
good fit of this model would indicate configural equivalence , i.e. the number of factors and pattern of item loadings are similar across the groups
model 3a : 2 group factor constrained model .
thirdly , model 2 was constrained by fixing the factor loadings to be equal across the two groups .
if there is no significant difference between this model and model 2 , then the factor structure would appear to be similar between the two groups as this tests if the two models can be considered as having similar factor loadings .
if there was a significant difference between model 3a and model 2 , then the lagrange multiplier ( lm ) test was used to identify the factor loading constraints that should be released to improve the measurement equivalence .
model 4 : 2 group factor and path constrained model . finally , model 3 ( a or b ) was further constrained by fixing the path coefficients to be equal between the two groups to test the equality of the structural regression paths .
a non - significant difference between this model and the model 3 would indicate that the same model appears appropriate for each subgroup , i.e. the models can be considered as having similar path coefficients , and hence there is structural equivalence of the subgroups .
if the models did appear to significantly differ , then the lm test was used to identify the paths that should be released to improve measurement equivalence , i.e. to identify the paths that were not equivalent .
the first model that was fitted was a baseline 3 factor ( i , a , p ) sem model with the combined data , but omitting dif items .
thus , model 1 may vary from the initial baseline model if some items were identified from the dif analysis and hence excluded for that particular subgroup analysis .
the second model to be fitted was the baseline 3 factor two group sem model tested simultaneously with no constraints .
good fit of this model would indicate configural equivalence , i.e. the number of factors and pattern of item loadings are similar across the groups
model 3a : 2 group factor constrained model .
thirdly , model 2 was constrained by fixing the factor loadings to be equal across the two groups .
if there is no significant difference between this model and model 2 , then the factor structure would appear to be similar between the two groups as this tests if the two models can be considered as having similar factor loadings .
if there was a significant difference between model 3a and model 2 , then the lagrange multiplier ( lm ) test was used to identify the factor loading constraints that should be released to improve the measurement equivalence .
model 4 : 2 group factor and path constrained model . finally , model 3 ( a or b ) was further constrained by fixing the path coefficients to be equal between the two groups to test the equality of the structural regression paths . a non - significant difference between this model and the model 3
would indicate that the same model appears appropriate for each subgroup , i.e. the models can be considered as having similar path coefficients , and hence there is structural equivalence of the subgroups .
if the models did appear to significantly differ , then the lm test was used to identify the paths that should be released to improve measurement equivalence , i.e. to identify the paths that were not equivalent .
the participants demographic and womac summary details are presented in table 1 .
table 1.participant characteristic table ( percents or means and standard deviations and median split values for the grouping variables).gender ( male)43.3%age ( years)69.56 ( 9.84 ) median = 70.88marital status ( married)72%ethnicity ( white)99.1%paid employment ( yes)33.7%social class i5.7% ii33.8% iiinm19.0% iii m23.4% iv14.7% v3.4%townsend quintiles ( lower = most affluent)median = 1.47 20%2.76 40%1.89 60%0.80 80%1.46bmi29.21 ( 5.30)affected joints hip oa487 knee oa612 both hip and knee oa336 hip oa only151 knee oa only276 no of affected joints2.64 ( 1.01)womac physical20.03 ( 14.51)womac pain for hip oa3.70 ( 4.16)womac pain for knee oa5.83 ( 4.34)womac stiffness hip oa1.70 ( 1.82)womac stiffness knee oa2.53 ( 1.92 )
participant characteristic table ( percents or means and standard deviations and median split values for the grouping variables ) . in brief
dcv identified that 87 of these items were tapping only a single icf construct ( 37 i items , 34 a items , 16 p items ; icc = 0.86 ) .
of the 47 items that were not uniquely classified , 12 items were classified to both a and i , 2 to a and p with the remaining items unable to be classified to i , a or p. the item analysis , using classic test theory and item response theory , reduced the items to 10 i , 16 a and 4 p items .
these items demonstrated good levels of reliability with cronbach s alpha for i = 0.92 , a = 0.96 and p = 0.75 .
there was also evidence of validity ; the new measures were most highly correlated with the appropriate subscales from the established measures of sf-36 and womac .
dif analysis indicated that for activity limitation , 3 items ( limited lifting groceries , problems getting in and out of the bath and maximum distance walk with pain ) were identified as having gender dif and one item was identified as having age dif ( difficulties putting on shoes , stockings , socks by bending forward ) .
hence , for the analysis by gender and age , the respective dif items were removed from the activity limitation measure .
table 2.items in the final i , a and p measures.impairment items how much bodily pain in the past month pain / discomfort pain during day over past year even with tablets / medication pain during the night over past year even with tablets / medication pain on walking over past year even with tablets / medication have you had pain in past month when start to move or walk do you have pain or discomfort during bed rest at night do you experience morning stiffness or pain that decreases after rising pain in last 48 hours at night while in bed how severe is the stiffness after sitting , lying or resting later in the dayactivity limitation items does health limit you doing moderate activities lifting or carrying groceries climbing several flight of stairs climbing one flight of stairs maximum distance can you walk with pain can you stand from sitting from a standard chair with no arms can you walk on uneven ground can you get in and out of a car can you squat down can you put on socks , stockings or socks by bending forward can you pick up an object from the floor are you able to get in and out of the bath difficulty standing difficulty bending to floor walking on the flat rising from bedparticipation restriction items has health limited your social activities do you have problems with usual activities taking part in holidays or outings going shopping
items in the final i , a and p measures .
dcv identified that 87 of these items were tapping only a single icf construct ( 37 i items , 34 a items , 16 p items ; icc = 0.86 ) .
of the 47 items that were not uniquely classified , 12 items were classified to both a and i , 2 to a and p with the remaining items unable to be classified to i , a or p. the item analysis , using classic test theory and item response theory , reduced the items to 10 i , 16 a and 4 p items .
these items demonstrated good levels of reliability with cronbach s alpha for i = 0.92 , a = 0.96 and p = 0.75 .
there was also evidence of validity ; the new measures were most highly correlated with the appropriate subscales from the established measures of sf-36 and womac .
dif analysis indicated that for activity limitation , 3 items ( limited lifting groceries , problems getting in and out of the bath and maximum distance walk with pain ) were identified as having gender dif and one item was identified as having age dif ( difficulties putting on shoes , stockings , socks by bending forward ) .
hence , for the analysis by gender and age , the respective dif items were removed from the activity limitation measure .
table 2.items in the final i , a and p measures.impairment items how much bodily pain in the past month pain / discomfort pain during day over past year even with tablets / medication pain during the night over past year even with tablets / medication pain on walking over past year even with tablets / medication have you had pain in past month when start to move or walk do you have pain or discomfort during bed rest at night do you experience morning stiffness or pain that decreases after rising pain in last 48 hours at night while in bed how severe is the stiffness after sitting , lying or resting later in the dayactivity limitation items does health limit you doing moderate activities lifting or carrying groceries climbing several flight of stairs climbing one flight of stairs maximum distance can you walk with pain can you stand from sitting from a standard chair with no arms can you walk on uneven ground can you get in and out of a car can you squat down can you put on socks , stockings or socks by bending forward can you pick up an object from the floor are you able to get in and out of the bath difficulty standing difficulty bending to floor walking on the flat rising from bedparticipation restriction items has health limited your social activities do you have problems with usual activities taking part in holidays or outings going shopping
items in the final i , a and p measures .
( a ) baseline overall model ( with all measurement items ) : the overall baseline model showed good fit .
overall significant paths were found between i , a and p with the strongest paths being between a and p ( path coefficient = 0.83 , p < 0.01 ) and i and a ( path coefficient = 0.76 , p < 0.01 ) with a much weaker but significant path , between i and p ( path coefficient = 0.11 , p < 0.05 ) ( figure 1a ) .
figure 1.icf structural paths between i , a and p. ( a ) base one group model ; ( b ) gender ; ( c ) social deprivation .
icf structural paths between i , a and p. ( a ) base one group model ; ( b ) gender ; ( c ) social deprivation . for the exploration of the model by gender ,
the base 1 and 2 group models both showed good fit ( model 1 and model 2 ) ( table 3 ; figure 1b ) .
the 2 group base model with factor loadings constrained to be equal ( model 3a ) also showed good fit , but was significantly worse than two group model without the constraints , indicating that not all the equality constraints were appropriate ( table 3 ) .
difficulty standing should be released ( as the factor loading for men appeared to be greater than for women ( standardised path men = 0.83 , women = 0.72 ) .
model 3b was only just significantly different from model 2 , suggesting the measurement model ( with one released constraint ) was reasonable .
the model with constrained structural paths added ( model 4 ) had worse fit and very significant chi - square difference from model 3 , and so was not structurally equivalent .
table 3summary table of the structural equation models for gender.modelchi-squarerobust chi - sqdfcfinfinnfirmseachi square change ( satorra
bentler)model 1sem base 1 group3694.81515.72270.9790.9750.9760.092model 2 ( m2)sem base2 group2339.01115.32980.9790.9720.9760.090m2 and m3a = 47.54 ( 16 ) p < 0.0005model 3a ( m3a)factor loadings constrained2405.61166.83140.9780.9700.9760.089model 3b ( m3b)with released factors if needed*2377.21148.43130.9790.9710.9770.089m2 and m3b = 24.97 ( 15 ) p = 0.05model 4 ( m4)factor loadings and paths constrained2433.41185.13160.9780.9700.9760.090m3b and m4 = 179.62 ( 3 ) p < 0.0005cfi : robust comparative fit index , nfi : robust normed fit index , nnfi : robust non - normed fit index , rmsea : robust root mean squared error of approximation.*constraint released 1 item : difficulty standing .
cfi : robust comparative fit index , nfi : robust normed fit index , nnfi : robust non - normed fit index , rmsea : robust root mean squared error of approximation .
the path between i and p was significant for men ( path coefficient = 0.12 , p < 0.05 ) , but not for women ( path coefficient = 0.007 , p < 0.05 ) .
the paths between a and p were similar for men and women ( path coefficients = 0.82 and 0.85 , respectively , p < 0.01 ) .
the lm test indicated that the path coefficients between i to a were significantly different for men and women ( path coefficients = 0.75 ( men ) and 0.62 ( women ) , p = < 0.01 ) ( figure 1b ) .
( c ) social deprivation ( townsend : 2 groups with median split = 1.47 ) for the exploration of the model by social deprivation group , the base 1 and 2 group models both showed good fit ( model 1 and model 2 ) ( table 4 ; figure 1c ) . the 2 group base model with factor loadings constrained to be equal ( model 3a ) also showed good fit , but was significantly worse than the two group model without the constraints ( table 4 ) .
the lm test indicated that the constraint on the item holidays / outings and the item pain in bed at night should be released ( with the factor loadings for those less deprived being greater than for those more deprived , 0.72 and 0.53 and 0.89 and 0.81 , respectively ) .
the model with these two released constraints ( model 3b ) was now not significantly better than model 2 and so indicated measurement equivalence .
the model with constrained structural paths added ( model 4 ) had worse fit and very significant chi - square difference from model 3b and so was not structurally equivalent .
table 4.summary table of the structural equation models for social deprivation.modelchi-squarerobust chi sqdfcfinfinnfirmseachi square change ( satorra
bentler)model 1sem base 1 group4077.41712.32960.9830.9790.9810.085model 2 ( m2)sem base 2 group2820.41346.34120.9830.9750.9810.083m2 and m3a = 37.34 ( 19 ) p = 0.007model 3a ( m3a)factor loadings constrained2858.31383.74310.9820.9750.9810.082m2 and m3b = 12.0 ( 17 ) p = 0.80model 3b ( m3b)with released factors if needed*2840.71366.44290.9830.9750.9810.081model 4 ( m4)factor loadings and paths constrained2894.81393.84320.9820.9740.9810.082m3b and m4 = 27.41 ( 3 ) p <
0.00005cfi : robust comparative fit index , nfi : robust normed fit index , nnfi : robust non - normed fit index , rmsea : robust root mean squared error of approximation.*constraints released for 2 items = holidays / outings and pain in bed at night .
cfi : robust comparative fit index , nfi : robust normed fit index , nnfi : robust non - normed fit index , rmsea : robust root mean squared error of approximation .
constraints released for 2 items = holidays / outings and pain in bed at night .
the path between i and p was significant for those less deprived ( path coefficient = 0.19 p < 0.05 ) , but was not significant for those more deprived ( path coefficient = 0.07 , p > 0.05 ) .
when the lm test was examined , this path did not quite reach statistical significance for the difference ( p = 0.08 ) .
the paths between i and a appeared similar for those less or more deprived ( path coefficients = 0.63 and 0.67 , respectively , p < 0.01 ) .
the paths between a and p were also both significant for those less or more deprived ( path coefficients = 0.79 and 0.92 , respectively , p < 0.01 ) , but the lm test indicated that they were not significantly different from each other ( figure 1c ) .
( d ) age : 2 groups with median split = 70.88 for the exploration of the model by age group , the base 1 and 2 group models both showed good fit ( model 1 and model 2 , see table 5 ) .
the 2 group base model with factor loadings constrained to be equal ( model 3 ) also showed good fit and was not significantly different to the two group model without the constraints ( model 2 ) , hence this supports measurement equivalence .
the model with the added structural path constraints ( model 4 ) was not significantly different from the model without the path constraints , so it appears that there was structural equivalence , i.e. the same model applies for both age groups .
table 5.summary table of the structural equation models for age.modelchi-squarerobust chi - sqdfcfinfinnfirmseachi square change ( satorra
bentler)model 1sem base 1 group3829.91578.82720.9830.9790.9810.085model 2 ( m2)sem base 2 group amend2583.91218.33720.9830.9760.9810.083m2 and m3a = 20.55 ( 18 ) p = 0.30model 3a ( m3a)factor loadings constrained2622.11243.43900.9830.9750.9820.081model 4 ( m4)factor loadings and paths constrained2618.31246.33920.9830.9750.9820.081m3a and m4 = 3.96 ( 3 )
p = 0.27cfi : robust comparative fit index , nfi : robust normed fit index , nnfi : robust non - normed fit index , rmsea : robust root mean squared error of approximation .
cfi : robust comparative fit index , nfi : robust normed fit index , nnfi : robust non - normed fit index , rmsea : robust root mean squared error of approximation . as men and those less deprived
had lower levels of impairment , activity limitation and participation restrictions , a post - hoc regression - based moderation analyses were carried out to explore if this would help explain the different models ( based on median splits of i , a and p ) .
however , these analyses did not offer evidence that the model significantly differed by level of i , a and p ( not shown ) .
as men and those less deprived had lower levels of impairment , activity limitation and participation restrictions , a post - hoc regression - based moderation analyses were carried out to explore if this would help explain the different models ( based on median splits of i , a and p ) .
however , these analyses did not offer evidence that the model significantly differed by level of i , a and p ( not shown ) .
significantly different models were found for gender and social deprivation group but not for age .
the paths between impairment and participation restriction were non - significant for women and those most deprived , but significant for men and those less deprived .
additionally , for men , the path between i and a was significantly stronger than for women .
no significant difference between models was found for people of different ages although further splits could be explored in future work .
post - hoc analyses indicated that the effects of gender and deprivation were not simply due to different levels of disability ( i , a , p ) in the sub - groups , and hence unlikely to be due to the effects of co - morbidities .
it appeared that the participation of men and those less deprived was more directly impacted by their impairment ( without going through activity ) than for women and those more deprived .
. participation restrictions that are not determined by activity limitations are more likely to be due to choices or decisions rather than being directly physically determined .
hence , it is possible that for men and those less deprived , the decision not to participate may be driven by different factors . on the one hand , groups may choose to cope with impairments using different coping strategies , e.g. by resting and avoiding exacerbation versus carrying on with tasks as usual . on the other hand
, groups may differ in the nature of their tasks and responsibilities and how readily they can withdraw from them , e.g. it may be more difficult to withdraw from household tasks usually undertaken by women .
this latter point might also explain why the path from i to a is weaker for women .
there is ample evidence that impairment may affect activity levels both directly and indirectly via individual goals , intentions and self - efficacy in performing activities [ 4,3436 ] .
additionally , qualitative studies have identified a range of barriers to activities ; nicholson et al
. found that barriers perceived by stroke survivors mainly fell into three domains of the theoretical domains framework , namely beliefs about capabilities , environmental context and resources and social influence .
thus , it might be that for women , these behavioural factors play a more important role relative to the biomedical impairment than they do for men .
there are various reasons why women might show a different pattern of limitations given similar impairments to men s , including their role in the home and their response to the conditions .
the type of participation may differ not only by gender but also by social deprivation group , and therefore influence the strength of the i to p path ; for example , those less deprived may be involved in work and leisure that is less reliant on activity limitation and hence their p may be directly impacted by i , for example our data indicated that those less deprived went to the cinema more than those more deprived .
also , as men and those less deprived drive more than women and those more deprived , their access to social and work activities may not be as dependent on their activity limitations .
this may also explain the significant i to p paths and the very strong path between a and p for the more deprived group .
hence , the nature of i , a and p for gender and by social deprivation group needs further exploration .
in particular , it may be important to examine if there is a tipping point for degree of social deprivation or a qualitative difference in living style associated with deprivation that influences the impact of impairments on participation .
there were similarities between all the models with the paths from i to a , and from a to p being the strongest paths and a weaker path between i and p. this is consistent with previous studies of people with oa . in practical terms , the results suggest that clinical interventions that reduce impairment might be expected to bring direct benefits in participation for men and those less deprived whereas other interventions , perhaps directed at reducing social burden or offering alternative methods of participation might be more helpful for women and those more deprived .
further , evidence of participation restrictions gives a less direct indication of problems in body structure or function for women and more deprived individuals .
we used cross - sectional data and can not therefore draw conclusions about causal relationships .
even longitudinal data can not test whether the relationships are truly causal and this will require experimental studies such as those conducted by fisher and johnston .
in this study we only explored i , a and p and not the contextual factors of the icf .
these contextual factors may have important moderating or mediating effects on the relationships between i , a and p. for example , our previous studies have found that psychological theories predict additional variance in a , beyond that explained by i , but have not investigated the impact of such variables on p .
the measures of i , a and p were derived and may need further validation and the number of items in the p measure was small and may not have fully covered the domain .
thus , the impact of oa appears to vary with respect to gender and social deprivation but not age , in this sample .
Output:
| purposethe aim of the study was to explore if the impact of osteoarthritis varies with respect to age , gender and social deprivation .
impact was defined as impairment , activity limitations and participation restriction ( international classification of functioning , disability and health ( icf ) ) . investigating the functioning of the icf model for subgroups is important both practically and theoretically.methodthe sample comprised a community sample of 763 people diagnosed with osteoarthritis .
uncontaminated measures of the icf constructs were developed using discriminant content validity from a pool of 134 items , including the womac and sf-36 .
multigroup structural equation modelling was used to explore if the same pathways exist for subgroups of gender , age and social deprivation.resultsdifferent significant paths were found for gender and social deprivation : impairment did not predict participation restriction for women and those most deprived , whereas these paths were significant for men and those less deprived .
no difference in the paths was found for age.conclusionsthe impact of osteoarthritis appears to vary with respect to gender and social deprivation but not age .
this suggests both that osteoarthritis per se does not adequately explain the health outcomes observed and that different clinical approaches may be appropriate for people of different gender and levels of deprivation.implications of rehabilitationthe icf model appears to vary with respect to gender and social deprivation for people with osteoarthritis.the icf model did not appear to vary with respect to age for people with osteoarthritis.different treatments and interventions for osteoarthritis may need to be targeted for specific gender and social deprivation groups . |
PubmedSumm118505 | ***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: , they spent an average 8.4 percent of their gdp on health care , up by 0.3 percentage points from 2000 .
pressures for further growth arise from rapid advances in medical technologies , population aging , and rising public expectations .
oecd data show that health care spending has outpaced economic growth over the past decade , even before the economic downturn of 2001 .
in fact , it was anticipated by several authors for individual countries , e.g. , the u.s .
( heffler et al . , 2003 ) and for canada ( canadian institute for health information , 2003 ) . over the 1990s
the gap between health spending growth and economic growth rates was roughly 1 percent for oecd countries on average , on a per - capita basis . in 2001 , the latest year available for international comparisons , health care spending growth has accelerated in several oecd countries , including the u.s .
( levit et al . , 2003 ) where it was above the unweighted oecd average .
the pressure on public budgets from accelerated health care spending has been a major policy concern in oecd countries during the past two decades ( docteur and oxley , 2003 ; imai , 2002 ; mossialos and le grand , 1999 ; ranade , 1998 ; saltman and figueras , 1997 ) .
recent economic slowdown and a new upsurge in health care spending , especially in the u.s . has prompted a new round of discussions about desirable health policies to influence aggregate health care spending ( altman et al .
, 2003 ; cutler , 2002 ) . a common approach of public health care policy in oecd countries has been to combine cost - containment strategies with long - term structural change to improve value - for - money in health care ( docteur and oxley , 2003 ; organisation for economic co - operation and development , 1995 ) . in sweden , for example ,
one of the major tools for cost containment was downscaling in the hospital sector and decreasing in the number of health care personnel .
sweden is also among the few oecd countries where the number of physicians per 1,000 population did not increase during the 1990s .
but it is cost - containment measures that are often the more visible part of reforms , and those which , in many cases , directly affect households who pay for higher cost sharing , or for goods and services that are no longer reimbursed under public programs ( ros , groenewegen , and delnoij , 2000 ) . among the most recent examples is the current reform proposal in germany ( financial times , 2003 ) .
a central part of the german reform proposal , recently enacted and due to be implemented at the beginning of next year , is a shift of health care expenditures to private financing ; for example , consumers will face higher cost sharing for prescription drugs and dental care .
in several countries , an important feature of the changes of health care financing in recent years has been a reduction in the autonomy granted to social insurance regimes to simply pass through higher costs into higher compulsory contributions .
this has been the case in the czech republic , france , germany , and hungary .
because of the depressive effect on employment that could result from higher employer paid social charges , the control of contribution rates has become an explicit policy target . in order to reconcile this with the financial viability of insurance regimes ,
three related strategies have been followed by governments : ( 1 ) impose budget constraints on providers , ( 2 ) require individuals to bear a greater share of expenditures , through increasing copayments , and ( 3 ) ensure that access to care remains available to the poor ( general taxation has financed a growing proportion of care , particularly by financing copayments for those on low incomes ) .
france has introduced municipal social insurance specifically to address this last point ( imai , jacobzone , and lenain , 2000 ) .
current problems in many countries , however , show that strong control on public spending on health care might lead to difficulties in terms of other policy goals ( docteur and oxley , 2003 ) .
, the declining federal health transfers put a strain on provincial health care systems ( matteo , 2000 ) . during 4 years in the mid-1990s ,
for instance , the proportion of people saying that the health care system needed only minor changes dropped from 56 percent in 1988 to 20 percent in 1998 .
concerns about underfunding , system administration , and access to specialty care were among the main public concerns ( donelan et al . , 1999 ) . following this period of restraint , public spending increased by an annual rate of 5.1 percent between 1997 and 2001 .
since 1998 public sector spending grew faster than that from private sources , and its share was about 73 percent of the total in 2001 .
the growth rate of total health care expenditures abated in the u.s . too , during the period of 1992 - 1999 .
while average growth rate of total health care expenditures was 5.5 percent in the 1980s ( 2.5 times higher than gdp growth ) , it was only 2.5 percent between 1992 and 1999 .
this slow - down is generally seen as due to managed care replacing indemnity insurance as the primary form of private health insurance .
managed care , coupled with robust economic growth , led to an unprecedented stability in the health expenditure share of gdp over this 7-year period ( cowan , et al . , 2001 ) . while governments in other countries managed to lower prices for providers unilaterally , a major tool of managed - care insurers was to exclude providers from their network .
as a result , lower prices came along with constrained access to providers in the united states , where it did not in other countries .
consumers in oecd countries are experiencing considerable waiting times for elective surgery ( hurst and siciliani , 2003 ) and increasing cost sharing .
in a recent survey , shortages of medical personnel , waiting times , and inadequate government funding led the list of concerns in australia , canada , new zealand , and the united kingdom ; high costs and inadequate coverage topped the list for the u.s .
furthermore , a wave of recent medical and technological advances and rising patients ' expectations can be expected to put increased pressure on public expenditure on health in the near future .
for oecd countries on average , the share of gdp devoted to health care increased markedly in 2001 after a period of relatively stable health care expenditures ratios ( table 1 and figure 1 ) .
, oecd countries spent an additional 1.1 percent of gdp on health care compared to 1990 , bringing the average up to 8.4 percent . the u.s . devoted the highest share of gdp to health throughout the decade , increasing to 13.7 percent in 2001 .
internationally harmonized expenditure ratios for the u.s . differ slightly from those published by cms .
moreover , the oecd definition for total health care expenditures excludes some small spending items , such as research and development , resulting in total health care spending which , for 2001 , is 2.3 percent lower than that reported nationally .
detailed documentation of national data sources and estimation methods used in health accounts is available as part of the oecd information system ( organisation for economic co - operation and development , 2003a ) . following the u.s . in 2001
was switzerland spending 10.9 percent , and germany spending 10.7 percent of gdp on health care . at the other end of the scale ,
the slovak republic and korea spent less than 6 percent of gdp on health care ( figure 2 ) . studying the growth patterns of health expenditure and gdp
separately provides further insight into international variations in the trend in health care expenditures ratios . in table 2 , both components have been expressed in per capita and in real terms , using the same gdp deflator .
the margin by which health care expenditures growth outpaced gdp growth can be read from figure 3 by the relative distance from the diagonal line .
this diagonal delimits the sample of countries with faster growth of per - capita health care spending than gdp growth . for an ( unweighted ) average of 24 countries
, there was a gap of 1 percentage point between the average annual growth of per - capita gdp and per - capita health care spending ( 3.1 versus 2.0 percent ) .
in other words , the annual increase in per capita spending on health care across oecd countries has outpaced overall economic growth per capita by around 50 percent over the past decade . for
health care expenditures trends in oecd countries , the last decade can be roughly divided into three different periods in terms of health care expenditures growth rate and health care expenditures ratio to gdp ( table 3 ) .
the first 3 years of the decade ( 1990 to 1992 ) saw considerably higher growth than the 5-year period from 1993 to 1997 , when governments in many countries applied cost - containment measures ( anell and svarvar , 1999 ; hkkinen , 1999 ; mossialos and le grand , 1999 ; orosz and burns , 2000 ) .
this is also reflected in the health care expenditures ratio to gdp . for oecd countries on average
health care expenditures started to rise again rapidly at the end of the 1990s and in the beginning of this decade , reflecting deliberate policies in some countries to relieve pressures arising from cost containment in previous years .
an example in case is the policy of high real rates of increase over a number of years in the united kingdom ( towse and sussex , 2000 ) .
it seems that an observation made about the u.s . health care system might hold true for many other countries : the wide range and sharp periodic cycles in spending growth produce disproportionate strains that contribute to the perception of a health system in constant crisis ( altman et al . , 2003 ) . behind the average oecd growth rate
there are wide variations , table 2 shows the oecd countries in order of their health care expenditures growth rates .
several countries ( e.g. , korea , ireland , and portugal ) with lower income and lower health care expenditures per capita in 1990 experienced high growth in health care expenditures during the 1990s ( colombo and hurst , 2002 ) . as a result , they narrowed the gap with the oecd average both in terms of per - capita expenditure and health care expenditures share of gdp . at the beginning of this decade , health care expenditures per capita in these countries was 50 - 100 percent higher than in 1990 ( table 2 ) .
a few high - income countries ( japan , australia , and united kingdom ) also experienced strong growth in health care expenditures over the past decade .
ireland experienced high growth in both health care spending and gdp ( 6.8 and 6.4 percent per year ) , and consequently the share of health care expenditures in gdp increased only slightly . despite the high growth in health care spending
it is important to recognize that a significant part of the increase is due to factors driving up the costs of health care without increasing the level of service provision ( deloitte & touche , 2001 ) . the rapid growth of the irish economy in the 1990s caused labor shortages in a number of sectors .
this also put an upward pressure on labor costs in the health care sector , and led to significant real increases in average wages for all categories of health care staff .
the united kingdom underfunding of the health care system resulted in growing dissatisfaction by the end of the 1980s . in 1991 - 1992 , in order to oil the wheels of major health care reform , the tory - government considerably increased public expenditure on health care ( as an average by 5.2 percent ) .
then , between 1992 and 1998 , the government exerted a strong cost - containment policy again ( koen , 2000 ) ; and the growth rate of total health care expenditures was only 2.6 percent ( which is below the oecd average ) .
since 2000 , the labour - government has given a higher priority to the national health statistics ( nhs ) : in january 2000 britain 's prime minister declared there would be an increase in spending on the nhs in order to reach the european union ( eu ) average measured by the proportion of gdp spent on health care by 2006 ( department of health , 2000 ; towse and sussex , 2000 ; ferriman , 2000 ) .
more recently , in mid-2002 after a review of the long - term trends affecting the nhs ( wanless , 2002 ) the chancellor confirmed that there would be a 43-percent increase in real terms in health spending over the next 5 years ( that is more than 7 percent annual average growth ) .
a public service agreement published by the department of health outlined the improvements that patients could expect , including reduced waiting times for hospital outpatient appointments to maximum 3 months and inpatient appointments to 6 months by 2005 ( coomber , 2002 ) . on the other hand , 12 oecd countries had below - average health care expenditures growth during the past decade ( table 2 ) . among these countries
two groups can be distinguished , taking into consideration gdp growth . in several countries ( e.g. ,
switzerland , france , and germany ) health care expenditures still grew faster than the economy , resulting in a considerable increase in the ratio of health care spending to gdp ( table 1 ) .
in other countries , low health care expenditures growth between 1990 and 2000 went together with a similar or somewhat higher gdp growth , resulting in a decrease in the ratio of health care spending to gdp in finland and hungary and a stabilization of the ratio in canada , italy , and sweden .
table 2 shows the proportional gap in real growth rates of gdp and health care expenditures during the 1990s . in the u.s .
it is interesting to note that while the real health care expenditures growth rate was slightly slower in the u.s .
than in the eu during the 1990s ( 3.0 percent compared to 3.2 percent ) , the gap between health expenditure and gdp growth was somewhat higher in the u.s .
( 50 percent compared to 40 percent ) . however , at the beginning of this decade both real health care spending growth and the gap in growth rates in the u.s .
has again considerably exceeded the eu average , and even the oecd average ( table 2 ) .
the phenomenon of excess growth prevalent in countries whose health care expenditures ratio was relatively low in 1990 ( figure 4 ) , has led to some convergence of expenditure ratios .
this figure plots the excess growth of health over gdp with the share of health care expenditures in 1990 , the beginning of the time period studied in this graph .
countries at the lower end of the health care expenditures ratios tend to have higher excess growth rates , whereas several countries at the higher end of the scale had low or no excess growth in health care spending over the gdp ( for example , denmark and canada ) .
this pattern is not unambiguous : the three countries with high expenditure ratios in 1990 ( germany , switzerland , and the u.s . ) had relatively high excess growth of health .
health care expenditures per capita converted to us$ purchasing power parity ( ppp ) is commonly used to compare the overall level of consumption of health care goods and services across countries . according to this measure , the u.s .
continues to spend far more on a per capita basis for health care than any other country .
it spent over us$4,880 per capita on health care in 2001more than twice the average of around us$2,080 ppp across oecd countries ( figure 5 ) .
next in this ranking for 2001 come switzerland , norway , germany , and canada ; and at the other end of the scale , mexico , poland , slovak republic , korea , and hungary spent less than us$1,000 on health care .
it is evident that differences in per capita values are far greater than in health care expenditures as percent of gdp .
the figure also reflects that , depending on economic development , countries having a high share of health care expenditures to gdp ratio might have low per capita expenditure , and vice versa .
for example , greece and france both spent around 9.5 percent of gdp on health care , but health care expenditures per capita in france was 70 percent higher .
differences in health care spending across countries are greater than differences in gdp per capita ( table 4 ) .
for instance , in 2001 , gdp per capita in the u.s . was 40 percent higher than the oecd average , while expenditure on health care was 135 percent greater .
most of the lower income oecd countries ( korea , czech republic , hungary , slovak republic , poland , mexico , and turkey ) see greater deviations from the oecd average in relation to health care expenditures per capita than for gdp per capita . over the past decade , however , the lower income oecd countries , with the only exception of hungary , narrowed their gap from the oecd average , both in terms of total and public expenditure on health .
for oecd countries on average , the statistical significance of a simple regression relationship between growth rates in per capita health care spending and per capita gdp has declined during the 1990s ( huber , 1999 ) .
this can be seen with the help of the scatter diagram in figure 3 . if the cluster of countries that excludes the two outliers of korea and ireland ( both saw exceptional health care expenditures and gdp growth during the 1990s ) is studied separately , the correlation between gdp growth and health care expenditures growth is not significantly different from zero . in all countries ,
health care is financed through a mixture of publicly - funded benefits and services , private social provision ( largely employer - sponsored social insurance , but also some cooperative mutual insurance ) and direct private purchase of medical services , pharmaceuticals and appliances , plus private voluntary insurance .
public third - party payment arrangements are either expenditures from general government revenues or based on social insurance systems . although the u.s .
health care system is thought of as primarily privately funded ( only about one - quarter of the u.s .
ranks fourth in the oecd in terms of spending per - capita from public funds , behind norway , luxembourg , and iceland ( docteur , suppanz , and woo , 2003 ) .
private sources of funding comprise out - of - pocket spending , private health insurance ( often funded by employers and subsidies by tax exemption ) , and other private sources .
these include direct health benefits such as occupational health care , or charities . from the view of private households and individual health care consumers
, an important boundary line is between out - of - pocket spending and all other health care funding , i.e. , the part of health care provided under a third - party payment arrangement , which can be either a public or a private program . according to this definition , out - of - pocket spending includes both over - the - counter and similar direct payment to providers that are not refundable , plus cost sharing of private households .
this includes the funding of services and medical goods that are ( at least partially ) covered under a third - party payment program .
figure 6 shows how oecd countries are ranked by their increasing share of out - of - pocket spending and by total health care expenditures .
the public sector is the main source of health care funding in all oecd countries , except the u.s . ,
during the 1970s , the public share of health care spending increased in oecd countries on average , but since 1980 has stabilized and even slightly declined in the 1990s . on average , the public share of health care funding accounted for 72 percent in 2001 .
the public share was more than 80 percent in several countries , including the czech republic , denmark , and the united kingdom ( table 5 and figure 6 ) .
the share of out - of - pocket payments was above 30 percent of total health care expenditures in switzerland , korea , and mexico .
it varies between 10 and 30 percent of total health care expenditures for most countries with available data ( table 5 ) . with a few exceptions ,
there is a tendency for the share of out - of - pocket spending to decline as health care expenditures per capita rises .
out - of - pocket spending on health care continues to be among the most dynamic components of private consumption in a majority of oecd countries .
there are substantial differences between countries in the baskets of goods and services that are paid out of pocket .
pharmaceuticals are one of the major components in all countries . however , countries differ markedly in the share of private spending that is devoted to services , such as denture and long - term care ( ltc ) in nursing homes and home - help services , also reflecting differences in public coverage of these items .
private insurance can provide both basic coverage for those not covered by public systems or provide complementary insurance for specific services or that part of service cost not covered under public programs .
examples of the first type of private insurance include employer - sponsored private insurance group contracts in the u.s . and private insurance contracts of state employees in germany .
complementary health care insurance is a common way of financing dental and medical appliances , or privately paid upgrades of hospital accommodation .
data for a number of countries suggest that out - of - pocket spending for health care rose as a share of total household consumption during the 1990s ( table 6 ) . of the 19 oecd countries for which this measure is available , all but 4 experienced such an increase ; the share remained constant in denmark and france , and decreased in korea and the u.s .
in all countries , health care is financed through a mixture of publicly - funded benefits and services , private social provision ( largely employer - sponsored social insurance , but also some cooperative mutual insurance ) and direct private purchase of medical services , pharmaceuticals and appliances , plus private voluntary insurance .
public third - party payment arrangements are either expenditures from general government revenues or based on social insurance systems . although the u.s .
health care system is thought of as primarily privately funded ( only about one - quarter of the u.s .
ranks fourth in the oecd in terms of spending per - capita from public funds , behind norway , luxembourg , and iceland ( docteur , suppanz , and woo , 2003 ) .
private sources of funding comprise out - of - pocket spending , private health insurance ( often funded by employers and subsidies by tax exemption ) , and other private sources .
from the view of private households and individual health care consumers , an important boundary line is between out - of - pocket spending and all other health care funding , i.e. , the part of health care provided under a third - party payment arrangement , which can be either a public or a private program . according to this definition ,
out - of - pocket spending includes both over - the - counter and similar direct payment to providers that are not refundable , plus cost sharing of private households .
this includes the funding of services and medical goods that are ( at least partially ) covered under a third - party payment program .
figure 6 shows how oecd countries are ranked by their increasing share of out - of - pocket spending and by total health care expenditures .
the public sector is the main source of health care funding in all oecd countries , except the u.s . ,
the public share of health care spending increased in oecd countries on average , but since 1980 has stabilized and even slightly declined in the 1990s . on average , the public share of health care funding accounted for 72 percent in 2001 .
the public share was more than 80 percent in several countries , including the czech republic , denmark , and the united kingdom ( table 5 and figure 6 ) .
the share of out - of - pocket payments was above 30 percent of total health care expenditures in switzerland , korea , and mexico .
it varies between 10 and 30 percent of total health care expenditures for most countries with available data ( table 5 ) . with a few exceptions ,
there is a tendency for the share of out - of - pocket spending to decline as health care expenditures per capita rises .
out - of - pocket spending on health care continues to be among the most dynamic components of private consumption in a majority of oecd countries .
there are substantial differences between countries in the baskets of goods and services that are paid out of pocket .
however , countries differ markedly in the share of private spending that is devoted to services , such as denture and long - term care ( ltc ) in nursing homes and home - help services , also reflecting differences in public coverage of these items
private insurance can provide both basic coverage for those not covered by public systems or provide complementary insurance for specific services or that part of service cost not covered under public programs .
examples of the first type of private insurance include employer - sponsored private insurance group contracts in the u.s . and private insurance contracts of state employees in germany .
complementary health care insurance is a common way of financing dental and medical appliances , or privately paid upgrades of hospital accommodation .
data for a number of countries suggest that out - of - pocket spending for health care rose as a share of total household consumption during the 1990s ( table 6 ) . of the 19 oecd countries for which this measure is available ,
all but 4 experienced such an increase ; the share remained constant in denmark and france , and decreased in korea and the u.s .
oecd countries differ in the ways health care expenditures are allocated according to type of service provided and medical goods consumed ( figure 7 ) . in 2001 , on average across oecd countries , 38 percent of total health care expenditures was allocated to inpatient care , 31 percent for ambulatory services ( including ancillary services and home care ) , 21 percent for medical goods ( including pharmaceuticals and medical appliances ) and the remaining 10 percent was spent on collective services ( administration and general public health prevention programs ) .
for example , denmark , the netherlands , and switzerland allocated 45 percent or more of their health care expenditures on inpatient care in 2001 , while countries such as the u.s .
and canada spent less than 30 percent on this component of their health care system ( figure 7 ) .
hungary and the slovak republic spent almost 40 percent of their total health care expenditures on medical goods ( including pharmaceuticals , such as prescription drugs ) , while denmark , switzerland , and the u.s . spent less than 15 percent on this item .
figure 7 shows that the relative shares of types of services in overall spending can refer to quite different absolute spending levels in countries .
each spent roughly the same share of their health care expenditures on inpatient care , but in dollar terms the u.s .
similarly , hungary devoted 30 percent of its health care expenditures to medical goods , compared to 12 percent in the u.s .
, but dollar spending in the u.s . was 2.1 times that in hungary ( figure 7 ) .
in fact , the relatively small share of pharmaceutical spending in the u.s . corresponds to the highest per - capita spending in the oecd ( figure 8) .
reasons for international differences in the distribution of expenditures among provider types can be traced back to several roots .
constant changes and innovation in medical technology , reforms in payment mechanisms , and the search for more efficient allocation of health care resources all act together over time to modify the division of labor in health care across provider industries .
this involves complex trends in specialization and integration , increasing the need for better coordination to bring basic services closer to consumers in the community .
pharmaceutical products represent an important and growing share of health care expenditures in most countries .
the number of new drugs increased considerably during the past decade , and the movement toward new , more expensive products has been one of the main driving forces in increasing pharmaceutical expenditure , thereby contributing to the increase in overall health care spending .
there are considerable differences in pharmaceutical spending across countries , reflecting differences in volume , structure of consumption , and price level .
the u.s . spends the most on pharmaceuticals , with expenditure per capita of us$605 ppp in 2001 .
, with spending of more than us$400 ppp per capita ( figure 8) . on average the annual growth rate of pharmaceutical expenditure was 30 percent higher than that of total health care expenditures during the 1990s resulting in increasing shares of pharmaceuticals in total spending ( figure 8) ( organisation for economic co - operation and development , 2003b ) .
oecd countries at the lower end of the income scale tend to spend a greater share of their health care expenditures on pharmaceuticals , partly because pharmaceuticals have international market prices while labor costs are usually based on national wage structures .
for example , hungary and the slovak republic spent around 30 percent of total health care expenditures on pharmaceuticals , while denmark and the netherlands spent around 10 percent . the share spent on pharmaceuticals can also be very different in countries having similar health care spending per capita .
for example , denmark spends 9 percent of total health care expenditures on pharmaceuticals while france spends 21 percent ( figure 8) , although both have roughly the same total health care spending per capita ( figure 7 ) .
pharmaceutical expenditure tends to be funded from private sources to a greater extent than inpatient and outpatient services , because copayments tend to be higher on pharmaceuticals and a considerable portion of pharmaceuticals are not covered under public insurance schemes ( organisation for economic co - operation and development , 2003b ) .
most oecd countries have been applying a mix of tools to try to control pharmaceutical expenditures over the past two decades
. increased cost sharing for pharmaceuticals has been a common feature ( mossialos , and le grand , 1999 ; saltman and figueras , 1997 ) .
the number of drugs not reimbursed has increased , mainly comfort drugs or those without proven therapeutic value .
the degree of cost sharing has been increased for many others . in a number of cases , flat - rate payments per prescription have been established .
reference price systems have also been introduced in several countries ( e.g. , germany , denmark , and the netherlands ) .
these arrangements increase cost sharing for individuals using high - cost products while promoting the use of less - costly generic drugs .
the reporting on trends in health care spending across countries in a timely , comparable , and policy relevant way needs a constant investment both by the international community and by individual countries to keep national reporting systems up - to - date with rapidly changing health care systems , and to ensure that a core set of expenditure indicators can be reported in an internationally harmonized way for comparative purposes . to facilitate this process
, the oecd secretariat has published an accounting framework which is now used by an increasing number of oecd member and non - member countries ( organisation for economic cooperation and development , 2000 ) .
oecd member countries are currently at different stages of implementing the sha manual , and/or of harmonizing their reporting on health care expenditures according to main categories and definitions of the international classification of health accounts ( icha ) as proposed by the sha ( organisation for economic co - operation and development , 2002 ) . in several countries ,
the reporting on health care accounts according to the sha framework is now part of national reporting ( e.g. , denmark , germany , hungary , japan , korea , mexico , netherlands , and switzerland ) .
other countries produce estimates according to the oecd framework , but mainly for purposes of reporting to the oecd health care data collection ( e.g. , australia , canada , france , and the u.s . ) and detailed results and comments on estimation methods are made available with the description of the national data sources and estimation methods ( organisation for economic co - operation and development , 2003a ) .
comparability of data is still restricted for countries where sha pilots are at an early or experimental stage ( e.g. , finland , and the united kingdom ) , and where the sha implementation has not been started ( e.g. , austria , , italy , portugal , and new zealand ) .
but even where results of the detailed tables of the sha framework are not yet available publicly , some experience with the sha manual has now been gained in at least 25 of the 30 oecd countries . during this process
, statisticians have re - examined their overall expenditure estimates and the basic breakdown according to various dimensions ( type of services and goods , industries of providers , and sources of financing ) .
as these more detailed estimates are being implemented in a growing number of countries , comparability of health care expenditures estimates is expected to constantly improve in the future . as a result of this work ,
two of the most significant are the boundary between health care and other social services , in particular for older persons in need of ltc , and the structure and amount of spending from a multitude of private sources .
for example , a better estimate of ltc increased the estimate for total expenditure in sweden by 7.7 percent in 2001 .
( it meant that the new estimate for total expenditure as a percentage of gdp was 8.7 percent , compared to 8.0 percent before adjustment for ltc . )
the oecd secretariat currently conducts in - house research on both issues in the framework of a project on ltc policies , and a project on private health insurance ( organisation for economic co - operation and development , 2003a ) .
there are initial reports from several countries that the trend of accelerated growth is continuing in 2002 , which once again brings the discussion of the limits of health care spending growth to the forefront of public policy debate ( e.g. canada , france , germany , and the u.s . ) .
evidence of growing health care expenditures ratios has come from preliminary results of national health accounts for canada , france , and the u.s .
( canada institute for health information , 2003 ; fnina and geoffroy , 2003 ; heffler et al . , 2003 ) , or from public spending trends that exceed expected gdp growth ( german federal ministry of health and social security , 2002 ) .
despite a general convergence of countries ' experience over the past decade , the u.s . remains significantly different . the u.s
. started the decade with a substantially higher level than other oecd countries both in absolute terms in per - capita ppp , and as a percent of gdp . during the 1990s , real annual health care spending growth in the u.s .
was compared to that of other oecd countries and to the eu average ( table 2 ) . however , the 2000 - 2001 real health care spending growth in the u.s .
was considerably above the eu average , and even the oecd average . in 2001 , the u.s .
spent more on health care by 2 percentage points of gdp than in 1990 ( 13.9 percent of gdp compared to 11.9 percent ) , while on average the eu spent more on health care by less than 1 percentage point of gdp ( 8.5 percent of gdp compared to 7.6 percent ) . in order to present a more complete story about value - for - money that the health care dollar buys , the data presented in this article need to be complemented by additional indicators .
it is access to quality services and the ability of a health care system to build confidence that these will be provided in efficient and effective ways , that determine a society 's willingness to dedicate a growing share of its overall resources to health care . in order to be able to suggest how close an oecd country comes to its individual ideal in this respect ,
in addition , substantially more work is needed on a more disaggregated level , but in ways that lead to internationally comparable results ( cutler , 2002 ) . on the aggregate level
, work is currently undertaken at the oecd secretariat to complement the currently available spending data by a more detailed breakdown of spending by type of service .
this will help answer questions such as : to what extent is a relatively generous coverage and high spending of ltc services ( for older persons , but also for younger adults ) a common feature of several of the highest spending countries ( e.g. , in canada , germany , and switzerland ) ?
an important part of the expenditure story is differences in prices , for both input and output of health - service provision ( especially pharmaceutical prices and labor costs ) .
part of this task , such as a basic data set for comparing income of health professions is also currently on the oecd agenda and can be found at http://www.oecd.org/health .
this will help in the future to be better able to decide to which degree differences in health expenditure are due to price differences ( anderson et al .
there is some evidence that differences in the availability of resources devoted to health care , which are also behind differences in expenditure , have an effect on outcomes ( or , 2000 ) .
countries operating all or parts of their health care system with tightly controlled resources ( for example , the hospital sector ) may experience waiting lists that are increasingly seen as problematic ( hurst and siciliani , 2003 ) . on a semi - aggregate level , the spread of technology has been linked to expenditure growth ( mose , 2003 ) .
finally , many questions on the relative efficiency of health care provision across countries can only be answered by detailed analysis using data on a much more disaggregated level , such as comparisons based on how certain health problems are tackled ( treatment of diseases ) .
the tentative conclusion from this type of study seems again to be that there is indeed some evidence that patients in the highest spending countries have some benefit from relative high spending ( organisation for economic co - operation and development , 2003c ) .
the main challenge for further work remains to build better data bridges between microdata and macrodata on health care activities , to find out more information about the most effective ways to spend additional health dollars and to understand better how technological progress contributes to both increasing cost and improved outcomes .
Output:
| this article presents data on health care spending for 30 oecd countries from oecd health data 2003 , the latest edition of oecd 's annual data collection on health systems across industrialized countries .
oecd data show health care expenditures as a proportion of gross domestic product at an all - time high , due to both increased expenditures and overall economic slowdown .
the article discusses similarities and differences across countries in how health care expenditures are funded and how the health care dollar is spent among types of services . |
PubmedSumm118506 | ***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: population studies showed a strong correlation between pro - inflammatory biomarkers ( such as c - reactive protein , interleukin-6 [ il-6 ] and tumour necrosis factor-[tnf- ] ) and perturbations in glucose homeostasis , obesity and atherosclerosis [ 2 , 3 ] .
another emerging risk factor is oxidized low - density lipoprotein ( ox - ldl ) that activates circulating monocytes , thereby increasing their ability to infiltrate the vascular wall .
the metabolic syndrome clusters several cardiovascular risk factors including obesity , dyslipidaemia , hypertension and insulin resistance ( ir ) [ 58 ] .
increased inflammation [ 9 , 10 ] and oxidative stress [ 11 , 12 ] were found to be associated with the metabolic syndrome .
it is a primary risk factor for diabetes and cardiovascular diseases [ 6 , 1320 ] .
recent data suggest that increased oxidative stress in adipose tissue is an early instigator of the metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for the obesity - associated metabolic syndrome .
oxidative damage of adipose tissues is associated with impaired adipocyte maturation , production of pro - inflammatory adipocytokines by dysfunctional adipocytes and increased infiltration of macrophages into the adipose tissues of obese persons where they produce inflammatory chemokines [ 22 , 23 ] .
the goal of this review is to give an overview of the molecular mechanisms in adipose and vascular tissues that can explain the vicious circle between oxidative stress and inflammation , in relation to atherosclerosis and cardiovascular diseases .
the initial event in atherogenesis is the increased transcytosis of ldl , and its subsequent deposition , retention and modification in the subendothelium within and outside the meshes of the hyperplasic basal lamina where ldl interacts with matrix proteins [ 25 , 26 ] .
it is followed by the recruitment of circulating monocytes into the vascular intima and their subsequent transformation into macrophage / foam cells are key elements of the initiation of atherosclerosis .
this infiltration occurs preferentially at sites with disturbed flow dynamics where the endothelium becomes dysfunctional at the cellular and molecular level . activated by the disturbed flow , the endothelium shows enhanced platelet adhesion , increased endothelial permeability to macromolecules such as ldl , and augmented endothelial gene expression of leucocyte adhesion molecules and chemotactic factors ( fig .
1 ) . activation of the leucocyte adhesion cascade ultimately leads to transmigration of monocytes into the subendothelial space of the intima and subsequent differentiation into macrophages .
adherence of circulating monocytes and t lymphocytes to the inflamed endothelium is mediated particularly by the vascular adhesion molecule-1 ( vcam-1 ) , the intercellular adhesion molecule-1 ( icam-1 ) and e- selectin and fibronectin .
the monocyte chemoattractant protein-1 ( mcp-1 ) and il-8 play an active role as chemoattractants in the infiltration of leucocytes into the arterial wall .
activated macrophages express enzymes such as myeloperoxidase ( mpo ) and nadph oxidase ( nox-1 ) , which together generate a range of oxidants , including superoxide , hydrogen peroxide and hypochlorous acid [ 27 , 28 ] .
each of them causes oxidative damage not only to invading micro - organisms , but also to host molecules in surrounding tissues . among them are phospholipids in cell membranes and circulating lipoproteins which contain polyunsaturated fatty acid chains , such as the abundant phospholipid 1-palmitoyl-2-arachidonyl - sn - glycero-3-phosphorylcholine ( papc ) that are particularly susceptible to oxidation by such mediators .
products of papc oxidation have been shown to accumulate at sites of inflammation , and in cells treated with inflammatory stimulants such as il-1 and tnf-. oxidation of papc leads to the formation of a mixture of products , ranging from epoxyisoprostanes to truncated chain derivatives that are collectively termed ox - papc .
oxidation of phospholipids in ldl , that infiltrates into the injured vessel wall , by mpo and nox-1 , results in the accumulation of ox - papc in ox - ldl ( fig .
endothelial dysfunction in relation to hypercholesterolemia , hypertension , type 2 diabetes , and smoking is associated with induction of adhesion molecules for inflammatory cells , icam-1 , vcam-1 , e - selectin and fibronectin .
the infiltration and activation of inflammatory cells are associated with the activation of the oxidant enzymes mpo and nox-1 , resulting in the production of ros and the oxidation of phospholipids and protein in ldl , resulting in the accumulation of ox - ldl .
it stimulates the endothelium to secrete mcp-1 and il-8 , which induce transmigration of leucocytes into the endothelial space .
macrophages secrete m - csf , thereby stimulating macrophage proliferation and inducing the expression of scavenger receptors cd36 , lox-1 and sr - a .
the scavenger receptor mediated uptake of ox - ldl by macrophages leads to massive cholesterol and lipid accumulation and formation of foam cells , finally resulting in apoptotic macrophages and exposure of thrombogenic lipids .
foam cells secrete mmps and sms resulting in the production of ceramide that induces smooth smc apoptosis ( black cells ) .
activation of sms also blunts the action of abca-1 and abcg-1 resulting in impaired cholesterol and lipid efflux from foam cells .
ox - ldl induces tlrs of which the ligands enhance the expression of inflammatory mediators il-6 and tnf-. ox - ldl induces migration inhibitory factor that stimulates smc migration . the uptake of ox - ldl by smcs leads to the production of smc foam cells and secretion of mmps that degrade the extracellular matrix proteins rendering the plaque more prone to rupture .
ox - ldl stimulates platelet adhesion and aggregation by decreasing endothelial production of nitric oxide , and enhances the pro - coagulant activity of endothelium by inducing the release of tissue factor .
ox - ldl reduces the fibrinolytic activity of endothelium by increasing the release of plasminogen activator inhibitor-1 .
finally , ox - ldl induces apoptosis in endothelial cells ( black ) contributing to plaque erosion and rupture .
the activation of macrophages is also characterized by increased expression of the scavenger receptor - a ( sr - a ) , cluster of differentiation ( cd)36 , and the lectin - like ox - ldl receptor ( lox-1 ) which internalize ox - ldl .
however , unregulated uptake of ox - ldl leads to production of lipid - loaded foam cells .
the unlimited accumulation of lipids , also as a consequence of defective cholesterol and lipid efflux , leads to apoptosis and cell burst resulting in exposure of extracellular lipids .
both apoptotic cells and thrombogenic lipids induce the formation of microthrombi which further stimulate the adhesion and infiltration of inflammatory cells , and the secretion of inflammatory cytokines , and the production of ros . besides its deleterious action in the production of foam cells , cd36 plays also a protective role as a receptor of thrombospondin ( tsp-1 ) .
this interaction is important for activating tsp-1-mediated phagocytosis , thereby preventing inflammation and macrophage - induced elastin degradation by matrix metalloproteinases ( mmps ) , and thus vessel wall degeneration and plaque rupture . by binding to tsp-1
, ox - ldl does not only impair phagocytosis but also prevents tsp-1-dependent tgf- activation , thereby increasing inflammation and atherogenesis . activated
macrophages secrete a number of growth factors such as the macrophage colony - stimulating factor ( m - csf ) that augments sr - a expression , and induces the production of cytokines and growth factors which stimulate intimal proliferation .
once resident in the arterial wall , the interaction between monocytes / macrophages and t cells results in a broad range of cellular and humoural responses that drive the progression of a relatively simple fatty streak to a more complex lesion .
modified forms of ldl are immunogenic and activate both cell - mediated and humoural immune responses . both types of responses are pro - inflammatory and are probably primary players in the perpetuation of the chronic inflammatory reaction characteristic of atherosclerosis . the immunologic response to modified ldl
can be directed to major histocompatibilty complex class ii ( mhc - ii)-associated peptides in the case of t helper cells , and to a variety of epitopes - modified lysine groups , modified phospholipids , proteins that become associated with ox - ldl ( such as 2 glycoprotein 1 ) in the case of b cell responses . at the other hand ,
indeed , recent data showed that alum precipitates , containing antigens derived from ox - ldl , increased regulatory t cells activated by tolerogenic antigen - presenting cells presenting ox - ldl antigens . similarly macrophages , endothelial cells and smooth muscle cells ( smcs ) appear to be activated , demonstrated by increased expression of mhc - ii molecules , and of toll - like receptors ( tlrs ) of which the ligands induce the release of numerous inflammatory products , such as tnf- , il-6 and mcp-1 .
recently , we found that ox - ldl can also induce inflammation by inducing tlr-2 and -4 and the interferon regulatory factor-1 ( fig .
1 ) . moreover , activated macrophages produce pro - inflammatory secretory phospholipase a ( 2 ) ( spla ( 2))-iia . this enzyme lipolyzes the phospholipid monolayers of ldl , increasing its affinity to proteoglycans , rendering it more susceptible to aggregation , and enhancing its ability to insert cholesterol into cells .
this modification may promote scavenger receptor independent ldl uptake by macrophages leading to the formation of foam cells .
in addition to spla2iia that does not hydrolyse phosphatydylcholine ( pc ) into lyso - pc ( lpc ) , there are at least three spla2 that degrade intact pc in human ldl leading to foam cells formation , including pla2g10 and pla2giii and to lesser extent pla2gv .
moreover there is a specific lipoprotein - associated pla2 ( lp - pla2 ; pla2g7 ) that degrades oxidized ceramide found in ox - ldl and that increases its inflammatory action [ 42 , 43 ] .
interestingly , we showed that ox - ldl induced the phospholipase expression by monocytes and macrophages .
furthermore , activation of inflammatory cells is associated with the activation of sphingomyelinases ( sms ) in the trans - golgi apparatus and in plasma membranes resulting in the synthesis of sphingomyelin ( sm ) , which transfers the phosphorylcholine moiety from phosphatidylcholine onto ceramide .
the interaction between sm , cholesterol , and glycosphingolipid drives the formation of sm - enriched lipid rafts resulting in an inhibition of the atp - binding cassette transporter ( abc ) a-1 and abcg-1-mediated lipid efflux .
this is important because macrophages can not limit the uptake of cholesterol , and therefore depend on cholesterol and lipid efflux pathways to prevent their transformation into foam cells .
however , by preventing fibrous cap formation , it renders plaques more susceptible to rupture , and increases the risk of acute coronary syndromes .
interestingly , enhanced ceramide production was observed in association with the activation of mmp-2 by ox - ldl .
the association between ox - ldl , foam cell formation and mmp secretion is , however , not limited to macrophages but does also occur in smcs .
finally , ox - ldl induces the macrophage migration inhibitory factor that stimulates the migration of smcs , contributing to intimal hyperplasia ( fig .
recently , we obtained a mouse model of the metabolic syndrome that allowed the study of molecular mechanisms explaining the relations of the metabolic syndrome components with enhanced inflammation and oxidative stress .
indeed , we found that mice with combined leptin and ldl receptor deficiency ( double knockout [ dko ] mice ) are obese and show severe hypertriglyceridaemia , hypertension and ir and diabetes .
this combination of metabolic syndrome factors was associated with accelerated atherosclerosis due to increased accumulation of macrophages in association with endothelial dysfunction demonstrated by increased expression of vcam-1 and icam-1 in the aorta of dko mice .
in addition , impaired high - density lipoprotein associated anti - oxidant activity in the blood was associated with more ox - ldl in the plaques .
we then investigated the relation between metabolic syndrome components and the oxidation of ldl further by assessing the effect of weight loss .
we selected this intervention because it had been demonstrated that the cardiovascular risk of insulin - resistant obese persons is higher than that of insulin - sensitive obese persons , and that weight loss reduces the risk of insulin - resistant obese persons .
weight loss in obese mice was associated with a decrease of metabolic syndrome components , resulting in reduced inflammation and oxidative stress . ultimately , these changes led to inhibition of atherosclerosis due to decreased accumulation of macrophages and deposition of ox - ldl .
we showed that weight loss was not only associated with a decrease of the volume of adipose tissues , but also with improved adipocyte maturation demonstrated by induction of peroxisome proliferator activated receptors ( ppars ) resulting in improved glucose uptake and insulin signalling , and fatty acid metabolism .
this improved metabolic profile was associated with increased anti - oxidant protection , supported by increased expression of superoxide dismutase ( sod ) , glutathione peroxidase ( gpx ) and nitric oxide synthase ( nos ) .
similar effects were obtained with rosuvastatin that is known to increase insulin sensitivity and inhibit the oxidation of ldl .
cell experiments indicated that ppar- can inhibit the accumulation of ox - ldl by increasing the anti - oxidant defence by up - regulating sod-1 and -3 and gpx ( fig .
the decrease of ox - ldl is associated with a reduction of the tlr - mediated inflammatory response .
ppar- also decreases expressions of monocyte - specific adhesion molecules and chemotactic factors , resulting in less macrophage accumulation .
in addition , ppar- increases nos production associated with improved endothelial function , induces the efflux of cholesterol and lipids from foam cells by up - regulating the liver x receptors ( lxr)- and abca-1 . finally , ppar- induces the expressions of the glucose transporter-4 and the insulin receptor substrate-2 ( irs-2 ) , which activate glucose uptake and insulin action .
the improved irs-2-mediated insulin signalling is associated with increased sod-2 expression , resulting in lower mitochondrial oxidative stress and ros production .
finally , ppar- activation was found to prime monocytes into alternative m2 macrophages with anti - inflammatory properties .
ppar- reduces the expressions of icam-1 , vcam-1 and mcp-1 , resulting in reduced macrophage accumulation , ros production and ox - ldl deposit .
in addition , ppar- increases expressions of cd36 and anti - oxidant enzymes sod and gpx , resulting in a further reduction of ox - ldl .
higher ppar- is also associated with increased lxr- and abca-1 expression , resulting in a decrease of cholesterol and lipids .
the reduction in ox - ldl is associated with a decrease of tlr - mediated inflammation , and thereby reduced ros production .
in addition this reduction is associated with higher nos production resulting in improved endothelial vasoreactivity , blood pressure regulation and left ventricle function .
reduction of ox - ldl results in restoring ppar- expression that is associated with increased irs-2 and glucose transporter-4 expressions , which are important regulators of insulin sensitivity and glucose uptake .
improved insulin action results in decreased mitochondrial oxidative stress , increased sod-2 expression and reduced ros production .
obesity is associated with reduced adipose tissue oxygenation and hypoxia , without the appropriate angiogenic response , due to defective activation of lxrs and vascular endothelial growth factor ( vegf ) , but with increased macrophage chemotaxis ( fig .
very recent findings suggest that obese adipose tissue activates cd8 t cells , which , in turn , promote the recruitment and activation of macrophages in this tissue and support the notion that cd8 t cells have an essential role in the initiation and propagation of adipose inflammation [ 58 , 59 ] . finally , it was found that lean , but not obese , fat is enriched for a unique population of regulatory t cells that protects against the harmful effect of metabolic parameters .
circulating monocytes adhere to activated endothelial cells . activated cd8 t cells and chemokines induce monocyte migration into adipose tissues where they differentiate into macrophages .
interaction of saturated fatty acids with tlrs leads to secretion of inflammatory cytokines / chemokines ( il-6 and tnf- ) . together with the adipocytokines leptin and resistin , they impair c - jun n - terminal kinase and nf-b signalling , resulting in ir and reduced adiponectin ( acrp-30 ) secretion , and thereby loss of adipocyte maturation . together
infiltration of inflammatory cells is associated with ros and ox - ldl production , endothelial cell apoptosis , impaired lxr and vegf signalling , and decreased blood flow leading to hypoxia and increased oxidative stress .
ox - ldl can further induce adipose tissue hyperplasia , and by inducing lipoprotein lipase it enhances lipid accumulation resulting in adipose tissue hypertrophy .
increased apoptosis also results from reduced acrp-30 secretion and growth arrest specific 6 mediated survival pathway .
apoptotic adipocytes attract macrophages which normally remove apoptotic adipocytes . however , ox - ldl impairs phagocytosis of dead adipocytes by inhibiting resolvin e1 and protectin d1 production . infiltrated inflammatory cells produce and secrete tnf- and il-6 contributing to the pathogenesis of ir , together with factors produced by dysfunctional adipocytes such as leptin and resistin .
a range of mouse models with loss - of - function mutations in genes important in macrophage recruitment ( mcp-1 and chemokine ( c - c motif ) receptor 2 ) , inflammatory cytokine production ( tnf- ) and pro - inflammatory activation ( nf-b [ nuclear factor of light polypeptide gene enhancer in b - cells ] and ib kinase [ ikk] ) have demonstrated to be protected against high - fat diet - induced ir [ 6264 ] .
interestingly , weight loss was associated with a reduction in the macrophage infiltration of adipose tissues , associated with an improvement of the inflammatory and oxidant profile of adipocytes and monocytes in adipose tissue and the circulation , respectively .
furthermore , weight loss resulted in enhanced insulin sensitivity and a decrease of the cardiovascular risk of insulin - resistant , obese persons .
in addition to their roles in inflammation , macrophages also promote vascular remodelling of adipose tissues by producing mmps .
this occurs preferentially at sites of adipocyte death where macrophages form a crown - like structure that envelopes and ingests the moribund adipocyte and its potentially cytotoxic remnant lipid droplets . as a consequence of lipid scavenging , macrophages within crown - like structures
become lipid - loaded foam cells that fuse to multinucleate giant cells that have lost their capacity to remove dead adipocytes . during resolution ,
specific -3 polyunsaturated fatty - acid - derived mediators , including resolvin e1 and protectin d1 , promote phagocyte removal during acute inflammation by inhibiting leucocyte infiltration and increasing macrophage ingestion of apoptotic cells .
this resolution is impaired in obesity leading to defective protection against oxidative stress - initiated inflammation by glutathione conjugates of lipid oxidation - derived aldehydes , such as 4-hydroxy - trans-2-nonenal present in ox - ldl .
a possible explanation for the relation between ox - ldl and obesity is that ox - ldl increases the volume of adipose tissues either directly by inducing adipocyte proliferation or indirectly by increasing the infiltration of inflammatory monocytes / macrophages which increase adipogenesis .
the increase in adipose tissue mass may also be explained by a cellular hypertrophy due to an increased lipid accumulation in the pre - existing adipocytes rather than an increase in cell number or differentiation .
indeed , ox - ldl increases triglyceride production by inducing the expression of lipoprotein lipase , and the accumulation of fatty acids in adipocytes .
interestingly , fatty acids stimulate the accumulation of ceramide that contributes to inflammation that , as discussed above , is associated with adipose hyperplasia .
ox - ldl was also found to decrease the production of adiponectin that in contrast with other adipocytokines is reduced in obese persons , and suppresses excess ros production under high - glucose conditions , an effect that has implications for vascular protection in diabetes .
in addition , the decrease of adiponectin results in a loss of its capacity to protect cells against inactivation of the growth arrest specific 6 mediated survival pathway by tnf-. the observed relations between obesity and ox - ldl are important to understand the relation of obesity with ir and the metabolic syndrome .
experimental , clinical and population studies demonstrated active roles of oxidative stress and inflammation in the development of obesity - associated metabolic syndrome and cardiovascular diseases . herein , we presented evidence of a vicious circle between inflammation and oxidative stress not only in vascular but also in adipose tissues .
inflammatory cells increase the production of ros and ox - ldl by secreting oxidant enzymes .
they impair the function of endothelial cells and smcs in vascular , and of endothelial cells and adipocytes in adipose tissues .
especially , inhibiting the irs - mediated insulin action is associated with a decrease in anti - oxidant enzymes , and an increase of mitochondrial oxidative stress in both tissue types . by inducing the production of foam cells ,
ox - ldl decreases the phagocytosis of apoptotic cells by macrophages , resulting in impaired insulin action . by attacking endothelial cells
in addition , we showed that ppar- and adiponectin protect against oxidative stress and inflammation .
loss of adiponectin - mediated signalling between adipose and arterial tissues is of particular importance in the development of obesity - associated atherosclerosis and cardiovascular diseases .
Output:
| abstractthe initial event in atherogenesis is the increased transcytosis of low density lipoprotein , and its subsequent deposition , retention and modification in the subendothelium .
it is followed by the infiltration of activated inflammatory cells from the coronary circulation into the arterial wall . there
they secrete reactive oxygen species ( ros ) and produce oxidized lipoproteins capable of inducing endothelial cell apoptosis , and thereby plaque erosion . activated t lymphocytes ,
macrophages and mast cells , accumulate in the eroded plaque where they secrete a variety of proteases capable of inducing degradation of extracellular proteins , thereby rendering the plaques more prone to rupture .
this review summarizes the recent advancements in the understanding of the roles of ros and oxidized lipoproteins in the activation of inflammatory cells and inducing signalling pathways related to cell death and apoptosis .
in addition , it presents evidence that this vicious circle between oxidative stress and inflammation does not only occur in the diseased arterial wall , but also in adipose tissues .
there , oxidative stress and inflammation impair adipocyte maturation resulting in defective insulin action and adipocytokine signalling .
the latter is associated with increased infiltration of inflammatory cells , loss of anti - oxidant protection and cell death in the arterial wall . |
PubmedSumm118507 | ***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: health care personnel and specially physicians in almost all countries , regardless of the level of development , work in more than one job or sector ( 1 , 2 ) . the practice has been mentioned in a number of studies as common and ubiquitous among physicians and other health staff ( 15 ) .
dual practice ( dp ) , dual job holding , moonlighting , multiple job holding , dual employment , multiple employment , dual working , double work , and pluri employment are different terms that has been used in the literature for describing this phenomenon .
in addition , there has been a great diversity in the literature in approaching the issue .
health professionals with multiple specialization ( e.g. cardiology and internal medicine ) , working within different paradigms of health ( e.g. allopathic medicine combined with traditional medicine ) , combining different forms of health - related practice ( e.g. clinical activities with research , teaching or management ) , combining professional health practice with an economic activity not related to health ( e.g. agriculture ) , and multiple health - related practices in the same or different sites or sectors , are various concepts that has been considered in different studies in this field around the world ( 3 ) . among all , health professionals engaging in multiple health related practices is one kind of the phenomenon that has more implications for various aspects of service delivery and has been regarded by the majority of researchers in this subject ( 3 , 69 ) .
garcia - prado and gonzalez classified different forms of this kind of dual practice based on two variables : the nature of the two jobs ( public versus private ) , and the contractual arrangement in place . according to this classification
there are three types of dual practice ( public on public dp , private on private dp , and public on private dp ) which the last one ( public on private dp ) has being conducted in four forms ( regular public post and private side practice , regular public job and private office , part - time public and part - time private , regular full - time private work and a part - time public post)(5 ) .
the third type ( public on private dp ) , is the most prevalent form of dual practice in many countries and has potentially adverse welfare implications ( 5 ) .
therefore , most of the researchers have focused on this particular form of dp and have conducted studies on different aspects of the issue . to our knowledge , there has not been a study , which comprehensively reviews and categorizes studies in physician dual practice field in the last 10 years . in this paper
, we aimed to review studies in this subject and categorize them in order to their main objectives and purposes .
we hope this study could describe a map of the knowledge about the phenomenon and highlight gaps in this field .
comprehensive literature searches were undertaken in order to obtain main papers and documents in dual practice field .
after that , descriptive mapping review methods were utilized to categorize eligible studies in this area .
search strategy for electronic databases was as follows :
search dual practice[t / a ] or dual practitioner[t / a ] or multiple job*[t / a ] or dual job*[t / a ] or moonlight*[t / a ] or
moonlighting[t / a ] or dual worker*[t / a ] or public sector job[t /
a ] or private sector job[t / a ] or multiple employmen*[t / a ] or dual worker[t / a ] or additional income[t / a ] or public sector employment[t / a ] or private sector employment[t / a].search health worker*[t / a ] or health professional*[t / a ] or physician*[t / a ] or doctor*[t / a ] or nurs*[t / a ] or clinician*[t / a ] or health staff[t / a ] or medic*[t / a ] or dent*[t / a ] or medical specialist*[t / a ] or surgeon*[t / a ] or
general practice[t / a ] or gp[t / a ] or health[t / a ] or healthcare[t / a].search # 1 and # 2 search dual practice[t / a ] or dual practitioner[t / a ] or multiple job*[t / a ] or dual job*[t / a ] or moonlight*[t / a ] or
moonlighting[t / a ] or dual worker*[t / a ] or public sector job[t /
a ] or private sector job[t / a ] or multiple employmen*[t / a ] or dual worker[t / a ] or additional income[t / a ] or
health professional*[t / a ] or physician*[t / a ] or doctor*[t / a ] or nurs*[t / a ] or clinician*[t / a ] or health staff[t / a ] or medic*[t / a ] or dent*[t / a ] or medical specialist*[t / a ] or surgeon*[t / a ] or general practitioner*[t / a ] or general practice[t / a ] or gp[t / a ] or health[t / a ] or healthcare[t / a ] .
we also ran general searches for dual practice into some search engines like google and google scholar in order to find reports and related documents in this field .
all of the designs such as cross sectional , qualitative , modeling , surveys , etc . were recognized eligible for inclusion .
studies that were reported in other languages except for english or persian , or did not include clinical professionals were excluded from the analysis .
two authors ( jm and aas ) screened the titles and abstracts of all obtained articles independently and excluded the papers that obviously did not meet the inclusion criteria .
after that , full texts of all potentially relevant articles selected by either of the authors were retrieved .
the two authors then independently assessed studies that if they met our inclusion criteria or not .
disagreements between the two review authors were resolved through discussion and consensus . the following elements abstracted independently from each study by the authors :
study references
first author and date of publication.document typethe journal or institution where published the study.location of the study.aims and purposesmethods
study designparticipantsmain results study references
first author and date of publication.document typethe journal or institution where published the study.location of the study .
comprehensive literature searches were undertaken in order to obtain main papers and documents in dual practice field .
after that , descriptive mapping review methods were utilized to categorize eligible studies in this area .
search strategy for electronic databases was as follows :
search dual practice[t / a ] or dual practitioner[t / a ] or multiple job*[t / a ] or dual job*[t / a ] or moonlight*[t / a ] or
moonlighting[t / a ] or dual worker*[t / a ] or public sector job[t /
a ] or private sector job[t / a ] or multiple employmen*[t / a ] or dual worker[t / a ] or additional income[t / a ] or
public sector employment[t / a ] or private sector employment[t / a].search health worker*[t / a ] or health professional*[t / a ] or physician*[t / a ] or doctor*[t / a ] or nurs*[t / a ] or clinician*[t / a ] or health staff[t / a ] or medic*[t / a ] or dent*[t / a ] or medical specialist*[t / a ] or surgeon*[t / a ] or general practitioner*[t / a ] or general practice[t / a ] or gp[t / a ] or health[t / a ] or healthcare[t / a].search # 1 and # 2 search dual practice[t / a ] or dual practitioner[t / a ] or multiple job*[t / a ] or dual job*[t / a ] or moonlight*[t / a ] or
moonlighting[t / a ] or dual worker*[t / a ] or public sector job[t /
health professional*[t / a ] or physician*[t / a ] or doctor*[t / a ] or nurs*[t / a ] or clinician*[t / a ] or health staff[t / a ] or medic*[t / a ] or dent*[t / a ] or medical specialist*[t / a ] or surgeon*[t / a ] or general practitioner*[t / a ] or general practice[t / a ] or gp[t / a ] or health[t / a ] or healthcare[t / a ] .
we also ran general searches for dual practice into some search engines like google and google scholar in order to find reports and related documents in this field .
all of the designs such as cross sectional , qualitative , modeling , surveys , etc . were recognized eligible for inclusion .
studies that were reported in other languages except for english or persian , or did not include clinical professionals were excluded from the analysis .
two authors ( jm and aas ) screened the titles and abstracts of all obtained articles independently and excluded the papers that obviously did not meet the inclusion criteria .
after that , full texts of all potentially relevant articles selected by either of the authors were retrieved .
the two authors then independently assessed studies that if they met our inclusion criteria or not .
the following elements abstracted independently from each study by the authors :
study references
first author and date of publication.document typethe journal or institution where published the study.location of the study.aims and purposesmethods
study designparticipantsmain results study references
first author and date of publication.document typethe journal or institution where published the study.location of the study .
electronic searches in the mentioned databases provided us with 522 papers . eliminating for duplicates ,
367 remaining titles were screened by the authors and unrelated ones were missed out from the list .
after that , authors examined 166 remaining abstracts independently and again omitted the studies , which clearly did not have the inclusion criteria .
latter , adding 37 other studies , which obtained from the web search , 81 full texts were retrieved and have been read by both authors .
finally , there were only 24 studies which be considered as related to our inclusion criteria ( fig.1 ) .
all of the studies in this group are article , and in terms of method , they applied quantitative ( two studies ) , qualitative ( two studies ) , and mixed method - both quantitative and qualitative-(one study ) approaches ( table 1 ) .
motivation , reasons and forces behind dual practice what south african medical specialists find satisfying about working in the public and private sectors how to better incentivize retention in the public sector .
although there are strong financial incentives for specialists to migrate from the public to the private sector , public work can be attractive in some ways .
for example , the public hospital sector generally provides more of a team environment , more academic opportunities , and greater opportunities to feel needed and relevant. public specialists suffer under poor resource availability , lack of trust for the department of health , and poor perceived career opportunities .
these non financial issues of public sector dissatisfaction appeared at least as important as wage disparities . for assistant physicians
higher wages at public hospitals affect negatively both the decisions to earn income externally , and level of income once active . for consultant physicians
few respondents said that money is the dominating objective , in that they would gladly give up the private practice in exchange for a pay rise in the nhs .
private practice was seen as offering an increase in strategic influence , clinical autonomy , and realization of individual aspirations as a clinician .
commitment to government services was found to be greater among doctors in primary health care who reported they would give up private practice if paid a higher salary . among doctors in secondary and tertiary care , the propensity to give up private practice was found to be low .
doctors have adopted individual strategies to accommodate the advantages of both government employment and private practice in their career development , thus maximizing benefit from the incentives provided to them e.g. status of a government job , and minimizing opportunity costs of economic losses e.g. lower salaries .
the two outstanding reasons why they engage in their various side activities were to meet the cost of living , and to support the extended family .
40 percent of participants reported that the median equivalent of one month 's public sector salary could be generated by 7 hours of private practice , but being a civil servant was important in terms of job security , and credibility as a doctor . also the social contacts and
public service gave access to power centers and resources , through which other coping strategies could be developed .
six studies were related to this category ( 1 , 8 , 1417 ) . all of the studies in this group are article- except for the reference ( 17 ) which is a report- , and in terms of method , they applied modeling ( four studies ) , review ( one study ) , and quantitative ( one study ) approaches ( table 2 ) .
the consequences of dual practice dual and single practitioners did not differ significantly in terms of the average length of work week , participation in non mandatory activities or duties outside normal working hours , including duties accepted with short notice and their preferences for working hours or turnover intention .
some of the effects depend on assumptions that are undermined in the broader literature ( e.g. the intention to maximize income )
allowing moonlighting always enhances aggregate consumer welfare , but equilibrium public - care quality may increase or decrease .
unregulated moonlighting may reduce consumer welfare as a result of adverse behavioral reactions , such as moonlighters shirking more and dedicated doctors abandoning their sincere behavior .
price regulation in the private market limits such adverse behaviors in the public system and improves consumer welfare .
crowds out public provision , and results in lower overall health care provision . while the health authority can mitigate this effect by offering a higher wage , a ban on dual practice
is more efficient if private sector competition is weak and public and private care are sufficiently close substitutes .
on the other hand , if private sector competition is sufficiently tough , a mixed system , with physician dual practice , is always preferable to a pure nhs system .
physician will have incentives to over - provide medical services when he uses his public activity as a way of increasing his prestige as a private doctor .
physicians dual practice can be either welfare improving or reducing , depending on the treatment policy that the health authority wants to implement ( if the priority is to contain costs , then the doctor s dual activity is negative .
if the priority is to minimize patients health losses , his dual practice affords the objective at a lower cost ) .
governments can meet the participation constraint of physicians without paying salaries commensurate to physicians abilities because physicians also value the non salary benefit of the opportunity to earn significant private practice revenues .
if dual - practitioner differentially refer higher income patients to private practice , public funding becomes more effectively targeted on the poor .
however , physician incentives to concentrate inducement on those most responsive to inducement - often the poor and uneducated may act counter to such a social objective . in the next step , we categorized these 24 studies into four groups according to their main objectives ( tables 14 ) .
policies and regulations about dual practice and their impacts the need for increasing the share of healthcare budget from the gross domestic product ( gdp ) , inefficient tariff and payment system , and difficulty in obtaining collaboration with other stakeholders are the main challenges of full - time practice program in iran .
inappropriate implementation of this program might lead to unexpected transfer of the experienced and high skilled physicians from public hospitals . to analyze and compare some of the most common regulations in dual practice . to investigate whether regulations that are optimal for developed countries are adequate for developing countries as well .
forbidding dual practice is seldom optimal , as it usually expels valuable professionals from the public system .
results offer theoretical support for the desirability of different regulations in different economic environments . in developed countries
the key factor is the potential negative effect of dual practice on public performance : when this effect is low the best option is not to intervene ; when it is sufficiently high the best option is to impose a limit on physician involvement . for developing countries , the design of the optimal policy is more complex as it also depends on the attractiveness of the private sector .
when this attractiveness is very high the best option is not to intervene and thereby avoid an exodus of highly skilled physicians from the public sector .
finally , if the potential gains from private practice are low , the optimal intervention is either to limit dual practice ( if the associated costs are low ) or to ban it ( if such costs are high ) .
there is not any scientifically rigorous study in this field ( rcts , nrcts , cba or its designs ) . allowing dual practice can improve welfare even when physicians have homogeneous quality / morality .
when information is asymmetric among physicians , patients and the planner , dual practice can be conceived as a tool to improve welfare in two ways : first , resource allocation within the hospital is more efficient ; second , allowing dual practice can save salary expenditure for the public hospital .
people with high opportunity cost ( high income ) in switching providers will be more likely to go to the hospital while people with low opportunity cost in switching providers ( low income ) will visit the gp first .
hence , after allowing dual practice , rich patients with mild cases are more likely to be induced to private clinics from the hospital .
low income patients , or patients with serious conditions , are more likely to be treated in the hospital .
therefore , physician dual practice can also be interpreted as an alternative instrument for sorting in terms of both illness severity and switching costs . under some conditions , allowing dual practice can lead to a second - best improvement in efficiency , compared with a situation in which dual practice is not allowed .
there are wide variations in how governments tackle this issue . banning dual practice , enforcing restrictions on private practice earnings of physicians , offering exclusive contracts in the public sector , encouraging public doctors to develop their private practice in public facilities , raising public sector salaries , and self - regulation are six mechanisms which have been used by different countries .
it causes dual practitioners to either move out of the province or stay and just shirk in effort .
these physicians , who want to dual practice but now is unable to , lowers the aggregate welfare of patients in the public sector by constantly maintaining low quality service rather than trying to improve the service . allowing dual practice without restrictions is unlikely to result in an improvement in the social welfare of patients .
the social welfare of people in canada s mixed health care system will be better off where restrictions on dual practice are present ( both exclusive contracts and price ceiling allow physicians to still use the over - providing strategy if they choose to dual practice , while also keeping public physicians in the public sector ) . dual practice can be a possible system solution to issues such as limited public sector resources , low regulatory capacity , and the interplay between market forces and human resources .
this paper offers some supports for policies that allow for the official recognition of such activity and embrace a degree of professional self regulation in highly resource constrained settings ( because evidence shows that dp is typically poorly regulated in these countries .
regulations are either lacking , or when they exist , are vague or poorly implemented because of low regulatory capacity ) .
dual practice could be found almost in all countries ( it is wide spread in many developing countries ) .
economic motives are not the only reason why physicians engage in dp . other non - pecuniary factors such as job complementarities , and institutional , professional , structural and personal variables
while dual providers may be tempted to skimp on time and effort in their main job , to induce demand for their private services , or to misuse public resources , the legalization of dual practice may also contribute to recruit and retain physicians with less strain on the budget and improve access to health services , especially in developing countries .
the article provides some qualified support for the use of rewarding policies to retain physicians in the public sectors of more developed countries , while limiting policies are recommended for developing countries - with the caveat that the policies should be accompanied by the strengthening of institutional and contracting environments dual practice is widespread and well - accepted .
however , broad macroeconomic influences on dual practice such as the oversupply of medical services , the deregulated nature of this market , and the economic crisis throughout the country were also important
policy responses to dual practice involve tighter controls on the supply of medical practitioners , alleviation of financial pressures brought by macro - economic conditions , and closer regulation of such activities to ensure some degree of collective action over quality and the maintenance of professional reputations . to provide a summary and comparison of five models of dual practice , including one we have developed based on total compensation theory and contracting limitations . to discuss whether theoretical predictions are consistent with empirical evidence from developed and developing countries .
all theories to date suggest that the impact of dual practice on public service quality is ambiguous .
the social trade - off between the benefits and costs of dual practice hinge on the quality of a country s contracting institutions . allowing dual practice may improve social welfare and the quality of public services , under specific circumstances .
the evidence does not support the perception that full - timers embody greater commitment and contribution to public sector provision .
dual practice is approached in the literature with great diversity : health professionals with multiple specialization , working within different paradigms of health , combining different forms of health - related practice , combining professional health practice with an economic activity not related to health , and multiple health - related practices in the same or different sites or sectors .
typologies of dp : in terms of sector location , dual practice may be public on public , public on private or private on private .
dual practice is probably present in all countries regardless of income , even in settings such as china where there are major regulatory restrictions .
negative impacts are predatory behavior ( self gain is preferred to the interests of others ) , conflict of interest ( lower the quality in the public sector to advertise for the private sector ) , brain drain ( to other countries , private sector , or urban areas ) , competition for time and limits to access , outflow of resources and corruption ( illegal use of public resources for private patients ) ; positive impacts : it 's ability to generate additional income for health workers , and higher professional satisfaction .
the extent of dual practice seems to vary according to urban or rural residence , according to professional group , according to specialty or occupation .
this evidence suggests that dual practice depends not so much on the personal , social ( marital status ) and professional characteristics of health workers , but on factors that are manageable .
adequate responses imply the identification of the main underlying reason for the observed dual practice .
governments have a wide range of responses to it based mostly on assumption , anecdote , and etc .
increasing income is likely to be the main reason for engaging in dp , but job complementarity , institutional and professional factors ( the desire to interact among professionals in the practice site , to secure approval from peers , and to influence fellow professionals and ... ) are probably also important .
efforts to address mjh should consider what could be done about both the systemic causes of mjh and its program and worker specific manifestations .
all mjh is not of equal importance for health outcomes and making services work for the poor .
governments should set priorities carefully , understand causes and effects , and engage in collaborative process with health workers to find solutions which are both acceptable to them and improve system outcomes .
governments should increase the benefits and reduce the costs ( negative effects ) in relation to government objectives through the best possible design of incentives and regulations to affect the behavior of health care workers given their demand for mjh ( banning mjh is not really a feasible and effective strategy in most countries , because they lack the capacity to enforce it , and these regulation are often not seen as legitimate by the health workers , their supervisors , and general population ; also removing the conditions creating the demand for mjh among health workers is rarely viable , because it needs sufficient resources and contractual and monitoring capacities which are not present in many countries ) .
dual practice was very low among physicians , less than twice a month . on average physicians
most doctors ( 85.6% ) think dp is acceptable and that it should be legal .
about 70% of respondents think that dp activities will result in negative influences in their hospital . the level of awareness of the relevant regulation on dp amongst doctors was low , at 24.4%
. over 70% of doctors complained that their income was lower than that in other comparable occupations , while 55% of patients think doctors income is quite high compared with other jobs in current chinese society ) .
different specialties have different opportunities to undertake dp : surgeons have more scope for dp than physicians .
all of the studies in this group are article- except for the references ( 20 ) and ( 22 ) which are thesis- , and in terms of method , they applied modeling ( three studies ) , review ( three study ) , and quantitative ( one study ) approaches ( table 3 ) .
this category refers to the documents , which considered more than one area of dp .
six studies fell into this category ( 2 , 3 , 5 , 2426 ) .
all of the studies in this group are articles - except for ( 25 ) and ( 26 ) which are reports- , and in terms of method , they applied review ( four studies ) , qualitative ( one study ) , and a combination of quantitative and qualitative ( one study ) approaches ( table 4 ) .
all of the studies in this group are article , and in terms of method , they applied quantitative ( two studies ) , qualitative ( two studies ) , and mixed method - both quantitative and qualitative-(one study ) approaches ( table 1 ) .
motivation , reasons and forces behind dual practice what south african medical specialists find satisfying about working in the public and private sectors how to better incentivize retention in the public sector .
although there are strong financial incentives for specialists to migrate from the public to the private sector , public work can be attractive in some ways .
for example , the public hospital sector generally provides more of a team environment , more academic opportunities , and greater opportunities to feel needed and
relevant. public specialists suffer under poor resource availability , lack of trust for the department of health , and poor perceived career opportunities .
these non financial issues of public sector dissatisfaction appeared at least as important as wage disparities . for assistant physicians higher wages at public hospitals
affect negatively both the decisions to earn income externally , and level of income once active . for consultant physicians
few respondents said that money is the dominating objective , in that they would gladly give up the private practice in exchange for a pay rise in the nhs .
private practice was seen as offering an increase in strategic influence , clinical autonomy , and realization of individual aspirations as a clinician .
commitment to government services was found to be greater among doctors in primary health care who reported they would give up private practice if paid a higher salary . among doctors in secondary and tertiary care , the propensity to give up private practice was found to be low .
doctors have adopted individual strategies to accommodate the advantages of both government employment and private practice in their career development , thus maximizing benefit from the incentives provided to them e.g. status of a government job , and minimizing opportunity costs of economic losses e.g. lower salaries .
the two outstanding reasons why they engage in their various side activities were to meet the cost of living , and to support the extended family .
40 percent of participants reported that the median equivalent of one month 's public sector salary could be generated by 7 hours of private practice , but being a civil servant was important in terms of job security , and credibility as a doctor . also the social contacts and public service gave access to power centers and resources , through which other coping strategies could be developed .
all of the studies in this group are article- except for the reference ( 17 ) which is a report- , and in terms of method , they applied modeling ( four studies ) , review ( one study ) , and quantitative ( one study ) approaches ( table 2 ) .
the consequences of dual practice dual and single practitioners did not differ significantly in terms of the average length of work week , participation in non mandatory activities or duties outside normal working hours , including duties accepted with short notice and their preferences for working hours or turnover intention .
some of the effects depend on assumptions that are undermined in the broader literature ( e.g. the intention to maximize income )
allowing moonlighting always enhances aggregate consumer welfare , but equilibrium public - care quality may increase or decrease .
unregulated moonlighting may reduce consumer welfare as a result of adverse behavioral reactions , such as moonlighters shirking more and dedicated doctors abandoning their sincere behavior .
price regulation in the private market limits such adverse behaviors in the public system and improves consumer welfare . allowing physician dual practice
crowds out public provision , and results in lower overall health care provision . while the health authority can mitigate this effect by offering a higher wage , a ban on dual practice
is more efficient if private sector competition is weak and public and private care are sufficiently close substitutes . on the other hand ,
if private sector competition is sufficiently tough , a mixed system , with physician dual practice , is always preferable to a pure nhs system .
physician will have incentives to over - provide medical services when he uses his public activity as a way of increasing his prestige as a private doctor .
physicians dual practice can be either welfare improving or reducing , depending on the treatment policy that the health authority wants to implement ( if the priority is to contain costs , then the doctor s dual activity is negative .
if the priority is to minimize patients health losses , his dual practice affords the objective at a lower cost ) .
governments can meet the participation constraint of physicians without paying salaries commensurate to physicians abilities because physicians also value the non salary benefit of the opportunity to earn significant private practice revenues .
if dual - practitioner differentially refer higher income patients to private practice , public funding becomes more effectively targeted on the poor .
however , physician incentives to concentrate inducement on those most responsive to inducement - often the poor and uneducated may act counter to such a social objective . in the next step , we categorized these 24 studies into four groups according to their main objectives ( tables 14 ) . policies and regulations about dual practice and their impacts the need for increasing the share of healthcare budget from the gross domestic product ( gdp ) , inefficient tariff and payment system , and difficulty in obtaining collaboration with other stakeholders are the main challenges of full - time practice program in iran .
inappropriate implementation of this program might lead to unexpected transfer of the experienced and high skilled physicians from public hospitals . to analyze and compare some of the most common regulations in dual practice . to investigate whether regulations that are optimal for developed countries are adequate for developing countries as well .
forbidding dual practice is seldom optimal , as it usually expels valuable professionals from the public system .
results offer theoretical support for the desirability of different regulations in different economic environments . in developed countries
the key factor is the potential negative effect of dual practice on public performance : when this effect is low the best option is not to intervene ; when it is sufficiently high the best option is to impose a limit on physician involvement . for developing countries , the design of the optimal policy is more complex as it also depends on the attractiveness of the private sector .
when this attractiveness is very high the best option is not to intervene and thereby avoid an exodus of highly skilled physicians from the public sector .
finally , if the potential gains from private practice are low , the optimal intervention is either to limit dual practice ( if the associated costs are low ) or to ban it ( if such costs are high ) .
there is not any scientifically rigorous study in this field ( rcts , nrcts , cba or its designs ) . allowing dual practice can improve welfare even when physicians have homogeneous quality / morality .
when information is asymmetric among physicians , patients and the planner , dual practice can be conceived as a tool to improve welfare in two ways : first , resource allocation within the hospital is more efficient ; second , allowing dual practice can save salary expenditure for the public hospital .
people with high opportunity cost ( high income ) in switching providers will be more likely to go to the hospital while people with low opportunity cost in switching providers ( low income ) will visit the gp first .
hence , after allowing dual practice , rich patients with mild cases are more likely to be induced to private clinics from the hospital .
low income patients , or patients with serious conditions , are more likely to be treated in the hospital .
therefore , physician dual practice can also be interpreted as an alternative instrument for sorting in terms of both illness severity and switching costs . under some conditions , allowing dual practice can lead to a second - best improvement in efficiency , compared with a situation in which dual practice is not allowed .
there are wide variations in how governments tackle this issue . banning dual practice , enforcing restrictions on private practice earnings of physicians , offering exclusive contracts in the public sector ,
encouraging public doctors to develop their private practice in public facilities , raising public sector salaries , and self - regulation are six mechanisms which have been used by different countries .
it causes dual practitioners to either move out of the province or stay and just shirk in effort .
these physicians , who want to dual practice but now is unable to , lowers the aggregate welfare of patients in the public sector by constantly maintaining low quality service rather than trying to improve the service .
allowing dual practice without restrictions is unlikely to result in an improvement in the social welfare of patients .
the social welfare of people in canada s mixed health care system will be better off where restrictions on dual practice are present ( both exclusive contracts and price ceiling allow physicians to still use the over - providing strategy if they choose to dual practice , while also keeping public physicians in the public sector ) . dual practice can be a possible system solution to issues such as limited public sector resources , low regulatory capacity , and the interplay between market forces and human resources .
this paper offers some supports for policies that allow for the official recognition of such activity and embrace a degree of professional self regulation in highly resource constrained settings ( because evidence shows that dp is typically poorly regulated in these countries .
regulations are either lacking , or when they exist , are vague or poorly implemented because of low regulatory capacity ) .
dual practice could be found almost in all countries ( it is wide spread in many developing countries ) .
. other non - pecuniary factors such as job complementarities , and institutional , professional , structural and personal variables play a relevant role .
while dual providers may be tempted to skimp on time and effort in their main job , to induce demand for their private services , or to misuse public resources , the legalization of dual practice may also contribute to recruit and retain physicians with less strain on the budget and improve access to health services , especially in developing countries .
the article provides some qualified support for the use of rewarding policies to retain physicians in the public sectors of more developed countries , while limiting policies are recommended for developing countries - with the caveat that the policies should be accompanied by the strengthening of institutional and contracting environments dual practice is widespread and well - accepted .
however , broad macroeconomic influences on dual practice such as the oversupply of medical services , the deregulated nature of this market , and the economic crisis throughout the country were also important . there were some support among doctors for tighter regulation .
policy responses to dual practice involve tighter controls on the supply of medical practitioners , alleviation of financial pressures brought by macro - economic conditions , and closer regulation of such activities to ensure some degree of collective action over quality and the maintenance of professional reputations . to provide a summary and comparison of five models of dual practice , including one we have developed based on total compensation theory and contracting limitations . to discuss whether theoretical predictions are consistent with empirical evidence from developed and developing countries .
all theories to date suggest that the impact of dual practice on public service quality is ambiguous .
the social trade - off between the benefits and costs of dual practice hinge on the quality of a country s contracting institutions . allowing dual practice may improve social welfare and the quality of public services , under specific circumstances .
the evidence does not support the perception that full - timers embody greater commitment and contribution to public sector provision .
dual practice is approached in the literature with great diversity : health professionals with multiple specialization , working within different paradigms of health , combining different forms of health - related practice , combining professional health practice with an economic activity not related to health , and multiple health - related practices in the same or different sites or sectors .
typologies of dp : in terms of sector location , dual practice may be public on public , public on private or private on private .
dual practice is probably present in all countries regardless of income , even in settings such as china where there are major regulatory restrictions .
negative impacts are predatory behavior ( self gain is preferred to the interests of others ) , conflict of interest ( lower the quality in the public sector to advertise for the private sector ) , brain drain ( to other countries , private sector , or urban areas ) , competition for time and limits to access , outflow of resources and corruption ( illegal use of public resources for private patients ) ; positive impacts : it 's ability to generate additional income for health workers , and higher professional satisfaction
the extent of dual practice seems to vary according to urban or rural residence , according to professional group , according to specialty or occupation .
this evidence suggests that dual practice depends not so much on the personal , social ( marital status ) and professional characteristics of health workers , but on factors that are manageable .
adequate responses imply the identification of the main underlying reason for the observed dual practice .
governments have a wide range of responses to it based mostly on assumption , anecdote , and etc .
increasing income is likely to be the main reason for engaging in dp , but job complementarity , institutional and professional factors ( the desire to interact among professionals in the practice site , to secure approval from peers , and to influence fellow professionals and ... ) are probably also important .
efforts to address mjh should consider what could be done about both the systemic causes of mjh and its program and worker specific manifestations .
all mjh is not of equal importance for health outcomes and making services work for the poor .
governments should set priorities carefully , understand causes and effects , and engage in collaborative process with health workers to find solutions which are both acceptable to them and improve system outcomes .
governments should increase the benefits and reduce the costs ( negative effects ) in relation to government objectives through the best possible design of incentives and regulations to affect the behavior of health care workers given their demand for mjh ( banning mjh is not really a feasible and effective strategy in most countries , because they lack the capacity to enforce it , and these regulation are often not seen as legitimate by the health workers , their supervisors , and general population ; also removing the conditions creating the demand for mjh among health workers is rarely viable , because it needs sufficient resources and contractual and monitoring capacities which are not present in many countries ) .
dual practice was very low among physicians , less than twice a month . on average physicians
most doctors ( 85.6% ) think dp is acceptable and that it should be legal .
about 70% of respondents think that dp activities will result in negative influences in their hospital .
the level of awareness of the relevant regulation on dp amongst doctors was low , at 24.4% . over 70% of doctors complained that their income was lower than that in other comparable occupations , while 55% of patients think doctors income is quite high compared with other jobs in current chinese society ) .
different specialties have different opportunities to undertake dp : surgeons have more scope for dp than physicians .
all of the studies in this group are article- except for the references ( 20 ) and ( 22 ) which are thesis- , and in terms of method , they applied modeling ( three studies ) , review ( three study ) , and quantitative ( one study ) approaches ( table 3 ) .
this category refers to the documents , which considered more than one area of dp .
six studies fell into this category ( 2 , 3 , 5 , 2426 ) .
all of the studies in this group are articles - except for ( 25 ) and ( 26 ) which are reports- , and in terms of method , they applied review ( four studies ) , qualitative ( one study ) , and a combination of quantitative and qualitative ( one study ) approaches ( table 4 ) .
we conducted a comprehensive search and assessed several articles , reports and other documents in the field of physician dual practice .
the results of the study yielded 24 published works , which had our inclusion criteria .
considering that the fourth category ( other studies ) is related to studies , which focused on more than one aspect of dp , in this section we reported and interpreted the results of this group in the appropriate areas .
although almost there was not any study with the primary aim of assessing the extent of physician dual practice , some evidence showed that this phenomenon is common and ubiquitous among physicians and other health staff in all countries more or less ( 15 ) .
physicians engage in dual practice to accommodate the benefits of both government employment and private practice in their career development ( 4 ) .
financial incentives seems to be the most important determinant of physician dual practice ( 35 , 1012 , 24 , 25 ) .
also non pecuniary factors like status and recognition , strategic influence , control over work and professional opportunities(13 ) , strengthen cooperation with other hospitals(26 ) , using more academic opportunities and greater opportunities to feel needed and relevant ( 11 ) , job complementarities and institutional , professional , structural and personal variables like interactions among professionals and secure approval from peers(5 , 25 ) have been stated as other main determinants of this phenomenon .
furthermore some studies have shown that specialization , level of care , and location ( urban or rural ) have significant effect on both the decision and extent of moonlighting among physicians ( 3 , 4 , 26 ) .
evidence indicated that it helps physicians to boost their income ( 3 ) , increase their professional satisfaction ( 3 ) , improve access to health services ( 5 , 17 ) , improve the quality in public sector(1 ) , and reduce the financial burden on governments to retain high quality physicians in the public sector ( 5 , 17 , 23 ) . on the other hand ,
for example , it crowds out public provision and also could results in lower overall health care provision ( 15 ) , predatory behavior and induce demand ( 3 , 5 ) , conflict of interest and reducing the quality in the public sector ( 3 ) , brain drain ( 3 ) , competition for time and effort which may lead to absenteeism , tardiness , inefficiency and lack of motivation in the public sector ( 3 , 5 , 9 ) , and outflow of resources from public to private sector and corruption ( 3 , 5 ) .
however , one should consider that most of the mentioned effects are based on assumptions which are undermined in the broader literature ( 8) .
in addition , some evidence showed that there is not any significant difference between the performance of dual practitioners and full timers ( 2 , 14 ) .
evidence showed that there is not a single recipe about managing physician dual practice for different countries , and governments have adopted a broad range of responses toward it ( 2 , 3 , 5 , 7 , 25 ) .
these responses comprise banning dual practice on one side of the spectrum to allowing it without any restrictions on the other side ( see reference ( 6 ) in table 4 ) .
although there is not any rigorous empirical study about the effects of these policies and interventions ( 9 , 25 ) , most of the related documents support allowing dp with restrictions ( 2 , 5 , 7 , 20 , 22 , 23 ) .
gonzalez showed that among all limiting strategies , limiting involvement is always more effective than limiting income ( see reference ( 7 ) in table 4 ) .
almost all of the studies concluded that the policy of banning dp is seldom optimal , as it could lead to leakage of high skilled physicians from public sector and worsen the quality and social welfare in public hospitals ( 7 , 22 , 23 ) .
first , we considered only studies , reported in english or persian because of practical reasons such as time and financial limitations .
although authors tried to capture relevant studies through searching in the reference lists of important papers and googling in the search engines , these limitations might lead to missing some related documents .
the reason behind this decision was the nature of dual practice field which does not yet have a well - developed scientific literature ( 19 ) .
to our knowledge , this was the first study , which reviewed and categorized the literature in physician dual practice field in the last 10 years .
it seems that there is a paucity of scientifically reliable evidence in some areas of dp , like dp prevalence , the consequences of dp , and effects of the related interventions .
the present study showed that there has been a propensity to over reliance on methods like modeling in predicting the effects and consequences of this phenomenon .
however studies showed that almost all of these models are based on assumptions which are undermined in the broader literature ( 8) . as a result , government s responses to dp have been based on these assumptions and anecdotal evidence ( 25 ) .
furthermore , the effects of these governments responses and interventions in dp ( 9 ) , and also their cost effectiveness have not been examined rigorously so far .
therefore , it is not clear that whether we need any intervention in this area , and which kind of policy is more appropriate and cost effective for countries in different levels of development .
we therefore suggest that meticulous empirical studies should be designed to detect the real consequences of dp .
in addition , it is recommended that rigorous evaluative studies should be planned to assess the effects of interventions and regulations which governments have implemented in this field .
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 : physician dual practice is a common phenomenon in almost all countries throughout the world , which could potential impacts on access , equity and quality of services .
this paper aims to review studies in physician dual practice and categorize them in order to their main objectives and purposes.methods:comprehensive literature searches were undertaken in order to obtain main papers and documents in the field of physician dual practice .
systematic searches in medline and embase from 1960 to 2013 , and general searches in some popular search engines were carried out in this way .
after that , descriptive mapping review methods were utilized to categorize eligible studies in this area.results:the searches obtained 404 titles , of which 81 full texts were assessed . finally , 24 studies were eligible for inclusion in our review .
these studies were categorized into four groups - motivation and forces behind dual practice , consequences of dual practice ,
dual practice policies and their impacts , and other studies - based on their main objectives .
our findings showed a dearth of scientifically reliable literature in some areas of dual practice , like the prevalence of the phenomenon , the real consequences of it , and the impacts of the implemented policy measures.conclusion:rigorous empirical and evaluative studies should be designed to detect the real consequences of dp and assess the effects of interventions and regulations , which governments have implemented in this field . |
PubmedSumm118508 | ***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 presence of bilateral normal eyes with open angles was confirmed by prior ophthalmoscopic examination .
the study was conducted in accordance with the ethical standards in the declaration of helsinki and was approved by the university of southern california institutional review board . written informed consent was obtained from all participants .
all participants underwent nonmydriatic as - oct imaging of both eyes using the cirrus and spectralis oct .
scans were obtained in a darkened room , with lighting standardized to 1 cd / m at the imaging plane , confirmed with a light meter with a reading of 0.2 foot candles at the eye ( light meter fc-840021 ; sper scientific , scottsdale , az ) . for the cirrus , 3 mm scan length ,
5-line anterior segment raster scans were captured , with a 0.25 mm distance between lines .
scans were performed perpendicularly on the inferior angle at the 6 oclock position . for spectralis , a single - line 270-degree
the oct b - scan images were then exported for subsequent masked grading at the reading center .
images were graded in a masked fashion by certified as - oct graders ( x.p . , j.m .
) , using a prespecified standardized grading protocol . in the cirrus and spectralis images ,
the inferior angle sl - aod and sl - tisa were measured with validated custom grading software ( image j 1.44p ; wayne rasbands , national institutes of health ) at the doheny image reading center . for all eyes ,
the grader computed 2 parameters : sl - aod and sl - tisa , using the 6 oclock line scan of the 5-raster set in the cirrus ( the other 4-line scans were used to refine the position of sl ) and single - line scan in the spectralis . because adequate quality images were confirmed by the operator at the time of acquisition with visualization of the angle and sl , no case was deemed to be ungradable .
the measurements from the first and second acquisition ( intrainstrument ) , from first and second grading of the same image by 1 observer ( intraobserver ) and from grading of the same images by different observers ( interobserver ) for both instruments were used for statistical analysis .
images from 21 participants ( 42 eyes ) were used to assess intrainstrument and interinstrument reproducibility .
intraobserver and interobserver reproducibility were evaluated in a subset of 15 patients ( 30 eyes ) .
intraclass correlation coefficients ( icc ) were computed to evaluate absolute agreement and bland - altman plots were generated with limits of agreement ( loa ) , accounting for inclusion of both eyes from each participant in the analysis .
linear regression models were used to establish a correction factor for comparisons between the 2 sd - oct instruments .
all statistical analyses were performed using commercial software ( spss version 18.0 ; spss inc . , armonk
the presence of bilateral normal eyes with open angles was confirmed by prior ophthalmoscopic examination .
the study was conducted in accordance with the ethical standards in the declaration of helsinki and was approved by the university of southern california institutional review board . written informed consent was obtained from all participants .
all participants underwent nonmydriatic as - oct imaging of both eyes using the cirrus and spectralis oct .
scans were obtained in a darkened room , with lighting standardized to 1 cd / m at the imaging plane , confirmed with a light meter with a reading of 0.2 foot candles at the eye ( light meter fc-840021 ; sper scientific , scottsdale , az ) . for the cirrus , 3 mm scan length ,
5-line anterior segment raster scans were captured , with a 0.25 mm distance between lines .
scans were performed perpendicularly on the inferior angle at the 6 oclock position . for spectralis , a single - line 270-degree
the oct b - scan images were then exported for subsequent masked grading at the reading center .
images were graded in a masked fashion by certified as - oct graders ( x.p . , j.m . ) , using a prespecified standardized grading protocol . in the cirrus and spectralis images ,
the inferior angle sl - aod and sl - tisa were measured with validated custom grading software ( image j 1.44p ; wayne rasbands , national institutes of health ) at the doheny image reading center . for all eyes ,
the grader computed 2 parameters : sl - aod and sl - tisa , using the 6 oclock line scan of the 5-raster set in the cirrus ( the other 4-line scans were used to refine the position of sl ) and single - line scan in the spectralis . because adequate quality images were confirmed by the operator at the time of acquisition with visualization of the angle and sl , no case was deemed to be ungradable .
the measurements from the first and second acquisition ( intrainstrument ) , from first and second grading of the same image by 1 observer ( intraobserver ) and from grading of the same images by different observers ( interobserver ) for both instruments were used for statistical analysis .
images from 21 participants ( 42 eyes ) were used to assess intrainstrument and interinstrument reproducibility .
intraobserver and interobserver reproducibility were evaluated in a subset of 15 patients ( 30 eyes ) .
intraclass correlation coefficients ( icc ) were computed to evaluate absolute agreement and bland - altman plots were generated with limits of agreement ( loa ) , accounting for inclusion of both eyes from each participant in the analysis .
linear regression models were used to establish a correction factor for comparisons between the 2 sd - oct instruments .
all statistical analyses were performed using commercial software ( spss version 18.0 ; spss inc . , armonk , ny ) .
thirteen of them were asian , 3 were indian , 1 was hispanic , and 4 of them were white .
the mean sl - aod for the first acquisition on the cirrus was 0.6740.213 mm and the second acquisition was 0.6810.215 mm .
the mean difference in sl - aod between the 2 acquisitions was 0.008 ( loa 0.096 to 0.081 ) mm ( table 1 ) .
the mean sl - aod for the first acquisition and the second acquisition on the spectralis was 0.6640.198 and 0.6600.185 mm , respectively , with a mean difference of 0.004 ( loa 0.068 to 0.076 ) mm .
the reproducibility was excellent for both the cirrus and spectralis for sl - aod , with an icc of 0.989 and 0.991 , respectively .
intrainstrument reproducibility with the cirrus sd - oct and the spectralis sd - oct the mean sl - tisa on cirrus on the first acquisition and the second acquisition was 0.2550.081 and 0.2580.085 mm , respectively ( table 1 ) .
for spectralis , the mean sl - tisa on the first acquisition and the second acquisition was 0.2500.076 and 0.2500.069 mm , respectively .
the loa in sl - tisa were 0.036 to 0.030 mm on cirrus and 0.041 to 0.041 mm on spectralis between the 2 acquisitions .
the icc was 0.989 for cirrus and 0.979 for spectralis . for sl - aod , the mean difference between the first and second grading was 0.005 ( 0.039 to 0.029 ) mm with cirrus and 0.005 ( 0.048 to 0.037 ) mm with spectralis . for sl - tisa ,
the mean difference was 0.001 ( 0.025 to 0.022 ) mm for cirrus and 0.005 ( 0.034 to 0.024 ) mm for spectralis .
the intragrader reproducibility was excellent for both devices when examining sl - aod and sl - tisa , with icc values > 0.992 ( table 2 ) .
intraobserver reproducibility with the cirrus sd - oct and the spectralis sd - oct high values for icc were also observed in the interobserver comparisons .
the mean difference for sl - tisa was 0.010 ( 0.082 to 0.063 ) and 0.032 ( 0.039 to 0.104 ) mm for cirrus and spectralis , respectively .
interobserver reproducibility with the cirrus sd - oct and the spectralis sd - oct the mean sl - aod measurements were 0.6620.156 mm for spectralis and 0.6770.213 mm for cirrus ( table 4 ) .
this corresponded to a mean difference of 0.016 ( loa 0.125 to 0.092 ) ( fig .
the sl - tisa differences were also small between the instruments , with a mean difference of 0.007 ( loa 0.056 to 0.043 ) mm ( fig .
the iccs for comparisons between the 2 instruments were 0.961 for sl - aod and 0.945 for sl - tisa .
interinstrument reproducibility for sl - aod and sl - tisa measurements acquired with the spectralis and the cirrus instruments in the same subjects a and b , bland - altman plots demonstrate interinstrument reproducibility for sl - aod and sl - tisa .
the horizontal lines indicate the mean difference ( solid line ) and the limits of agreement ( dotted lines ) .
aod indicates angle opening distance ; sl , schwalbe line ; tisa , trabecular iris space area .
based on measurements from 21 od eyes with both cirrus and spectralis , a linear regression line of fit of y=1.1175x0.054 represents the relationship between the instruments .
this line of fit was used to predict the cirrus measurement values in the 21 os eyes based on inputting spectralis measurements into the regression line equation .
the average measured sl - aod with the cirrus was 0.6620.208 mm , whereas the predicted value from the spectralis was 0.6770.217 mm . the predicted and the measured value had an absolute difference of 0.0430.035 mm ( % difference 6.4275.427% ) .
the results show that the average measured sl - tisa with cirrus was 0.2500.082 mm , whereas the predicted value from spectralis was 0.2540.085 mm . the predicted value and measured value had an absolute difference of 0.0240.018 mm ( 0.001 to 0.074 mm , % difference 10.58.88% ) .
thirteen of them were asian , 3 were indian , 1 was hispanic , and 4 of them were white .
the mean sl - aod for the first acquisition on the cirrus was 0.6740.213 mm and the second acquisition was 0.6810.215 mm .
the mean difference in sl - aod between the 2 acquisitions was 0.008 ( loa 0.096 to 0.081 ) mm ( table 1 ) .
the mean sl - aod for the first acquisition and the second acquisition on the spectralis was 0.6640.198 and 0.6600.185 mm , respectively , with a mean difference of 0.004 ( loa 0.068 to 0.076 ) mm .
the reproducibility was excellent for both the cirrus and spectralis for sl - aod , with an icc of 0.989 and 0.991 , respectively .
intrainstrument reproducibility with the cirrus sd - oct and the spectralis sd - oct the mean sl - tisa on cirrus on the first acquisition and the second acquisition was 0.2550.081 and 0.2580.085 mm , respectively ( table 1 ) .
for spectralis , the mean sl - tisa on the first acquisition and the second acquisition was 0.2500.076 and 0.2500.069 mm , respectively .
the loa in sl - tisa were 0.036 to 0.030 mm on cirrus and 0.041 to 0.041 mm on spectralis between the 2 acquisitions .
for sl - aod , the mean difference between the first and second grading was 0.005 ( 0.039 to 0.029 ) mm with cirrus and 0.005 ( 0.048 to 0.037 ) mm with spectralis . for sl - tisa ,
the mean difference was 0.001 ( 0.025 to 0.022 ) mm for cirrus and 0.005 ( 0.034 to 0.024 ) mm for spectralis .
the intragrader reproducibility was excellent for both devices when examining sl - aod and sl - tisa , with icc values > 0.992 ( table 2 ) .
intraobserver reproducibility with the cirrus sd - oct and the spectralis sd - oct high values for icc were also observed in the interobserver comparisons .
the mean difference for sl - tisa was 0.010 ( 0.082 to 0.063 ) and 0.032 ( 0.039 to 0.104 ) mm for cirrus and spectralis , respectively .
the mean sl - aod measurements were 0.6620.156 mm for spectralis and 0.6770.213 mm for cirrus ( table 4 ) .
this corresponded to a mean difference of 0.016 ( loa 0.125 to 0.092 ) ( fig .
the sl - tisa differences were also small between the instruments , with a mean difference of 0.007 ( loa 0.056 to 0.043 ) mm ( fig .
the iccs for comparisons between the 2 instruments were 0.961 for sl - aod and 0.945 for sl - tisa .
interinstrument reproducibility for sl - aod and sl - tisa measurements acquired with the spectralis and the cirrus instruments in the same subjects a and b , bland - altman plots demonstrate interinstrument reproducibility for sl - aod and sl - tisa .
the horizontal lines indicate the mean difference ( solid line ) and the limits of agreement ( dotted lines ) .
aod indicates angle opening distance ; sl , schwalbe line ; tisa , trabecular iris space area .
based on measurements from 21 od eyes with both cirrus and spectralis , a linear regression line of fit of y=1.1175x0.054 represents the relationship between the instruments .
this line of fit was used to predict the cirrus measurement values in the 21 os eyes based on inputting spectralis measurements into the regression line equation .
the average measured sl - aod with the cirrus was 0.6620.208 mm , whereas the predicted value from the spectralis was 0.6770.217 mm . the predicted and the measured value had an absolute difference of 0.0430.035 mm ( % difference 6.4275.427% ) .
the results show that the average measured sl - tisa with cirrus was 0.2500.082 mm , whereas the predicted value from spectralis was 0.2540.085 mm . the predicted value and measured value had an absolute difference of 0.0240.018 mm ( 0.001 to 0.074 mm , % difference 10.58.88% ) .
to the best of our knowledge , this is the first study to compare the aca measurements between 2 sd - oct instruments ; cirrus and spectralis .
measurements were performed in the same eyes in sequential fashion using the same strict lighting conditions .
the intrainstrument , intraobserver , and interobserver measurement reproducibility for both oct machines was also assessed .
importantly , the present study provides direct evidence of consistency of quantitative metrics from both devices , since the effect of consecutive image acquisitions , between and within the observer factors did not produce significant measurement variability .
first , the excellent reproducibility in the intrainstrument , intraobserver , and interobserver measurements provides confidence in using those measurements for clinical use for screening , management or to follow patients in a longitudinal fashion .
second , the excellent comparability of the results between the 2 sd - oct devices may allow development of cross - platform standardized measurements that could be correlated clinically to define narrow versus open angles . in this study
, no significant differences were found in the quantitative aca values derived from the 2 sd - octs , thus making them practically interchangeable .
the reproducibility of the newer fourier domain oct systems has only been assessed in a few studies in the literature .
qin et al10 investigated the interobserver and intraobserver reproducibility of the sl - aod and sl - tisa metrics for images acquired with the rtvue sd - oct .
eyes with narrow angles were included in that study and the visibility of sl was as high as 97% to 100% .
, we also reported excellent reproducibility values for cirrus sl - based quantitative angle metrics in open angle eyes.11 in addition , the swept - source oct , with a light source of 1310 nm , was also found to exhibit high reproducibility in angle measurements , with icc values for interobserver and intraobserver reproducibility higher than 0.83.12 noteworthy , the reproducibility values were found to be better for experts , compared with nonexperts , since the measurement process remains subjective and involves identification of landmarks in the aca.13 the reliability metrics , including the high icc achieved in our study are better , compared with previously published reproducibility results using the visante as - oct and the slit - lamp oct.1418 using td - oct , the scleral spur has been an important anatomic landmark to define quantitative angle parameters used to assess angle opening.5 based on initial studies , these instruments have been shown to be variable in respects to repeatability and reproducibility in scleral spur - based aod500 , aod750 , tisa500 , and tisa750 measurements.16,19 kim et al17 evaluated the interobserver reproducibility of aod500 , aod750 , tisa500 , and tisa750 and reported low intersession and interoperator reproducibility with iccs between 0.662 and 0.892 using the visante td - oct . on the other hand ,
tan et al16 obtained iccs with the visante between 0.978 and 0.988 . using the slit lamp - oct , muller
one reason for the differences in reproducibility in these studies could be based on the lack of visualization in some images and variable placement of the scleral spur.17,20 this necessity introduces an important human factor in the analysis of a td - oct image , possibly generating non - negligible intraobserver and interobserver variance .
studies investigating the visibility of the scleral spur with as - oct showed visualization between 70% and 78.9%.20,21 in sd - oct , location of sl allows calculation of novel angle metrics based on location of sl and the end of the trabecular meshwork .
despite the fact that the analysis of as - oct images is not automated and still requires subjective identification of sl from the observer , our results did indicate that this variability does not introduce a high degree of error .
disparities between reproducibility levels in the various studies on aca metrics could also result from differences in the study populations , acquisition protocols , quadrants , and the light levels used for assessment .
pupil size variation is an important factor to obtain reproducible angle measurements.22 because of the importance of standardizing the lighting conditions for repeatable angle measurements , in the present study , the imaging was performed in tightly controlled lighting conditions that were tested with a light meter . a darkened room with a light meter reading below 0.2 foot candles at the eye allows for optimal measuring conditions based on pupil dilation and its effect on angle opening .
studies have also shown significant regional differences in different quadrants.12 since the objective of this study was to examine the variability of the sd - oct in measuring the aca , we focused only on the inferior angle for both instruments .
the present study provides evidence of an excellent agreement between cirrus and spectralis angle measurements .
this also shows that the instruments are interchangeable and a correction factor is not necessary .
recent studies that included narrow angle patients had a different study design and have shown only moderate agreement between sd - oct instruments in terms of detecting angle closure .
quek et al23 compared the ivue and cirrus sd - oct devices in a cohort with a high percentage of narrow angles based on gonioscopy .
they reported only moderate agreement between the 2 instruments and low interobserver reproducibility values for both devices in detecting angle closure .
owing to the apparent differences in study design , sample characteristics and instruments used , a direct comparison with the present study where quantitative measurements of the angle were assessed in open angle eyes can not be done . in another study comparing cirrus , visante , and gonioscopy , the authors found only moderate agreement in detecting angle closure between the 2 octs and slight - to - fair agreement with gonioscopy.24 finally , in another study assessing the performance of the rtvue sd - oct in the diagnosis of angle closure , the authors reported a decreased ability of this device to image the various aca landmarks , including the sl and the scleral spur , hence impeding the ability to diagnose a closed angle.25 it is thus unclear whether the performance of the 2 instruments investigated in the present study will be different when imaging eyes with angle closure .
furthermore , the high level of reproducibility reported in this study is often achievable by using experienced , certified anterior segment reading center graders .
however , since the results were strong and the sds were small , a larger population size may not be necessary for this type of study .
our study also has several strengths including the use of standardized acquisition and grading protocols .
importantly , our study was the first , to our knowledge , to compare sl - based metrics from different anterior segment sd - oct instruments .
consistency in measurements and interchangeability across various sd - oct platforms from different manufacturers is important to define standardized criteria for screening for narrow angles and assessment of longitudinal change in angle parameters .
exploration and validation of sd - oct devices for imaging anterior segment is an essential first step in achieving this goal for standardization .
Output:
| purpose : to compare anterior chamber angle parameters based on the location of schwalbe line ( sl ) from 2 spectral domain optical coherence tomography ( sd - oct ) instruments and to measure their reproducibility.methods:forty-two eyes from 21 normal , healthy participants underwent imaging of the inferior irido - corneal angle with the spectralis and cirrus sd - oct under tightly controlled low - light conditions . sl - angle opening distance ( sl - aod ) and sl - trabecular iris space area ( sl - tisa ) were measured by masked , certified graders at the doheny imaging reading center using customized grading software .
interinstrument and intrainstrument , as well as interobserver and intraobserver reproducibility of sl - aod and sl - tisa measurements were evaluated by intraclass correlation coefficients ( iccs ) and bland - altman plots with limits of agreement ( loa).results : the mean sl - aod was 0.6620.191 mm in spectralis and 0.6770.213 mm in cirrus .
the mean sl - tisa was 0.2500.073 mm2 in spectralis and 0.2560.082 mm2 in cirrus .
the agreement for intrainstrument ( iccs>0.979 ) , intragrader ( iccs>0.992 ) , and intergrader ( iccs>0.929 ) was excellent .
excellent agreement between the 2 devices was also documented with a mean difference of 0.016 ( loa 0.125 to 0.092 ) mm for sl - aod and 0.007 ( loa 0.056 to 0.043 ) mm2 in sl-tisa.conclusions:both sd - octs provided comparable measurements and permitted calculation of sl - based angle metrics .
there was excellent interinstrument and intrainstrument and intraobserver and interobserver reproducibility for spectralis and cirrus sd - octs , suggesting true interchangeability between sd - oct devices .
this has the potential to lead to development of standardized grading assessments and quantification of angle parameters that would be valid across various sd - oct devices . |
PubmedSumm118509 | ***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: refractive surgery is an evolving ground in recent ophthalmology and photorefractive keratectomy ( prk ) is one of the most popular means to correct refractive error of the eye .
many studies have carried to evaluate long - time stability , complications and causative factors in eyes underwent prk .
kim et al . , showed that myopic regression can occur up to 5 years after surgery and pre - prk refraction is the most important factor .
alteration in extracellular components after prk along with generation of myo - fibroblast may reduce corneal transparency which may present as sub - epithelial haze and can be clinically significant in many cases . applying intraoperative mitomycin c ( mmc ) as an effort to reduce
the rate of corneal haze has tried earlier and in numerous studies prophylactic use of mmc 0.02% was associated with lower rates of haze formation and better visual outcomes .
majmudar et al . , revealed that topical application of mmc ( 0.02% ) may be a successful method of preventing recurrence of subepithelial fibrosis after corneal surgery .
anyway , concerns persist regarding mmc toxicity and long - term complications such as corneal melting and endothelial cell loss .
there is one report of corneal edema after phototherapeutic keratectomy ( ptk ) including intraoperative use of mmc 0.02% .
although evidences of keratocyte apoptosis and myo - fibroblast death which had leaded to reduced corneal cellularity after mmc use is of great concern.[811 ] effect of mitomycin c application on endothelial cells has reported in many studies when the ocular surface alteration is also possible . because the standard dose of intraoperative mmc ( 0.02% ) has driven empirically based on pterygium removal and glaucoma filtering surgery results many controversies persist in dosing and timing of mmc usage .
because timing of mmc application seems less important than the dosage , this study tries to find the effect of low dose mmc ( 0.01% ) intraoperative use in prk versus standard dose ( 0.02% ) in preventing corneal haze and promoting desirable visual outcome .
all the patients with inclusion criteria were informed of the study and written consent obtained .
these patients were myopic patients with ages between 20 and 30 years who will to correct their refractive error by prk .
primary evaluation of refraction , uncorrected visual acuity ( ucva ) , best corrected visual acuity ( bcva ) , slit - lamp examination with fundus evaluation performed and eyes with any disorder that could influence postoperative outcomes were excluded .
after all , the eyes divided into two arms , in each patient one eye randomly assigned to be treated by low dose intraoperative mmc ( ldmmc ) and other eye by standard dose mmc ( sdmmc ) .
after scrub by povidone - iodine topical anesthetic drop instilled and eyes were treated by technolas 217z-100 laser ablation and then mmc applied by weck - cell spongefor 45 seconds . then the surface irrigated by balanced salt solution .
postoperative examination done 1 week , 1 month , 3 month and 6 month afterwards , regarding refraction , uncorrected distant visual acuity ( ucdva ) , best corrected distant visual acuity ( bcdva ) and haze formation score , respectively .
haze intensity according to the frantes scale was graded as no haze , trace , 1 , 2 , 3 and 4 .
then t - test and mann - whitney tests were used to analysis the outcome considering 85% power .
170 eyes of 85 patients underwent photorefractive keratectomy between may and november 2011 ( 23 men and 62 women ) .
mean age of the patients in this study was 25.98 years ( range : 20 - 30 years ) .
the mean preoperative refraction in ldmmc eyes was 3.08 ( sd 1.65 ) sphere and 0.92 ( sd 0.88 ) cylinder .
these values for sdmmc eyes were 3.25 ( sd 1.80 ) sphere and 0.81 ( sd 0.84 ) cylinder .
mean postoperative sphere in ldmmc group was 0.132 ( sd 0.503 ) and 0.138 ( sd 0.484 ) in 3 and 6 months after prk .
these results was 0.041 ( sd 0.501 ) and 0.076 ( sd 0.489 ) for sdmmc group .
mean postoperative cylinder 3 and 6 month after prk was 0.435 ( sd 0.218 ) and 0.423 ( sd 0.255 ) in ldmmc group and 0.435 ( sd 0.247 ) and 0.426 ( sd 0.261 ) in sdmmc group .
in third month 14 eyes in ldmmc group presented with grade 1 score of clinical haze . from these eyes only 2 still had this haze after 6 month .
7 eyes in sdmmc group had grade 1 clinical haze at third month - but no clinical haze was seen at the end of 6 month .
comparison of two arms of this study did not disclose any significant difference in preoperative parameters including refraction , ucdva and bcdva .
t - test study also reveals no meaningful difference in these parameters in postoperative measurements .
comparison of haze formation rate in these two groups by mann - whitney test demonstrated no significant difference in results ( p = 0.104 3 month and p = 0.156 6 month after operation ) .
application of intraoperative mmc is a valuable mean to prevent corneal haze especially in high myopic patients but concerns about its side effects lead us to determine if a lower dose of mmc may be as effective as the standard dose .
goldsberry et al . also remarks no side effect of mmc on endothelial quantitative and qualitative parameters .
although netto et al . reported that mmc may cause keratocyte and myo - fibroblast apoptosis and decrease in anterior stromakeratocyte density may lead to future complications . according to our study
there was no significant difference in visual outcome or haze formation by use of lower dose of mmc ( 0.01% ) compared with standard dose ( 0.02% ) .
our findings shows that low dose intraoperative mmc has the same effect as standard dose in prevention of corneal haze and visual outcomes have no meaningful difference while it promises lower side effects and long - term complications .
Output:
| background : this study aimed to compare two doses of mitomycin c in reducing haze formation after photorefractive keratectomy.methods:170 eyes of 85 patients enrolled ; in each patient one eye randomly assigned to be treated by low dose intraoperative mmc ( ldmmc ) and other eye by standard dose mmc ( sdmmc ) .
then the patients were followed up to 6 months and refraction , uncorrected distant visual acuity ( ucdva ) , best corrected distant visual acuity ( bcdva ) and haze formation submitted in each postoperative exam.results:the mean preoperative refraction in ldmmc eyes was 3.08 ( sd 1.65 ) sphere and 0.92 ( sd 0.88 ) cylinder .
these values for sdmmc eyes were 3.25 ( sd 1.80 ) sphere and 0.81 ( sd 0.84 ) cylinder .
mean postoperative sphere in ldmmc group was 0.132 ( sd 0.503 ) and 0.138 ( sd 0.484 ) in 3 and 6 months after prk .
these results was 0.041 ( sd 0.501 ) and 0.076 ( sd 0.489 ) for sdmmc group .
mean postoperative cylinder 3 and 6 month after prk was 0.435 ( sd 0.218 ) and 0.423 ( sd 0.255 ) .
in ldmmc group and 0.435 ( sd 0.247 ) and 0.426 ( sd 0.261 ) in sdmmc group . in third month 14 eyes in ldmmc group presented with grade 1 score of clinical haze . from these eyes only 2 still had this haze after 6 month .
7 eyes in sdmmc group had grade 1 clinical haze at third month- but no clinical haze was seen at the end of 6th month.conclusion:the results of the two doses of mitomycin c were not significant .
we suggest to use the lower dose to reduce its side effects . |
PubmedSumm118510 | ***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 novel influenza a ( h1n1 ) virus was identified in april 2009 that rapidly spread worldwide . the clinical syndrome associated with 2009 pandemic influenza a ( h1n1 ) [ 2009 h1n1 ]
some host risk factors such as chronic pulmonary disease , pregnancy , immunosuppression , neuromuscular disease , and morbid obesity among others have been associated with more severe outcomes .
recently , a mutation in the hemagglutinin gene at position 222 from aspartic acid to glycine ( had222 g ) in 2009 h1n1 virus was identified in individuals with severe illness or death in scotland , norway , and hong kong , but not in upper respiratory tract specimens in persons with mild illness , suggesting the possibility of a correlation with more severe clinical outcomes or viral tropism .
2009 h1n1 strains possessing d222 g have been shown to have enhanced capacity for binding to alpha23 receptors expressed on ciliated cells of the lower respiratory tract ( bronchioles , alveoli , type ii pneumocytes ) .
another viral factor that could affect influenza illness outcomes is antiviral resistance . a single mutation at position 275 ( n1 numbering ) from histidine to tyrosine in the neuraminidase protein ( nah275y )
is associated with oseltamivir resistance , but such virus strains are susceptible to zanamivir . the predominant seasonal influenza a ( h1n1 ) virus strains circulating during the 200809 northern hemisphere influenza season contained the h275y mutation , but were susceptible to m2 channel blockers . to date , only sporadic reports of oseltamivir resistance have been identified among circulating 2009 h1n1 virus strains , accounting for 13% of us isolates . as part of surveillance for changes in circulating influenza viruses ,
the minnesota department of health ( mdh ) public health laboratory began limited partial ha and na gene sequencing of respiratory specimens collected from 2009 h1n1 fatal cases and identified a single patient whose specimen contained mutations for both nah275y and had222 g .
all persons hospitalized with influenzalike illness and all persons with a critical illness or death of a suspected infectious etiology without an alternate cause are reportable to the mdh as required by state law .
investigations of reportable diseases are considered public health response and are classified as exempt by the mdh institutional review board .
original specimens were tested by realtime reverse transcription pcr ( rrtpcr ) for 2009 h1n1 viral rna based on cdc protocol ,
and pyrosequencing for nah275y and ha222 variants was performed .
viral rna was extracted via corbett life science s xtractor gene utilizing qiagen s qiaamp virus biorobot 9604 kit ( qiagen , hilden , germany ) per manufacturer s instructions .
reverse transcriptase pcr ( rtpcr ) amplifications were performed using superscript iii onestep rtpcr system with platinumtaq high fidelity ( invitrogen , carlsbad , ca , usa ) to amplify partial gene regions of both the na and ha genes . na amplicons were generated , and the h275y mutation was detected according to the cdc pyrosequencing protocol
with the following modifications : qiagen s pyromark q24 system was employed , and a final pyrosequencing primer concentration of 20 m was used .
ha amplicons were analyzed on the pyromark q24 system following the cdc protocol for the detection of ha222 variants utilizing only the customized dispensation order .
from april 2009 to february 2010 , there were 60 deaths reported in minnesota associated with 2009 h1n1 , of which 53 ( 88% ) had respiratory specimens available for testing .
adequate nucleic acid to perform pyrosequencing for h275y mutational analysis was present in 39 ( 74% ) fatal cases , of which 38 ( 97% ) had wildtype sequence ( h275h ) and 1 ( 3% ) had the h275y mutation .
adequate nucleic acid to perform pyrosequencing for ha222 was present in 43 ( 81% ) fatal cases , of which 38 ( 88% ) had wildtype sequence only ( d222d ) , 4 ( 9% ) had mixed infection with quasi species of 2009 h1n1 strains identified with three sequences ( d222d , d222n and d222 g ) , and 1 ( 2% ) had only d222 g mutation . the clinical specimen with
the h275y mutation identified by pyrosequencing was the same specimen that was identified with the d222 g mutation by pyrosequencing .
this was a bronchial alveolar lavage ( bal ) fluid specimen collected on symptom day 19 that was tested within 48 hours of collection .
realtime rtpcr testing of the bal specimen was positive for influenza a , swine h1 , and swine influenza a targets with c
t values all < 35 .
a 59yearold male with systemic lupus erythematosus since 2006 presented in november 2009 with 10 days of dry cough and 48 hours of progressive dyspnea on exertion .
he was taking 60 mg daily of prednisone , mycophenolate mofetil , trimethoprim / sulfamethoxazole , and levofloxacin .
he had been hospitalized briefly 1 month prior for heart failure symptoms and was diagnosed with pulmonary hypertension and biopsydemonstrated glomerulonephritis . at discharge and several weeks subsequently , he had minimal pulmonary symptoms .
the patient was admitted on illness day 10 with bibasilar crackles but no jugular venous distension .
his white blood cell count was 55 cells/l ( normal , 32106 ) , including 53 neutrophils/l ( normal , 1370 ) and 008 lymphocytes/l ( normal , 0831 ) .
direct fluorescent antibody testing of a nasopharyngeal specimen was positive for influenza a , and oseltamivir 75 mg twice daily was started for 5 days ( figure 1 ) .
oseltamivir 150 mg twice daily for 1 day was restarted per gastric tube , followed by 75 mg twice daily .
computed tomography of the chest revealed bilateral ground glass densities and superimposed irregular nodules most pronounced in the lower lobes .
a bal was performed on symptom day 19 and tested for influenza rrtpcr at mdh public health laboratory .
bronchial alveolar lavage fluid was also sent for viral culture to a clinical laboratory that grew influenza a virus using centrifuged shell vial technique .
his respiratory status declined with worsening pulmonary infiltrates , bilateral pneumothoraces , refractory hypoxemia , and worsening renal function requiring dialysis .
to our knowledge , this is the first clinical description of a patient with 2009 h1n1 virus infection identified with nah275y and had222 g .
this patient had multiple underlying medical conditions that increased the risk of severe complications from 2009 h1n1 virus infection .
aspergillus infection associated with severe 2009 h1n1 disease has been described in two other cases .
oseltamivir resistance may have developed during treatment in this patient as has been previously described ; however , initial infection with an oseltamivirresistant strain can not be excluded . while there are documented instances of nonsustained persontoperson transmission of 2009 h1n1 virus strains containing h275y , these appear to be rare events .
it is possible that oseltamivir resistance may impact clinical outcomes particularly among patients with immunosuppression and prolonged influenza viral replication .
a comparison of patients infected with oseltamivirresistant versus susceptible strains found that immunosuppression was the only risk factor significantly associated with oseltamivir resistance .
because of this increased risk of development of oseltamivir resistance during or after oseltamivir treatment , clinicians should consider the use of zanamivir as primary therapy for immunosuppressed patients with influenza , and especially for patients with suspected or 0confirmed oseltamivir resistance .
,
recombinant clones of 1918 pandemic h1n1 virus with a hemagglutinin mutation at position 222 ( 225 in h3 numbering system ) from aspartic acid to glycine were found to change viral tropism from alpha26 sialic acids to dual tropism for alpha23 and alpha26 sialic acids , suggesting the potential importance of a single substitution at the receptorbinding site of the hemagglutinin .
recent reports have suggested a link between the had222 g mutation in 2009 h1n1 virus infection with severe and fatal outcomes .
if the had222 g mutation results in greater affinity for receptors with alpha23 sialic acids found predominantly in the human lower respiratory tract , it is possible that a had222 g subpopulation would be preferentially selected by lower respiratory tract sampling from a heterogeneous influenza pool , especially in persons with severe lower respiratory tract disease and with prolonged viral replication . in a recent study of paired nasal swab and bal specimens ,
d222 g mutants accounted for 40% of the lower respiratory tract viral population compared with only 10% in the upper respiratory tract .
influenza virus mutations have also been identified more frequently among isolates obtained after growth in cell culture compared with primary clinical specimens , suggesting that replication of virus in tissue cell culture can lead to selection of virus variants with altered receptor specificity .
therefore , it is essential that molecular testing for influenza viruses is performed on original specimens and not viral culture isolates to limit this possibility .
as this was not a study and with only a single isolate available for testing , it is not possible to ascertain whether the combination of nah275y and had222 g mutations contributed to illness severity .
future studies should prospectively collect the following specimens from patients for influenza testing by rrtpcr , genetic sequencing , and other molecular analyses : ( i ) multiple , serial respiratory specimens from close to illness onset or early in the clinical illness , prior to or at the time of initiation of antiviral therapy , following antiviral treatment , and later in the clinical course if possible ; and ( ii ) paired ( obtained at the same time ) clinical specimens from both the upper and lower respiratory tract if possible , especially for critically ill patients .
sampling should be carried out for persons with mild uncomplicated influenza illness and for persons with severe complications requiring hospitalization and critical care management .
integration of clinical ( including information on antiviral treatment ) , epidemiological , and virologic data in such comparative studies will facilitate interpretation and contribute to improved understanding of viral changes that might lead to severe clinical outcomes of influenza virus infection .
Output:
| please cite this paper as : devries et al .
( 2012 ) neuraminidase h275y and hemagglutinin d222 g mutations in a fatal case of 2009 pandemic influenza a ( h1n1 ) virus infection .
influenza and other respiratory viruses 6(601 ) , e85e88.oseltamivirresistant 2009 h1n1 influenza virus infections associated with neuraminidase ( na ) h275y have been identified sporadically .
strains possessing the hemagglutinin ( ha ) d222 g mutation have been detected in small numbers of fatal 2009 h1n1 cases .
we report the first clinical description of 2009 h1n1 virus infection with both nah275y and had222 g mutations detected by pyrosequencing of bronchioalveolar lavage fluid obtained on symptom day 19 .
the 59yearold immunosuppressed patient had multiple conditions conferring higher risk of prolonged viral replication and severe illness and died on symptom day 34 .
further investigations are needed to determine the significance of infection with strains possessing nah275y and had222 g . |
PubmedSumm118511 | ***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: mutations in the alpha and beta globin genes of hemoglobin ( hgb ) frequently occur . among the most
commonly encountered worldwide is the 6gluval substitution defining hgb s. in sickle cell disease both beta globin genes are affected while in sickle cell trait ( sct ) one normal and one mutated beta globin gene result in a pancellular distribution of hgb s accounting for about 40% of the total hgb . a number of studies have found the prevalence of sct in the african - american population to be about 7 - 8% , but it is also identified in persons of other ethnic backgrounds at a lower frequency translating into about 3 million affected individuals in the united states and 300 million worldwide .
a study of us military personnel similarly showed that 7.8% of black recruits had sct suggesting that there is no apparent selection against enrollment in the military service .
the incidence of sct in athletes is not well defined although its prevalence in black football players in the national football league was 39/579 ( 6.7% ) similar to that in the general population .
studies on the physiologic effects of exertion have long established that exercise can induce a metabolic acidosis .
notable among these studies is the observation that repeat exertion to exhaustion can lead to extreme acidosis , and this exercise pattern is similar to some currently used regimens of athletic training . in patients with sickle cell disease , triggers for vaso - occlusion include acidosis , dehydration and hypoxia , raising the suspicion that extreme exertion may be sufficient under certain circumstances to trigger similar complications in individuals with sct .
additional in vitro data indicates that red blood cells ( rbcs ) from sct individuals may become irreversibly sickled at a po2 of ~25 mmhg , and this effect is enhanced by acidosis .
this is confirmed by studies in sct individuals that showed venous sickling at low oxygen tension .
subsequently a small study comparing individuals with and without sct who underwent intensive exercise showed that a small percentage of irreversibly sickled cells could be identified in all the individuals with sct but none of those without hgb s. no untoward clinical effects were identified , but this raises the concern that under some conditions , extensive formation of irreversibly sickled cells may occur that lead to clinical consequences .
in addition to hypoxia and acidosis , other conditions that may trigger such events have also been suspected including increased core body temperature , ambient heat index , blood viscosity , dehydration , inflammation and oxidative stress , but the relative role of each of these factors is not fully defined . on the other hand ,
some studies have failed to show a clear physiologic effect from sct on exercise even under some stressful conditions .
the consequence has been that when fatalities have occurred in individuals with sct , they are perceived as rare and unpredictable events . however , in 1987 , the seminal study by kark and associates found non - traumatic sudden death in black military recruits to be 32 fold higher than in individuals identified as non - black . among black recruits ,
the relative risk of sudden unexplained death was 27.6 fold higher in the individuals with sct , thus providing clear epidemiologic evidence that the presence of hgb s contributed to these deaths .
harmon and colleagues have also reported a 37-fold greater risk of exertion - related death in division 1 college football in individuals with sct .
recently , a summit on sct composed of military , athletic and medical experts tried to identify clinical guidelines for this problem and have termed these events as exercise collapse associated with sickle trait ( ecast ) .
the purpose of this manuscript is to evaluate the reported cases of sudden death in college football players related to sct and to examine current recommendations for prevention and treatment of ecast .
data searches were performed of both medical literature and lay press to identify cases of potential ecast .
once cases were identified , these were limited to lethal events within 48 hours among american college football players from 2000 - 2010 , for these patients had less variation in their physical fitness than the general population .
circumstances surrounding their deaths were noted , including activities prior to the collapse and climate conditions at the time of these events .
recommendations regarding sct among professional organizations involved in either hematology or sports medicine were identified as described in the most recent stances published on their websites .
their positions on universal screening for sct were identified , and their recommendations on prevention , detection , and treatment of ecast were also recorded .
table 1 summarizes the sct related deaths that occurred in college football between 2000 - 2010 . while each case is unique , they share many characteristics , such as the athletes or their coaches encouraging the participants despite evolving symptoms of ecast .
many experienced unusual cramps , muscle weakness , extreme fatigue , and even a first collapse before slumping to the ground for their last time . in one reported instance , the athlete was reprimanded for his perceived weakness and neglected by trainers , and a teammate was rebuked for assisting him off the field . additionally , these cases all occurred below an elevation of 645 m above sea level , so high altitude hypoxia is not necessary for ecast to occur .
while conditions were warm and humid in some cases , the weather alone was not typical of that which places athletes at a high risk for heat - related illness . while several of the initial reports cited heat - related illness or other causes as the primary reasons for death , autopsies later revealed that sickle cells were identified and likely contributed to the athletes death .
although a personal or family history of sct was available in some cases , in no case was sct suspected as the cause of the collapse , so there was no clear medical intervention or focused treatment .
table 2 shows the positions of various health and sports organizations on screening , prevention and treatment of sct .
while the national collegiate athletic association ( ncaa ) mandates the universal screening of its participants , the american society of hematology ( ash ) is unequivocally against universal screening for sct .
other organizations vary in their positions on screening and prevention . in the absence of strong medical evidence ,
the national athletic trainers association ( nata ) has made clear recommendations on preventative measures , and other organizations reference the nata s guidelines .
these recommendations include longer rest and recovery between conditioning repetitions , exclusion from performance tests , hydration , and available supplemental o2 .
while these guidelines are directed at athletes with sct , some organizations , such as ash , american medical society for sports medicine ( amssm ) , and sickle cell disease association of america ( scdaa ) , advise using similar recommendations as universal precautions concluding that this would safeguard all athletes from heatrelated illness and other effects of overexertion .
whether this approach will prove effective in preventing ecast is not clear and remains controversial .
other organizations that agreed with ash include the american public health association , association of public health laboratories , american society of clinical pathology , and the american society of pediatric hematology - oncology ( aspho ) , but none of these added any further recommendations . in contrast , most sports organizations do not specify these guidelines for universal precautions by all athletes , favoring a targeted approach .
few organizations provided guidelines for detecting and treating a sickling - related collapse , but those who did generally support the nata s policy in these areas .
sickle cell trait as a cause of sudden death in athletes was first noted in 1974 with the death of an american collegiate football player . since that time
there have been a number of widely publicized cases in the non - scientific literature .
most of these have involved college football players rather than younger students or older professional athletes , and the reasons for this are not clear although the widespread public interest in college football may explain this in part .
while fitness levels could potentially affect the athlete s likelihood of ecast since these deaths occurred during pre - season conditioning , these athletes were generally recognized to be in excellent physical condition .
nevertheless , improved conditioning may modulate several biological factors , notably inflammation and oxidative stress . in accord with the known pathophysiology
, it seems more likely that a decrease in venous po2 in concert with acidosis occurring during extreme exertion were major contributors . while it is conceivable that the presence of sickled rbcs occurred postmortem , the clear epidemiologic evidence linking sct to sudden death is a compelling argument for a direct causal effect . at present in the united states ,
it is likely that almost all high school aged students and an increasing number of older athletes have already been tested for hgb s as part of newborn screening .
adopted as a guideline by the national institutes of health for all individuals in 1987 , hemoglobinopathy testing became incorporated into newborn screening programs in all states by 2006 , so sickle cell status should be available for all children and adolescents born after that time . despite this , the prevalence of sct in athletes participating in organized sports is generally unknown . in the case of college football ,
ethnicity data collected on players in the ncaa over the span from 2000 - 2010 shows an increase in participation by african - americans from 16,200 participants ( 28.1% ) to 22,892 ( 34.5% ) . assuming a prevalence of sct of 7% , this would indicate that there are currently ~1600 athletes playing ncaa football who are at risk . based on the recent reported deaths of about one athlete with sct every 1 - 2 years described in table 1
, this would suggest the estimated risk of death from ecast to be 26 - 51/100,000/100,000 participants . by comparison ,
calculations for fatal traumatic injuries in any college football player is 0.45/100,000 and the risk for other non - traumatic death is 2.1/100,000 .
an analysis of all ncaa division i athletes in all sports estimated over 2,000 participants with sct and predicts about 7 deaths over a 10 year period consistent with the current review . just as identifying the key pathophysiologic triggers for ecast has proven to be difficult , determining the risk of sct remains a vexing problem .
for example , if the prevalence of sct in football players is lower than in the general population , then the relative risk would be significantly higher than estimated .
in addition , if other non - fatal complications such as heat stroke can be attributed at least in part to sct , then serious but non - fatal complications could be significantly higher than assumed . on the other hand , if deaths attributed to sct are overestimated , then the relative risk may be lower .
better defining the population at risk for ecast and other sickle cell related complications by identifying individuals with hgb s would seem to be a prerequisite to studying the natural history and clinical consequences of sct . according to clinicaltrials.gov ,
at least one such effort along these lines is underway by collecting self - reported health data in current or former high school or college football players with sct . in the absence of a clear understanding of both the inciting pathophysiology and the identification of individuals at risk of ecast ,
a number of organizations involved in the direct care of athletes and military service personnel have provided guidelines on the screening for sct and , in a few cases , recommendations for prevention , recognition , and treatment of ecast ( table 2 ) .
most contentious among these recommendations has been whether or not to employ universal screening to identify individuals with sct .
a number of organizations have advocated for universal screening , and most notably the ncaa has incrementally implemented universal sickle cell screening by mandating either current testing , evidence of previous testing , or a signed waiver deferring legal liability for athletes to participate .
this policy was initiated to identify participants at risk so that coaches , trainers and staff are aware of these individuals and can implement preventative measures and early treatment against ecast .
additionally , this policy was driven in part by the litigation that arose from the unexpected death of an individual who was unaware of his sickle cell status .
when the ncaa policy was implemented , a survey indicated that only about 22% of responding institutions screened all athletes , but this is likely to have increased significantly over time .
in contrast to the ncaa , ash set forth a position paper in 2012 outlining the case against universal screening , including the maintenance of privacy of personal health information for those athletes .
however , screening can be completed with one of several commercially available blood tests at a cost of $ 3.00 - 4.00/sample with high reliability , and additional confirmatory testing such as high performance liquid chromatography ( hplc ) analysis could be offered to individuals identified to have a sickling hgb .
another concern is whether the knowledge of sct status will jeopardize the playing career or lead to prejudicial judgments regarding participation in any activity .
this has been noted in the past when sct individuals were excluded from certain military occupations .
more recently , we identified scant evidence that military personnel or competitive athletes who have sct are excluded from their respective activities .
some organizations remain concerned that screening would violate the athlete s privacy and lead to discrimination .
other ongoing concerns regarding a universal screening policy include a lack of genetic counseling for affected individuals .
furthermore , while the us army has abolished universal screening in favor of universal precautions , the us marine corps continues to test all recruits .
less often discussed but of considerable importance are specific recommendations for prevention , detection , and treatment of ecast .
recommendations for prevention have been made by a number of organizations and have common themes although vary in their details . whether universal precautions against sickling for all participants or some form of targeted prevention for individuals with confirmed sct is the most effective is not defined .
the nata published a consensus statement with recommendations regarding prevention of sudden death in sports , especially with environmental stress .
of note , nata has suggested a framework to distinguish between a sickling - related collapse and other diagnoses so that athletes and staff could recognize the issue and respond to it appropriately .
the scdaa , aossm , nfhs , and ncaa have referenced nata s information on the detection of ecast .
additionally , eichner has recently described features of a sct associated collapse along with prevention and treatment suggestions . based on the anecdotal data , it seems reasonable that all coaches , trainers and players involved in sports at risk should be familiar with prevention guidelines and their potential for implementation . by increasing staff and player education about sct
, it is reasonable to conclude that most cases of ecast and its consequences are preventable .
optimal treatment of ecast is undefined and is usually a medical emergency that falls to first responders rather than to hematologists or others with expertise in sickle cell disease .
only a few organizations have published treatment recommendations , and there are no well - designed studies in the medical literature describing successful ( or unsuccessful ) approaches .
while many organizations have overlapping ideas on how to manage ecast , their suggestions and opinions vary and fail to provide consistent advice for those caring for athletes or others who might be at risk .
rare cases have been reported in which athletes initially diagnosed with heat stroke were subsequently identified as having ecast and recovered . among the organizations providing recommendations regarding ecast ,
one common theme arises : athletes and military personnel should not be barred or limited in opportunities because they have sct .
since these organizations all support the success of athletes with sct , an agreed upon set of guidelines for coaches , trainers , athletes and medical personnel to follow in order to maintain player safety should be a priority .
while the issue of ecast has been raised most frequently in the setting of military service and competitive athletics , sudden death in individuals with sct has been noted in other circumstances of strenuous activity including firefighter training and altercations with law enforcement . while screening and prevention may be possible in some of these circumstances
, this may not always be the case , and rapid recognition of the illness and proper emergent treatment remain key issues .
we believe that the lack of a consensus on the approach to ecast poses an opportunity for additional research in both the understanding of the pathophysiology and of the risks linked to sct , as well as the clinical approach to prevention , diagnosis and treatment of ecast .
the lack of understanding of who may be at risk hinders further clinical studies , so screening for research purposes could prove beneficial .
whether or not milder forms of clinically significant ecast exist and are preventable or treatable might become apparent and , if present , may also lead to the identification of biomarkers for people at risk . the possible relationship to heat - related illness , rhabdomyolysis , and other abnormalities such as glucose-6-phosphate dehydrogenase
furthermore , a well - conceived approach to ecast including recognition and treatment in other settings beyond the military and athletics needs to be delineated .
sickle cell trait as a cause of sudden death in athletes was first noted in 1974 with the death of an american collegiate football player . since that time
there have been a number of widely publicized cases in the non - scientific literature .
most of these have involved college football players rather than younger students or older professional athletes , and the reasons for this are not clear although the widespread public interest in college football may explain this in part .
while fitness levels could potentially affect the athlete s likelihood of ecast since these deaths occurred during pre - season conditioning , these athletes were generally recognized to be in excellent physical condition .
nevertheless , improved conditioning may modulate several biological factors , notably inflammation and oxidative stress . in accord with the known pathophysiology
, it seems more likely that a decrease in venous po2 in concert with acidosis occurring during extreme exertion were major contributors . while it is conceivable that the presence of sickled rbcs occurred postmortem , the clear epidemiologic evidence linking sct to sudden death is a compelling argument for a direct causal effect . at present in the united states ,
it is likely that almost all high school aged students and an increasing number of older athletes have already been tested for hgb s as part of newborn screening .
adopted as a guideline by the national institutes of health for all individuals in 1987 , hemoglobinopathy testing became incorporated into newborn screening programs in all states by 2006 , so sickle cell status should be available for all children and adolescents born after that time . despite this , the prevalence of sct in athletes participating in organized sports is generally unknown . in the case of college football ,
ethnicity data collected on players in the ncaa over the span from 2000 - 2010 shows an increase in participation by african - americans from 16,200 participants ( 28.1% ) to 22,892 ( 34.5% ) . assuming a prevalence of sct of 7% , this would indicate that there are currently ~1600 athletes playing ncaa football who are at risk . based on the recent reported deaths of about one athlete with sct every 1 - 2 years described in table 1
, this would suggest the estimated risk of death from ecast to be 26 - 51/100,000/100,000 participants . by comparison ,
calculations for fatal traumatic injuries in any college football player is 0.45/100,000 and the risk for other non - traumatic death is 2.1/100,000 .
an analysis of all ncaa division i athletes in all sports estimated over 2,000 participants with sct and predicts about 7 deaths over a 10 year period consistent with the current review . just as identifying the key pathophysiologic triggers for ecast has proven to be difficult , determining the risk of sct remains a vexing problem .
for example , if the prevalence of sct in football players is lower than in the general population , then the relative risk would be significantly higher than estimated .
in addition , if other non - fatal complications such as heat stroke can be attributed at least in part to sct , then serious but non - fatal complications could be significantly higher than assumed . on the other hand , if deaths attributed to sct are overestimated , then the relative risk may be lower .
better defining the population at risk for ecast and other sickle cell related complications by identifying individuals with hgb s would seem to be a prerequisite to studying the natural history and clinical consequences of sct . according to clinicaltrials.gov ,
at least one such effort along these lines is underway by collecting self - reported health data in current or former high school or college football players with sct .
in the absence of a clear understanding of both the inciting pathophysiology and the identification of individuals at risk of ecast , a number of organizations involved in the direct care of athletes and military service personnel have provided guidelines on the screening for sct and , in a few cases , recommendations for prevention , recognition , and treatment of ecast ( table 2 ) .
most contentious among these recommendations has been whether or not to employ universal screening to identify individuals with sct .
a number of organizations have advocated for universal screening , and most notably the ncaa has incrementally implemented universal sickle cell screening by mandating either current testing , evidence of previous testing , or a signed waiver deferring legal liability for athletes to participate .
this policy was initiated to identify participants at risk so that coaches , trainers and staff are aware of these individuals and can implement preventative measures and early treatment against ecast .
additionally , this policy was driven in part by the litigation that arose from the unexpected death of an individual who was unaware of his sickle cell status .
when the ncaa policy was implemented , a survey indicated that only about 22% of responding institutions screened all athletes , but this is likely to have increased significantly over time .
in contrast to the ncaa , ash set forth a position paper in 2012 outlining the case against universal screening , including the maintenance of privacy of personal health information for those athletes .
however , screening can be completed with one of several commercially available blood tests at a cost of $ 3.00 - 4.00/sample with high reliability , and additional confirmatory testing such as high performance liquid chromatography ( hplc ) analysis could be offered to individuals identified to have a sickling hgb .
another concern is whether the knowledge of sct status will jeopardize the playing career or lead to prejudicial judgments regarding participation in any activity .
this has been noted in the past when sct individuals were excluded from certain military occupations .
more recently , we identified scant evidence that military personnel or competitive athletes who have sct are excluded from their respective activities .
some organizations remain concerned that screening would violate the athlete s privacy and lead to discrimination .
other ongoing concerns regarding a universal screening policy include a lack of genetic counseling for affected individuals .
furthermore , while the us army has abolished universal screening in favor of universal precautions , the us marine corps continues to test all recruits .
less often discussed but of considerable importance are specific recommendations for prevention , detection , and treatment of ecast .
recommendations for prevention have been made by a number of organizations and have common themes although vary in their details . whether universal precautions against sickling for all participants or some form of targeted prevention for individuals with confirmed sct is the most effective is not defined .
the nata published a consensus statement with recommendations regarding prevention of sudden death in sports , especially with environmental stress .
of note , nata has suggested a framework to distinguish between a sickling - related collapse and other diagnoses so that athletes and staff could recognize the issue and respond to it appropriately .
the scdaa , aossm , nfhs , and ncaa have referenced nata s information on the detection of ecast .
additionally , eichner has recently described features of a sct associated collapse along with prevention and treatment suggestions .
based on the anecdotal data , it seems reasonable that all coaches , trainers and players involved in sports at risk should be familiar with prevention guidelines and their potential for implementation . by increasing staff and player education about sct ,
it is reasonable to conclude that most cases of ecast and its consequences are preventable .
optimal treatment of ecast is undefined and is usually a medical emergency that falls to first responders rather than to hematologists or others with expertise in sickle cell disease .
only a few organizations have published treatment recommendations , and there are no well - designed studies in the medical literature describing successful ( or unsuccessful ) approaches .
while many organizations have overlapping ideas on how to manage ecast , their suggestions and opinions vary and fail to provide consistent advice for those caring for athletes or others who might be at risk .
rare cases have been reported in which athletes initially diagnosed with heat stroke were subsequently identified as having ecast and recovered . among the organizations providing recommendations regarding ecast ,
one common theme arises : athletes and military personnel should not be barred or limited in opportunities because they have sct .
since these organizations all support the success of athletes with sct , an agreed upon set of guidelines for coaches , trainers , athletes and medical personnel to follow in order to maintain player safety should be a priority . while the issue of ecast has been raised most frequently in the setting of military service and competitive athletics , sudden death in individuals with sct has been noted in other circumstances of strenuous activity including firefighter training and altercations with law enforcement . while screening and prevention may be possible in some of these circumstances , this may not always be the case , and rapid recognition of the illness and proper emergent treatment remain key issues .
we believe that the lack of a consensus on the approach to ecast poses an opportunity for additional research in both the understanding of the pathophysiology and of the risks linked to sct , as well as the clinical approach to prevention , diagnosis and treatment of ecast .
the lack of understanding of who may be at risk hinders further clinical studies , so screening for research purposes could prove beneficial .
whether or not milder forms of clinically significant ecast exist and are preventable or treatable might become apparent and , if present , may also lead to the identification of biomarkers for people at risk . the possible relationship to heat - related illness , rhabdomyolysis , and other abnormalities such as glucose-6-phosphate dehydrogenase
furthermore , a well - conceived approach to ecast including recognition and treatment in other settings beyond the military and athletics needs to be delineated .
compared to some other medical subspecialties , the role of the hematologist in sports medicine has been modest .
in addition to the understanding of ecast in competitive athletics , it is also important for hematologists to take a leadership role in other areas of sports medicine in which hematologic issues arise .
examples of these include the study of the risk , prevention and treatment of bleeding in casual or competitive athletes with hemophilia or on anticoagulants and the study of the role of iron supplementation in optimizing athletic performance .
this , along with determining guidelines for the prevention , detection , and treatment of ecast , allows more athletes to participate safely in sports without otherwise benign blood conditions hindering their participation .
Output:
| sickle cell trait ( sct ) occurs in about 8% of african - americans and is often described to be of little clinical consequence . over time , a number of risks have emerged , and among these are rare but catastrophic episodes of sudden death in athletes and other individuals associated with physical activities which is often described as exercise collapse associated with sickle trait ( ecast ) . despite an epidemiologic link between sct and sudden death as well as numerous case reports in both medical literature and lay press , no clear understanding of the key pathophysiologic events has been identified .
strategies for identification of individuals at risk and prevention of ecast have been both elusive and controversial .
stakeholders have advocated for different approaches to this issue particularly with regard to screening for hemoglobin s. furthermore , the recommendations and guidelines that are in place for the early recognition of ecast and the prevention and treatment of the illness are not well defined and remain fragmented . among the cases identified , those in collegiate football players in the united states are often highlighted .
this manuscript examines these case studies and the current recommendations to identify areas of consensus and controversy regarding recommendations for prevention , recognition and treatment of ecast . |
PubmedSumm118512 | ***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: . however , the blush grade does not take into account the area of the blush
. it would be better if both the blush grade , and area of blush can be calculated .
vogelzang et al . have developed a computer program that allows the calculation of the quantitative blush evaluator .
when the operator has drawn the polygonal area , the program calculates the area in mm .
yang et al . used the video densitometry to study the grayscale changes with time after contrast injection into the coronary artery .
the darker the myocardium , the higher the grayscale is . however , the variation of grayscale is too big to be of significant value according to our own experience .
the blush area times the degree of mpg is the total blush in our study . theoretically , the better the perfusion , the better the left ventricular function is .
we , therefore , correlated the ejection fraction ( ef ) with syntax score , summed difference score ( sds ) , total blush , blush area , and mpg to see if better perfusion can also translate into better left ventricular function or better long term prognosis .
the patients with coronary artery disease ( cad ) in people 's liberation army general hospital were consecutively recruited from march 2008 to august 2011 between the ages of 2080 years .
the inclusion criteria were : both coronary angiography ( cag ) and single photon emission computed tomography ( spect ) were performed , and data were collected .
the patients were divided into 3 groups , stenosis versus chronic total occlusion ( cto ) , mpg 1 , 2 versus mpg 3 , successful versus unsuccessful recanalization .
the exclusion criteria were as follows : previous coronary artery bypass graft ( cabg ) ; severe illness such as severe heart failure , respiratory disease , terminal cancer ; pregnancy ; renal function of chronic kidney disease 3 or more ; allergy to iodine contrast .
the relevant ethics committee of our hospital approved the protocol , and informed consents were taken from the patients before enrolment into the study . a special dedicated computer manufactured by crealife company ( crealife medical technology , beijing , china )
scintigraphic technetium 99 m methoxyisobutyl - isonitrile ( 401 institute , beijing , china ) rest ( before pci ) and stress ( after pci ) images were evaluated quantitatively after spect imaging ( dual - probe spect / ct , ge infinia hawkeye 4 , usa ) that employs a 17-segment left ventricular model with a common five - point scoring system ( 0 = normal perfusion ; 4 = no perfusion ) .
the results were interpreted by two co - investigators blinded to clinical feature and laboratory test results .
the summed stress scores ( sss ) and summed rest scores ( srs ) of all segments were determined .
an sds 4 was defined as stress - induced ischemia and counted as pathological spect - myocardial perfusion imaging ( mpi ) .
cag was performed by the ge innova 3100 angiography system ( ge healthcare , usa ) through the femoral or radial artery according to the physician preference .
continuous data representing normal distribution were expressed as mean standard deviation , and continuous data that did not pass the normality test were expressed as median ( p25 , p75 ) .
the t - test and chi - square test were used to determine their significance .
multivariate linear regression correlation with ef as the dependent factor and syntax score , sds , total blush , blush area , and mpg as the independent factors was performed
the patients with coronary artery disease ( cad ) in people 's liberation army general hospital were consecutively recruited from march 2008 to august 2011 between the ages of 2080 years .
the inclusion criteria were : both coronary angiography ( cag ) and single photon emission computed tomography ( spect ) were performed , and data were collected .
the patients were divided into 3 groups , stenosis versus chronic total occlusion ( cto ) , mpg 1 , 2 versus mpg 3 , successful versus unsuccessful recanalization .
the exclusion criteria were as follows : previous coronary artery bypass graft ( cabg ) ; severe illness such as severe heart failure , respiratory disease , terminal cancer ; pregnancy ; renal function of chronic kidney disease 3 or more ; allergy to iodine contrast .
the relevant ethics committee of our hospital approved the protocol , and informed consents were taken from the patients before enrolment into the study .
a special dedicated computer manufactured by crealife company ( crealife medical technology , beijing , china ) was employed to calculate the total blush .
scintigraphic technetium 99 m methoxyisobutyl - isonitrile ( 401 institute , beijing , china ) rest ( before pci ) and stress ( after pci ) images were evaluated quantitatively after spect imaging ( dual - probe spect / ct , ge infinia hawkeye 4 , usa ) that employs a 17-segment left ventricular model with a common five - point scoring system ( 0 = normal perfusion ; 4
the results were interpreted by two co - investigators blinded to clinical feature and laboratory test results .
the summed stress scores ( sss ) and summed rest scores ( srs ) of all segments were determined .
an sds 4 was defined as stress - induced ischemia and counted as pathological spect - myocardial perfusion imaging ( mpi ) .
cag was performed by the ge innova 3100 angiography system ( ge healthcare , usa ) through the femoral or radial artery according to the physician preference .
continuous data representing normal distribution were expressed as mean standard deviation , and continuous data that did not pass the normality test were expressed as median ( p25 , p75 ) .
the t - test and chi - square test were used to determine their significance .
multivariate linear regression correlation with ef as the dependent factor and syntax score , sds , total blush , blush area , and mpg as the independent factors was performed
the perfusion indices of total blush , sds , and syntax score were not statistically significant between the two groups [ tables 1 and 2 ] . however , left ventricular end diastolic ( lved ) was larger in cto than in stenosis ( p < 0.05 ) .
comparison between cto and stenosis ef : ejection fraction ; lved : left ventricular end - diastolic volume ; sap : stable angina pectoris ; uap : unstable angina pectoris ; ami : acute myocardial infarction ; omi : old myocardial infarction ; cag : coronary angiography ; hf : heart failure ; dm2 : type 2 diabetes mellitus ; rf : renal failure ; bp : blood pressure ; tnt : troponin t ; bnp : brain natriuretic peptide ; hcy : homocysteine ; crp : c - reactive protein ; tc : total cholesterol ; ldl : low - density lipoprotein ; cto : chronic total occlusion ; pci : percutaneous intervention ; sds : summed difference score . comparison between mpg 1 , 2 and mpg 3 mpg : myocardial perfusion grade ; pci : percutaneous intervention ; sds : summed difference score ; ef : ejection fraction ; lved : left ventricular end - diastolic volume ; bp : blood pressure ; sap : stable angina pectoris ; uap : unstable angina pectoris ; ami : acute myocardial infarction ; omi : old myocardial infarction ; cag : coronary angiography ; hf : heart failure ; dm2 : type 2 diabetes mellitus ; rf : renal failure ; tnt : troponin t ; bnp : brain natriuretic peptide ; hcy : homocysteine ; crp : c - reactive protein ; ldl : low - density lipoprotein .
thirty - three patients tried recanalization therapy while 3 of them had the poor image quality to calculate mpg .
the increased mpg was associated with increased total blush , higher syntax score , and ef ( p < 0.05 ) [ table 2 ] .
after pci both the total blush and mpg increased significantly ( p < 0.05 ) .
pci resulted in better perfusion indicated by increased total blush and mpg ( p < 0.05 ) ; however , syntax score , ef , and sds did not change significantly [ table 3 ] . comparison between successful and unsuccessful pci pci : percutaneous intervention ; mpg : myocardial perfusion grade ; sds : summed difference score ; ef : ejection fraction ; lved : left ventricular end - diastolic volume ; sap : stable angina pectoris ; uap : unstable angina pectoris ; ami : acute myocardial infarction ; omi : old myocardial infarction ; cag : coronary angiography ; hf : heart failure ; dm2 : type 2 diabetes mellitus ; rf : renal failure ; bp : blood pressure ; tnt : troponin t ; bnp : brain natriuretic peptide ; hcy : homocysteine ; crp : c - reactive protein ; ldl : low - density lipoprotein .
it was found in some patients the recanalization of the occluded artery did not result in improved left ventricular function .
spect , positron emission tomography , and magnetic resonance imaging remained the most frequently used examination for cardiac muscle viability .
most importantly , it is impossible to do the myocardial imaging and coronary artery imaging at the same time .
yang et al . used the video densitometry to study the grayscale changes with time after contrast injection into the coronary artery .
the darker the myocardium , the higher the grayscale , and thus higher the video density . however , the variation of grayscale is too big to be of great significant value according to our own experience
. it might be due to panning the table during the procedure or the respiration which contributes to the big variation of the grayscale or density .
the blush area times the degree of mpg is the total blush in our study . to investigate the utility of crealife workstation ,
the patients were divided into three groups , stenosis versus cto , mpg 1 , 2 versus mpg 3 , and successful versus unsuccessful recanalization .
the study clearly demonstrated that the severity and the extent of the coronary lesions were correlated closely with a total blush .
after the recanalization , the total blush improved significantly indicated by the larger area of blush and darker myocardial staining . in the methods section
figure 1 shows the total blush in a patient with chronic left anterior descending occlusion .
the dashed area represented blush area that was very small in size , and staining was weak despite successful recanalization ( a ) and the patient had a big anterior infarct ( b ) .
theoretically , the blush grade does not take into account the area of the blush .
after pci both the total blush and mpg increased significantly . at present , we only know that the perfusion was better , lved smaller and ef higher after pci .
however , more multi - center control studies need to be performed to see if the results could be repeated by other investigators .
the dashed area was blush area which was very small in size , and staining was weak despite successful recanalization ( a ) .
ef was the gold standard for left ventricular systolic function and had a strong prognostic implication .
we performed multivariate linear correlation with ef as the dependent factor and syntax score , sds , total blush , blush area , and mpg as the independent factors [ table 4 ] .
the syntax score , sds , total blush , and blush area correlated well with ef , but the mpg correlated less well with ef .
the syntax score was a well proven and accepted indicator of the complexity of cad .
the total blush was a new indicator of myocardial perfusion , whether this could lead to an increase in ef remained to be seen in the follow - up .
multivariate linear regression analysis sds : summed difference score ; mpg : myocardial perfusion grade . in other studies , similar grading system named thrombolysis in myocardial infarction ( timi ) myocardial perfusion ( tmp ) grade was used .
although the name of the grading system was different , the criteria was , however , similar .
the lowest mortality rate was in those patients with tmp grade 3 , intermediate in tmp grade 2 , and highest in tmp grades 0 and 1 .
in steigen tk 's study , mpg 0/1 post - pci had a lower lvef and a higher heart rate at 1-year follow - up .
in patients with st - elevation myocardial infarction and timi grade 3 flow after primary pci , mpg 2 was associated with poor myocardial salvage , a larger infarct , and higher 5-year mortality rate than mpg = 3 .
although our results indicate an association between total blush and myocardial perfusion , the present study was not a prospective cohort design in nature , and it had only small sample size of a single center with significant gender bias . in the further study , more cases from multicenters would be recruited . in conclusion
, the calculation of cag total blush can be accomplished by a specialized computer which can provide important information on myocardial perfusion and left heart function .
Output:
| background : myocardial perfusion grade ( mpg ) is an accepted method of evaluating myocardial perfusion .
however , it does not take into the account , the extent of the perfusion .
we hypothesized that myocardial blush area times mpg ( total blush ) would be more accurate than simple mpg , and yield better prognostic information.methods:about 34 patients were recruited after they had consented to both coronary angiography ( cag ) and single photon emission computed tomography ( spect ) , and divided into two groups .
a special dedicated computer was employed to calculate the total blush .
the cag was performed as a conventional way .
scintigraphic technetium 99 m methoxyisobutyl - isonitrile rest and stress images were evaluated quantitatively .
the comparison was made between stenosis versus chronic total occlusion ( cto ) , mpg 1 , 2 versus mpg 3 , percutaneous intervention ( pci ) successful versus failure .
a correlation was made between ejection fraction ( ef ) and myocardial perfusion by mpg , total blush , spect , and syntax score.results:the perfusion indices of total blush , summed difference score ( sds ) and syntax score were insignificant between the two groups ( p > 0.05 ) . however , the left ventricular end diastolic volume was significantly larger in cto ( p < 0.05 ) .
the patients with stenosis had better mpg than with cto ( p < 0.05 ) .
the increased mpg was associated with increased total blush , higher syntax score , and ef ( p < 0.05 ) .
successful pci resulted in better perfusion indicated by increased total blush , and mpg ( p < 0.05 ) but successful pci did not change syntax score , ef and sds significantly .
multivariate linear analysis with ef as the dependent factor and syntax score , sds , total blush , blush area , and mpg as the independent factors showed a significantly higher degree of correlation ( r = 0.87 , p < 0.05).conclusion : after pci the total blush and ef improved significantly indicating its potential application in the future . |
PubmedSumm118513 | ***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: leishmaniasis refers to the spectrum of diseases caused by leishmania species , which are protozoa of order kinetoplastida .
clinically leishmaniasis is divided into visceral ( kala - azar ) , cutaneous , mucosal , and mucocutaneous syndromes and pkdl .
kala - azar is most commonly caused by l. donovani , l. infantum , and l. chagasi [ 13 ] .
the vast majority of these cases ( 90% ) occur in poor rural area of india , bangladesh , sudan , brazil , and nepal [ 4 , 5 ] .
l. donovani is responsible for visceral leishmaniasis in eastern india , bangladesh , nepal , and vast areas of east africa [ 1 , 3 ] .
it is estimated that more than 6 million people in nepal are at risk of leishmania infection .
prevalence of epistaxis in visceral leishmaniasis up to 51% was found in sudan and the mediterranean littoral area . the exact prevalence and cause of epistaxis was not clear in our setup .
this study was done to find out the prevalence and hematological risk factor of epistaxis among vl patients .
this study was conducted at department of otolaryngology and head and neck surgery and department of internal medicine in b. p. koirala institute of health sciences dharan , nepal over a period of one year from january 2007 to january 2008 .
vl was diagnosed based on clinical profile and the presence of rk-39 from peripheral smear and ld bodies from bone marrow or tissue biopsy . before starting anti - kala - azar treatment ,
exclusion criteria were the following .
patient already on anti - vl treatment.any other established condition / comorbidities giving rise to similar manifestation.patient not willing to participate in the study .
patient already on anti - vl treatment.any other established condition / comorbidities giving rise to similar manifestation.patient not willing to participate in the study .
any other established condition / comorbidities giving rise to similar manifestation . patient not willing to participate in the study .
nasal bleeding was found in 19 ( 23.8% ) cases with age ranging from 7 to 66 years and median age 31.85 12.15 years . 13 ( 68.5% )
male - to - female ratio was 2.17 : 1 ( table 1 ) .
unilateral bleeding was seen in 11 ( 57.9% ) cases , whereas bilateral bleeding was seen in 8 ( 42.1% ) cases ( table 2 ) .
fourteen ( 74% ) cases were anterior type and 5 ( 26% ) were posterior ( table 3 )
10 gm / dl with mean 8.1 gm / dl , 17 ( 89.5% ) had total leucocyte count < 4000 with mean 2940/mm , and 19 ( 100% ) had platelet count < 150 0000 with mean 81526/mm at presentation ( table 4 ) .
leishmaniasis is not a single disease but a variety of syndromes that are complex and cosmopolitan .
visceral leishmaniasis is caused by l. donovani which is endemic in eastern terai of nepal .
prevalence of epistaxis in visceral leishmaniasis was around 51% in sudan and the mediterranean littoral area and 4788% in the study of zijlstra and el - hassan .
in our study it was only 23.8% , it may be due to the different zoographical locations and hospital - based study .
bilateral bleeding occured in 11 ( 57.9% ) of cases and unilateral in 8 ( 42.1% ) .
most of the bleeding was of the anterior type ( 14 ( 73.7% ) cases ) .
there was no specific pattern of bleeding as most of cases had diffuse mucosal bleed .
posterior bleeding refers to active bleeding refractory to adequate anterior packing or when no bleeding point is identified on anterior rhinoscopy .
the pathogenesis of epistaxis occurring in early phase of disease is not understood , but that occurring late in the disease is probably due to a combination of deficient clotting factor and thrombocytopenia [ 6 , 10 ] . in our study out of 19 epistaxis patients , 84.2% had hb < 10 gm / dl ,
89.5% had tlc < 4000/mm , and 100% had platelet count < 150 000/mm .
sequestration and destruction of erythrocyte and haemolysis lead to shortened half - life , iron deficiency , and folate deficiency reported [ 1113 ] .
but it is not known whether the observed neutropenia and thrombocytopenia is due to increased margination , splenic sequestration , or an autoimmune process or combination of those factors .
renal function test ( serum urea and creatine ) was within normal limits . among the patients with epistaxis ,
marginally prolonged prothrombin time has been reported by el - hassan et al . .
epistaxis was correlated with different hematological parameters like haemoglobin , tlc , platelet count , pt , and inr .
epistaxis was significantly correlated with thrombocytopenia ( p = 0.02 ) . in our study , all patients were managed initially with nasal decongestant , though 17 ( 89% ) required chemical cautery , nasal packing with abgel . in 7 patients anterior nasal packing and in 5 patients posterior nasal packing using foley catheter
posterior nasal packing was done for nasal bleeding . in spite of blood transfusion and packing ,
the bleeding usually responds well to symptomatic therapy ( nasal tamponade using gauze with 1% lignocaine ) but it often recurs .
further studies with larger series of cases and followup are needed to be taken into consideration .
Output:
| objective . to study the prevalence of epistaxis in visceral leismaniasis and its correlation with hematological profile
. methods .
out of 80 diagnosed cases of visceral leishmaniasis , 19 patients with epistaxis were included in the study .
diagnosis was made by rk-39 from peripheral smear and ld bodies from bone marrow . before starting anti - kala - azar treatment , nasal examination findings and hematological profile were noted . study design .
prospective cross - sectional hospital - based study . results .
epistaxis was found in the age group of 766 years .
epistaxis was observed in 19 ( 23.8% ) cases .
one patient died because of epistaxis and neck hematoma .
conclusion .
epistaxis is a common ent finding in endemic area of visceral leishmaniasis like our case . |
PubmedSumm118514 | ***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 details of study methodology and questionnaires were reported previously . in brief , we used retrospective , comparative , small sample study design with structured and unstructured questionnaires to obtain data from 136 patients on patient satisfaction between october and december 2007 from the two rural vcs serving the communities in easily accessible rural locations ( erl ) and two remote rural locations ( rrl ) .
erl is a large village with around 20,000 populations with a well - developed market .
1 . selection of sample for the study using our field experience and qualitative data on vcs , we presumed that there would be a minimum of 10% difference in the effectiveness of service delivery of the vcs of erl over the vcs of rrl ( with a margin of error at 5% ) .
accordingly , a sample of 136 subjects was needed in this study . to obtain 136 eligible patients ,
we sampled every fourth patient on the list with the starting point for the sample being randomly selected from the list of the first four patients [ fig . 1 ] .
the selection criteria for the 136 sampled patients included : ( a ) patients above 16 years who received eye screening and spectacles at least 6 months prior to the study ( b ) patients who lived within 10 km distance ( since majority patients come from 10 km and also because of study logistics ) from the vc locations .
we obtained informed consent of the participated subjects after explanation of the nature and possible consequences of the study .
we defined patient satisfaction as positive evaluation of specific aspects of health care facility,[1820 ] assessing responses on 5-point likert scale from 0 ( very dissatisfied ) to 4 ( very satisfied ) .
assessment of patients satisfaction includes ratings of the two vcs facilities for the services received and the outcome of the use of spectacles .
the details about how the questionnaires were developed and administered on sample patients have been reported previously . in brief
, the initial questionnaire with 16 items ( developed from qualitative data ) was piloted on 60 patients who accessed the vcs that were not part of the study . at the pilot stage ,
the questionnaire was verified and reduced to 12 items to suit the context of vc - based eye care services .
the cronbach 's statistic method was used to determine the internal consistency of the 12 items of the questionnaire ( cronbach 's =0.767 for 12 items ) .
cohen 's kappa statistic method was used to find the agreement between the two investigators for each item used to assess patient satisfaction ( n=60 patients ) and the kappa values ranged from 0.71 to 0.87 for all the items , except two items : quality ( 0.41 ) and affordability of the vcs services ( 0.46 ) .
after the pilot , the field investigators were retrained and the repeated agreement was found to be satisfactory .
the near final questionnaire was repeated three times and was translated to the local language .
two trained investigators interviewed the 127 of the 136 sampled patients at their residences 6 months after their visit to the vcs using the final questionnaire .
second , these factors were used as dependent variables in the linear regression models to explain variance in - patient .
we considered 12 items used for assessing patient satisfaction ( outcome variable ) for factor and reliability analysis .
independent variables were excluded as these were included in linear regression models to examine the associations between factors and demographic and socio economic items .
the stage - wise data reduction of 12 variables produced three reliable factors ( 1.)vt ; ( 2 . )
location of vc ; and ( 3 . ) access to the services of vc comprised four , three , and five variables , respectively .
the author has considered these factors as the three components of dependent / outcome variables , that is , patients satisfaction .
the linearity of the relationship between dependent and independent variables and no serial correlation were the assumptions used to justify the use of linear regression models .
the linear regression models were adjusted for the demographic characteristics of the patients geographical area , age , gender , perceptions of travel convenience , and ease in identifying the vc building .
the spss16 ( spss inc , chicago , il , usa ) was used for the data analysis .
the details about how the questionnaires were developed and administered on sample patients have been reported previously . in brief , the initial questionnaire with 16 items ( developed from qualitative data ) was piloted on 60 patients who accessed the vcs that were not part of the study . at the pilot stage ,
the questionnaire was verified and reduced to 12 items to suit the context of vc - based eye care services .
the cronbach 's statistic method was used to determine the internal consistency of the 12 items of the questionnaire ( cronbach 's =0.767 for 12 items ) .
cohen 's kappa statistic method was used to find the agreement between the two investigators for each item used to assess patient satisfaction ( n=60 patients ) and the kappa values ranged from 0.71 to 0.87 for all the items , except two items : quality ( 0.41 ) and affordability of the vcs services ( 0.46 ) .
after the pilot , the field investigators were retrained and the repeated agreement was found to be satisfactory .
the near final questionnaire was repeated three times and was translated to the local language .
two trained investigators interviewed the 127 of the 136 sampled patients at their residences 6 months after their visit to the vcs using the final questionnaire .
second , these factors were used as dependent variables in the linear regression models to explain variance in - patient .
we considered 12 items used for assessing patient satisfaction ( outcome variable ) for factor and reliability analysis .
independent variables were excluded as these were included in linear regression models to examine the associations between factors and demographic and socio economic items .
the stage - wise data reduction of 12 variables produced three reliable factors ( 1.)vt ; ( 2 . )
location of vc ; and ( 3 . ) access to the services of vc comprised four , three , and five variables , respectively .
the author has considered these factors as the three components of dependent / outcome variables , that is , patients satisfaction .
the linearity of the relationship between dependent and independent variables and no serial correlation were the assumptions used to justify the use of linear regression models .
the linear regression models were adjusted for the demographic characteristics of the patients geographical area , age , gender , perceptions of travel convenience , and ease in identifying the vc building .
the spss16 ( spss inc , chicago , il , usa ) was used for the data analysis .
a total of 127 patients from the two vcs at erl and the two vcs at rrl were interviewed ( 9 sampled patients were not available ) .
the total participation rate was 93%.the characteristics of the two samples were compared in table 1 .
the number of females ( n=61 ) was almost equal to the number of males ( n=66 ) in both the samples .
the mean ages were 52.79.4 for erl setting and 53.010.9 for rrl setting and was not significantly different ( p=0.625 ) .
the three factors obtained from factor analysis were entered in three linear regression models to explain the association of patient demographics with patient satisfaction of vc services .
characteristics of sample from easily accessible rural locations and prl vision centers the table 2 shows the stage - wise data reduction of 12 variables has allowed us to extract three reliable factors that comprised four , three , and five variables , respectively .
the factor-1 ( services of the vt ) consists of four variables namely ( a ) amount of time spent with the vt,(b ) personal care received from the vt , ( c ) information and guidance received from the vt , and ( d ) overall impression about the behavior of the vt at the vc .
the factor-2 ( access to the location of the vc ) yielded two variables ( a ) transport convenience and(b ) ease to identify the vc location , and thus explains 13.9% patients satisfaction .
lastly , the factor-3 ( services of vc facility ) consists of six variables ( a ) the waiting time at the vc,(b ) the cost of spectacles at the vc,(c ) the quality of spectacles received at the vcs , ( d ) the value placed on vcs services , ( e ) the affordability to access the vt 's services as compared with other providers , and ( f ) spectacles dispensing time at the vc . factor-3
the three components together accounted for 61.50% of the total variance and can explain the patients satisfaction with the vcs services in the rural settings of the indian state of andhra pradesh .
results of factor analyses of patient satisfaction with vision center facility the three linear regression models [ table 3 ] , refer to an association between factor 1 , factor 2 , and factor 3 and patients characteristics as presented below : association between factor 1 , factor 2 , and factor 3 and patient characteristics
factor-1 , labeled as service of vt :
the adjusted r for factor-1 was 0.61 ; f1,124=144.36 , p<0.001 , using the stepwise method .
the respondents who had difficulty to travel to the place of vc had 0.47 units of lower satisfaction levels with the vt 's services as compared with those who felt they had ease in traveling to the place of vc facility ( p=<0.001).the respondents perceived severity of eye problem was associated with patients satisfaction .
those who reported somewhat blurred as the eye problem had 0.2 units of lower satisfaction level with the vc 's services as compared with those who felt they had severe eye problem ( p=<0.002 ) . the respondents perceived ability to pay
those patients who perceived that they can afford to pay for eye care services had 0.3 units decreased satisfaction level with
vt 's services as compared with those who can not afford to pay for eye care services ( p<0.004).factor-2 , labeled as
access to location of vc : the adjusted r for factor-2 was 0.18 ; f1,124= 29.5 , p<0.001 using the stepwise method .
the respondents difficulty to identify the building of vc had 0.4units decreased patients satisfaction as compared with those who had no difficulty to identify the vc building ( p<0.001).factor 3 , labeled as
services of vc : the adjusted r for factor-3 was 0.36 ; f1,124=45.6 , p<0.001 , using the stepwise method.the significant variables are : the respondents traveling area ( geographical setting to which they had to travel to access vc facility ) was associated with patients satisfaction . those who had to travel less distance ( < 5kms ) to the center had 0.4 units of increased satisfaction level with the services of vc as compared with those who had to travel more distance .
factor-1 , labeled as service of vt : the adjusted r for factor-1 was 0.61 ; f1,124=144.36 , p<0.001 , using the stepwise method .
the respondents who had difficulty to travel to the place of vc had 0.47 units of lower satisfaction levels with the vt 's services as compared with those who felt they had ease in traveling to the place of vc facility ( p=<0.001).the respondents perceived severity of eye problem was associated with patients satisfaction .
those who reported somewhat blurred as the eye problem had 0.2 units of lower satisfaction level with the vc 's services as compared with those who felt they had severe eye problem ( p=<0.002 ) .
those patients who perceived that they can afford to pay for eye care services had 0.3 units decreased satisfaction level with
vt 's services as compared with those who can not afford to pay for eye care services ( p<0.004 ) .
access to location of vc : the adjusted r for factor-2 was 0.18 ; f1,124= 29.5 , p<0.001 using the stepwise method .
the respondents difficulty to identify the building of vc had 0.4units decreased patients satisfaction as compared with those who had no difficulty to identify the vc building ( p<0.001 ) .
factor 3 , labeled as services of vc : the adjusted r for factor-3 was 0.36 ; f1,124=45.6 , p<0.001 , using the stepwise method.the significant variables are : the respondents traveling area ( geographical setting to which they had to travel to access vc facility ) was associated with patients satisfaction .
those who had to travel less distance ( < 5kms ) to the center had 0.4 units of increased satisfaction level with the services of vc as compared with those who had to travel more distance .
the respondents who perceived difficulty to travel to the place of vc had 0.24 units of decreased satisfaction levels with the services of vc as compared with those who felt they had ease in traveling to the place of vc facility ( p=<0.001 ) .
this paper addresses the issue of what determines patient satisfaction with primary eye care services through the concept of vc from the perspective of the patient .
three components of vc model ; vt ( factor-1 ) , location of vc ( factor-2 ) and access to the services of vc ( factor-3 ) , respectively , explained 61.5% cumulative variance of patient satisfaction . three linear regression models predicted the association between patients characteristics and the three components of patients satisfaction . according to the first model ( adjusted r value = 0.61 ; f1,124=144.36 , p<0.001 ) ,
the vt components with which the patients were satisfied were : ( a ) convenience of transportation to access the vt 's services , ( b ) personal care ( good listening , good behavior , and empathy ) , and ( c ) the duration of time spent with the patient .
communication of information to patients appears to be the source of satisfaction with vision care similar to the findings reported in a study .
these results are consistent with a prior study in which a good doctor - patient relationship was associated with general satisfaction .
the reason for this association is that a good patient vt relationship is an essential component of primary eye care .
this evidence also suggests that the satisfaction with the vcs services depends on multiple conditions such as the perceived severity of eye problem by the patient and the good outcome of services , ( positive impact of appropriate refraction by the vt and the quality of spectacles ) the way services are delivered ( personal care with empathy ) and the ease with which patients are able to access the services ( transportation ) .
communication , respect and patient engagement in provider - patient relationship are important in determining patient 's satisfaction .
this finding was similar to the report that mentioned patients were more satisfied with their empathetic providers . in the second model ( r=0.18 ; f1,124=29.5 ; p<0.001 ) , the level of satisfaction with the component location of vc was significantly higher among the patientswho had ease to identify the vc building as compared with those who had difficulty in identifying the vc facility . according to one study ,
the access to facility was reported to be an important source of satisfaction.[231820 ] finally , even though the clinical settings for the vc were the same in both the settings of rrls and erls , the satisfaction of the patients with the component
access to vc facility was significantly different as explained by the third model ( r=0.25 ; f1,124=42.6 ) .
those who were able to access the vc facility with ease and had to travel less were significantly more satisfied with the vcs services .
this finding implies that the patients inclination in utilizing the vcs services increases with the increased convenience in accessing the facility .
this is particularly important since 42% of total 127 sampled patients had expressed discomfort in accessing the vcs [ table 1 ] . in our study
, we did not find any significant difference in satisfaction levels among men and women .
this data indicate that patients expect the vt at the vc to be ( a ) an effective communicator , ( b ) a provider of personal care with empathy , and ( c ) a guide for giving appropriate information and education .
this data corroborates with the statement that patient satisfaction is assumed to be the fulfillment of expectations . and
the quality of communication between the vt and patients is associated with patient satisfaction . using this data
, one can argue that a combination of factors such as good vt , transport convenience , ability to pay , etc . can enhance higher patient satisfaction and this in turn could lead to higher patient participation , which needs to be tested further .
it is found that the general satisfaction with the items used in this study needs to be standardized using a larger sample size .
the questionnaire items used in this study could measure only over 61.5% of satisfaction indicating that there are unmeasured items that should have been in the instrument.further studies are required to comment on the remaining 40% of unmeasured aspects such as cultural acceptance , patients expectations of eye care delivery , awareness levels and health status , etc .
although statistically significant , the difference in the percentage of patients who were satisfied was small and may not suggest clinical difference .
the study results may not be generalized due to its small sample size . besides this
, the participants were approached after 6 months of use of services and may have affected by recall bias . moreover ,
the respondents were restricted to only four vcs , which could also be a potential source of selection bias . in conclusion , this study data on patient satisfaction can be useful for service providers to evaluate the quality care , as an outcome variable , and as a method for quality improvement of vc services .
Output:
| aim : this paper intends to discuss the patients perspective on the determinants of primary eye care services from vision centers ( vc ) in rural india.materials and methods : a retrospective study design and interview method was used on 127 randomly selected patients who accessed the 4 vcs in 2007 .
factor analyses and linear regression models were used to predict the associations with patient satisfaction.results:the three factors derived from factor analyses were : ( 1)-vision technician ( vt ) , ( 2)-location of vc , and ( 3)-access to vc ; explaining 60% of the variance in total patients satisfaction with vc . the first model ( r2 : 0.61 ; f1,124=144.36 , p<0.001 ) , indicated that respondents who had difficulty to travel to the place of vc and those who can afford to pay had less satisfaction with vt services . the second model ( r2=0.18 ; f1,124=29.5
, p<0.001 ) explained that respondents difficulty to identify the building of vc had decreased patients satisfaction and the third model ( r2=0.36 ; f1,124=45.6 , p<0.001 ) indicated that those who had to travel<5 km to the vc and had 0.38 units of increased satisfaction level with the services of vc.conclusion:a good vt can enhance patient satisfaction .
however , patient expectations are not only confined to the provider but also other factors such as ability to pay and convenient transportation that helps patients reach the location of the vc with ease . |
PubmedSumm118515 | ***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: high cholesterol levels are associated with increased risk of coronary heart disease ( chd ) and stroke ( 1 ) .
since chd is one of the most common diseases both in the developed and developing countries , high total cholesterol ( tc ) is a major cause of disease burden and mortality .
generally worldwide , high tc is estimated to cause 4.5% of total mortality ( 2.6 million deaths ) and 2.0% of total disability adjusted life years ( dalys ) , or 29.7 million dalys .
therefore , detecting and lowering high level of tc can be helpful in reducing chd and total mortality ( 2 ) .
understanding the distribution of serum cholesterol levels in each country is valuable index for use in public health planning . in 1985 , national institute of health ( nih ) constructed nomorgarms of tc levels for us population . on the basis of that nomogram , tc levels were divided into three categories so that , cholesterol below the 75 percentile was defined as the desired level , between the 75 and 90 percentile was defined as moderate risk and greater than the 90 percentile was defined as high risk ( 3 ) .
three years later in 1988 , the expert panel of the us national cholesterol education program ( ncep ) proposed a newer classification for hypercholesterolemia which was unrelated to age . in this classification total cholesterol < 200mg / dl was defined as desirable , 200239 mg / dl as borderline and > = 240 mg / dl as high ( 4 ) . according to consequent treatment based classification ,
adult treatment panel ( atp iii ) , recommended treatment to be initiated at levels higher than 240 mg / dl and life style modification at levels higher than 200 mg / dl ( 5 ) .
in fact , the association of total cholesterol values with the adverse consequences such as diabetes , coronary artery diseases ( cad ) , and stroke and all - cause mortality depends on age , sex and ethnicity ( 68 ) .
americans because of their life style and particularly their diet ( 9 , 10 ) have higher cholesterol levels than iranians .
this study aimed to construct nomograms of cholesterol levels and establish the cut points for borderline and high serum tc levels specific to iranian population .
we used data on 19630 non - institutionalized 2564 years old iranian individuals obtained from third national survey on non - communicable diseases in 2007 for analysis ( 11 ) .
the study was in line with stepwise approach of the who to non - communicable disease risk factor surveillance ( 12 ) .
this study received ethics approval from the center for disease control ( cdc ) of iran . prior to inclusion
, verbal consent was taken from all individuals . in each 30 provinces of the country , a multistage random cluster sampling method , stratified by sex and age group was used to collect the data . in each province
50 clusters were taken . each cluster comprised of 20 individuals , 10 men and 10 women , living in neighboring households .
the age of target population was classified into five age groups ( 1524 , 2534 , 3544 , 4554 , and 5564 years ) .
all individuals were visited at their home by trained interviewers appointed by collaborating medical schools .
data were obtained in three steps . in first step data regarding demographic and behaviors of individuals ( diet , physical activity , tobacco use , history of hypertension , and history of diabetes )
were gathered using a questionnaires based on who steps instrument ( core and expanded ) ( 11 ) . in step 2
individuals underwent physical measurements ( e.g. weight , height , waist circumference and blood pressure ) using the same protocol for all of recruited individuals . in step 3
trained laboratory technicians took 10 ml of venous blood in sitting position after 10 to 12 hours of fasting from participant 25 years and older .
blood samples transferred in cold boxes to a referral laboratory center in at most 4 h from sampling sites .
serum total cholesterol was measured by enzymatic method ( parsazmun , karaj , iran ) with the coefficient of variation of 5% .
in addition , in laboratory sites 10% of the blood samples were centrifuged and sera kept frozen at 20c and then transferred to the national reference laboratory , a who collaborating center in tehran , for double checking .
the survey received ethics approval of the center for disease control ( cdc ) of iran because of the sampling method , complex sample survey ( svy ) analysis was performed using stata statistical software ( release 11.0 , statacorp , college station , tx ) ( 13 ) .
the provinces were defined as strata , and in each strata clusters were defined as sampling units .
primarily , weights for each sex and age groups were assigned according to the distribution of sex and age groups of the 2006 national census in each province . then , to account for the missing data primary weights were divided by the number of measurements in the corresponding sex - age group category to correct for missing observations .
nomograms were constructed by modeling data using fractional polynomial ( 14 ) . to derive the cholesterol nomograms ( reference standard curves ) ,
first the cholesterol measurements were transformed to the logarithmic scale in order to obtain approximate normal distributions .
then the variations in mean ( ) and standard deviation ( sd ) of the transformed cholesterol measurements were modeled with age using fractional polynomials .
first , for the appropriate modeling of mean of the transformed data ( ) , the powers of age were obtained using fracpoly procedure .
then age was centered to obtain robust estimation of the model parameters . to model the mean of the logarithm of cholesterol , the powers of centered ages were used as covariates in svy regression module , which accounts for the structure and weights of the data .
second , the absolute residuals were computed for the above model and regressed on age using svy module and multiplied by
/2 to estimate the age - specific standard deviation ( 15 ) .
finally , the p percentiles of the logarithm of cholesterol levels were computed by + zp sd ( eg , the zp=1.645 for computing the 95 centile ) . the nomograms derived by back transformation .
the goodness of fit of the nomograms was assessed by comparing the number of cholesterol measurements in regions defined by the seven centiles ( 5 , 10 , 25 , 50 , 75 , 90 , and 95 ) with expected number of observations for all ages using a chi - squared test .
we summarized 75 and 90 percentiles of tc in three age groups ( 2534 , 3544 and 4564 ) .
then , 75 and 90 percentiles in each age group were rounded to derive cut - points for borderline and high levels of tc specific to iranian population .
because of the sampling method , complex sample survey ( svy ) analysis was performed using stata statistical software ( release 11.0 , statacorp , college station , tx ) ( 13 ) .
the provinces were defined as strata , and in each strata clusters were defined as sampling units .
primarily , weights for each sex and age groups were assigned according to the distribution of sex and age groups of the 2006 national census in each province .
then , to account for the missing data primary weights were divided by the number of measurements in the corresponding sex - age group category to correct for missing observations .
nomograms were constructed by modeling data using fractional polynomial ( 14 ) . to derive the cholesterol nomograms ( reference standard curves ) ,
first the cholesterol measurements were transformed to the logarithmic scale in order to obtain approximate normal distributions .
then the variations in mean ( ) and standard deviation ( sd ) of the transformed cholesterol measurements were modeled with age using fractional polynomials .
first , for the appropriate modeling of mean of the transformed data ( ) , the powers of age were obtained using fracpoly procedure .
then age was centered to obtain robust estimation of the model parameters . to model the mean of the logarithm of cholesterol , the powers of centered ages were used as covariates in svy regression module , which accounts for the structure and weights of the data .
second , the absolute residuals were computed for the above model and regressed on age using svy module and multiplied by
/2 to estimate the age - specific standard deviation ( 15 ) .
finally , the p percentiles of the logarithm of cholesterol levels were computed by + zp sd ( eg , the zp=1.645 for computing the 95 centile ) . the nomograms derived by back transformation .
the goodness of fit of the nomograms was assessed by comparing the number of cholesterol measurements in regions defined by the seven centiles ( 5 , 10 , 25 , 50 , 75 , 90 , and 95 ) with expected number of observations for all ages using a chi - squared test .
we summarized 75 and 90 percentiles of tc in three age groups ( 2534 , 3544 and 4564 ) .
then , 75 and 90 percentiles in each age group were rounded to derive cut - points for borderline and high levels of tc specific to iranian population .
serum total cholesterol levels of 19,630 individuals ( 9,369 men and 10,261 women ) aged 2564 years from all over the iran were used for construction of the cholesterol level nomograms .
fractional polynomial with degree 2 was applied for modeling the mean and standard deviation of logarithmic transformation of the total cholesterol level of men with age .
the powers for age were found to be in the form of 1 and 3 for mean and of 3 and 3 for standard deviation .
also , mean logarithmic transformation of the total cholesterol level of women were modeled with age using a degree 2 fractional polynomial .
furthermore , a model of the form of 2 and 3 were the powers of age when the standard deviation of the total cholesterol of women were modeled .
the rate of missed cholesterol measurements were significantly more in men and younger ages and found to vary across provinces .
the distribution of other non - missing available variables including body mass index ( bmi ) , duration of exercise , frequency of consuming vegetables , fruit and oil , job related physical activity between missing and non - missing individuals in each sex and age groups were found non - significant ( p>0.05 ; data not shown ) . in general , for overcoming the problem of missingness one can use imputation or weighting the data .
therefore , the following analyses were carried out using the weights computed from the national census 2006 which were divided to the number of individuals attended in each age - sex category .
table 1 presents the smoothed 5 , 10 , 25 , 50 , 75 , 90 , and 95 percentiles of the men serum total cholesterol levels for each age . as table 1 shows the cholesterol percentiles of men
the median total cholesterol level of men at age of 25 was 161 mg / dl , which increased steadily to 184 mg / dl at the age of 45 , and then flatten up to the age of 59 and eventually thereafter the tc level decreased around 1 mg / dl to age 64 .
the average yearly increase of median of tc for men up to the age of 45 was 1.15 mg / dl .
the 90 percentile of the total cholesterol level also rose steadily from 212 mg / dl at the age of 25 to 240 mg / dl at the age of 41 , and then this trend slowed down resulting in the 90 percentile of 245 mg / dl at the age of 50 which only decreased1 mg / dl after that .
the chi - squred test showed that the overall difference between observed and expected numbers of male cholesterol measures in eight region defined by the seven centiles ( 5 , 10 , 25 , 50 , 75 , 90 , and 95 ) was not significant , = 6.63 , df=7 , p=0.47 ; implying a good fit of the model to data .
the median cholesterol level at the age of 25 was 169 mg / dl and increased steadily to 209 mg / dl at the age 64 .
the yearly increase of total cholesterol for females up to the age of 64 was 1.03 mg / dl .
the 90 percentile of the total cholesterol was 221 mg / dl at the age of 25 and increased steadily to 277 mg / dl at the age of 64 .
the overall fit of smoothed centiles to the cholesterol levels of females was fine ) = 11.29 , df=7 , p=0.13 ) .
the comparison of serum total cholesterol levels of males and females are presented in figure 1 .
the sex difference between 10 , 50 , 90 percentiles is 6 , 8 and 9 mg / dl at the age of 25 , respectively .
this difference decreased up to the age of 33 and after that increased by age and reached to 16 , 24 and 33 mg / dl for the 10th , 50th and 90th percentiles at the age of 64 , respectively .
table 3 summarizes the 50 , 75 and 90 percentiles of different sex and age groups .
these values were used to derive the cut points for borderline and high cholesterol levels specific to iranian population ( panel 1 ) .
in this study we constructed cholesterol nomograms for the iranian population specific for sex and age and proposed cut off values for borderline and high cholesterol levels .
indeed , in recent years some countries tried to present normal cholesterol levels specific to their population ( 16 , 17 ) .
the mean total cholesterol level of americans was on average 200 mg / dl in 2006 ( 18 ) which is considerably higher than 186 mg / dl ( derived from current data ) in iranians in 2007 . in our data in males , the total serum cholesterol level of 200 mg / dl on average lay on 78 , 66 and 63 percentiles for the age groups of 2529 , 3039 and 4064 years , respectively .
the cholesterol level of 240 mg / dl lay on percentiles 94 , 91 , and 88 for these age groups , respectively . in females , the total serum cholesterol level of 200 mg / dl on average lay on percentiles of 75 , 63 and 49 for the age groups of 2529 , 3039 and 4064 years . in addition , for these age groups , the total serum cholesterol level of 240 mg / dl lay on percentiles of 93 , 89 , and 72 , respectively .
this data shows the difference of cholesterol levels between iranian and americans and warrants specific normal cholesterol levels for iranian population .
this increase is more pronounced up to the age of 45 . in men after the age of 45 , age increase does not change the tc which means after the age of 45 the change of tc levels is independent of age .
oppositely , in women increase in tc levels with age continues after the age of 45 and remains dependent to age up to 64 .
overall , in men tc increases with age up to middle - ages but in woman this increase continues to older ages .
several studies have shown consistent results with our study regarding the change of tc levels with age in men and women .
the increase in tc levels with age is partly attributed to impairment in ldl receptors in older ages .
ldl receptor is responsible for endocytosis of cholesterol rich - ldl . as a consequence of peripheral impairment in uptake of ldl with age , tc concentration in blood increases .
weight gain is more pronounced between 25 to 50 years of age ( this is also true in our data , data not shown ) .
this may explain why increase in tc levels in men is more obvious up to middle - ages . in women ,
lack of estrogen after menopause removes its stimulatory effect on production of ldl receptors which lead to the increase in tc levels in blood ( 1921 ) . since the cholesterol levels seems to be different in men and women and changes with age we proposed iranian cut - points for borderline and high cholesterol levels separate for men and women and in three different age groups ( 2534 , 3544 and 4564 ) .
we proposed the age and sex related high tc values based on 75th and 90th percentiles of iranian population .
men with younger ages were more prone to be missed in obtaining blood sample ( for measuring cholesterol levels ) .
the fact that younger males were more commonly missed can be attributed to the coincidence of the blood sampling time with the work - hour of younger male individuals . however , other non - missing available variables were the same between missing and non - missing individuals in each sex and age groups .
indeed we think the missing data in each sex and age groups was in random . to compensate for missing data
the primary weights derived from national census in 2006 were divided to the number of individuals attended in each age - sex category .
epidemiologic studies to evaluate cvd rate and mortality in conjunction with tc levels are warranted to set more accurate cut points for high cholesterol levels in the country ( 16 ) .
the laboratory standardization panel for cholesterol of ncep at nih in the us recommended the inaccuracy of measurements to be less than 5% .
this was accordingly 5% in our study . although it has been shown that when evaluating extremely large numbers of subjects , inaccuracy of measurement do not change the distribution of cholesterol levels ( 22 ) .
total cholesterol level of iranians is lower than americans . in addition , cholesterol level changes with age and is different in men and women . with taking it into account , we presented the age and sex specific cholesterol nomograms for iranian population and proposed cholesterol borderline and high cutoff values for men and women in three age group 2534 , 3544 and 4564 years .
further epidemiologic studies are needed to determine the predictive abilities of these suggested cholesterol levels for chd events and mortality .
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 : high cholesterol levels are associated with increased risk of coronary heart disease and stroke . understanding the distribution of serum cholesterol levels in each country is valuable index for use in public health planning .
this study aimed to construct nomograms of total cholesterol ( tc ) levels and establish the cut - points specific to iranian population.methods:data on serum tc levels of 19,630 non - institutionalized individuals aged 2564 years from third national survey on non - communicable diseases ( surfncd ) in 2007 were used to construct cholesterol nomograms .
we proposed cutoff values for borderline and high tc levels based on rounded 75th and 90th percentiles in three age groups ( 2534 , 3544 and 4564 ) respectively.results:average yearly increase of tc for males up to the age of 45 and females up to 64 were 1.15 and 1.03 mg / dl , respectively .
tc levels were higher in females . in males , cutoff values for borderline and high tc levels were 195 and 220 mg / dl in 2534 , 210 and 240 mg / d in 3544 and 215 and 245 mg / dl in 4564 years old individuals . in women , these values were 200 and 225 mg / dl in 2534,215 and 240 mg / dl in 3544 and 235 and 265 mg / dl in 4564 years old individuals respectively.conclusion:since tc levels are different in two sexes and change with age , we proposed different cutoffs for sex and age group .
we think these cutoffs could be used in national public health planning . |
PubmedSumm118516 | ***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: anti - n - methyl - d - aspartate receptor ( nmdar ) encephalitis is a recently described form of autoimmune encephalitis that has characteristic clinical features that include psychosis , dyskinesia , encephalopathy , seizures , and autonomic dysfunctions.13 as one of the main symptom in anti - nmdar encephalitis , catatonia presents with motor and behaviour abnormalities that include alterations in thought , mood , and vigilance .
the common signs of catatonia are posturing , rigidity , mutism , and negativism.4 half of anti - nmdar encephalitis patients do not display any abnormalities in brain magnetic resonance image ( mri ) exams and the other half only show nonspecific changes in grey and white matter.5 there are only a few studies that assess anti - nmdar encephalitis with f - fluorodeoxyglucose positron - emission tomography ( fdg - pet ) scans .
these studies found reduced glucose metabolism in temporal cortex regions6 and global hypometabolism with a prominent focal intense hypermetabolic lesion in the right cerebellar cortex.3 in addition , a recent fdg - pet study reported an increased cerebral metabolism gradient along the frontotemporal to occipital axis that correlates with disease severity as assessed by a modified rankin scale.7 however , no studies have correlated metabolic changes in pet with detailed clinical symptoms such as the severity of catatonia and rigidity .
recently we experienced three serologically confirmed anti - nmdar encephalitis with fdg - pet scan who presented with variable degrees of catatonia symptoms such as behavioural , motor , autonomic , and breathing abnormalities .
three patients were admitted to the asan medical centre in seoul , korea between 2011 and 2012 .
these patients initially presented with marked agitation , psychotic behaviour , dyskinesis , and intermittent seizures .
seizures were observed in two patients ( patients 2 and 3 ) and disappeared 23 weeks after symptom onset . after admission , these patients showed varied degrees of catatonia symptoms such as behavioural , motor , autonomic , and breathing abnormalities .
the patients were diagnosed with anti - nmdar encephalitis after antibodies to nmdars were found in their serum and cerebrospinal fluid ( csf ) . during this acute phase of the encephalitis , all three patients had catatonia with rigidity and tonic posturing in their extremities that was more severe on the left side .
the catatonic symptoms were relatively mild in patient 1 , were moderate in patient 2 , and were severe in patient 3 ( table 1 ) .
clinical improvements were obtained after methyl - prednisolone therapy in patient 1 , after methyl - prednisolone with electroconvulsive therapy ( ect ) in patient 2 , and after methyl - prednisolone , immunoglobulin , and ect in patient 3 .
fdg - pet image were acquired 67 weeks after the onset of clinical symptoms ( acute phase ) and follow - up pet studies were performed at 1123 weeks from the onset of symptoms ( recovery phase ; patient 1 at 11 weeks , patient 2 at 23 weeks , and patient 3 at 21 weeks ) .
none of the patients had clinical seizures the day before the pet scans . to compare the brain area of metabolic change
, the brain images were normalised with the statistical parametric mapping software package ( spm2 ) with a 12 mm full width at half maximum ( fwhm ) . for single - subject analyses , the scaled fdg - pet brain image of a patient
was compared voxel - by - voxel with corresponding images from the age - matched normal control groups .
one - sided , two sample t - tests for detecting areas of hypermetabolism and hypometabolism was done with false discovery rate ( fdr ) < 0.05 in the acute phase ( multiple comparisons with voxel size > 100 ) and uncorrected p < 0.001 in the recovery phase ( multiple comparisons with voxel size > 100 ) . the clinical symptoms and pet findings from the three patients are summarised in table 2 .
the pet images in all three patients showed the various extent of increased metabolism in the right frontotempoparietal regions including the right orbitofrontal cortex , in the right insular cortex , in the bilateral basal ganglia ( more prominent on the right side ) , in the cerebellum , and in the left frontal cortex depending on the severity of catatonia .
by contrast , increased metabolism was observed in the brainstem and right thalamus of patients 2 ( fig .
1c ) , with the increase being more prominent in patient 3 . widespread decreased metabolism in the bilateral occipital cortex and the various extent of hypometabolism in the frontal lobe was observed in all three patients .
follow - up pet showed normal finding in two patients ( patient 1 and 2 ) who did not show catatonia or tonic rigidity , but , showed mild increased metabolism in the right basal ganglia in patient 3 who showed mild intermittent rigidity and tonic posturing in the left extremities without behavioural abnormalities ( fig .
three patients were admitted to the asan medical centre in seoul , korea between 2011 and 2012 .
these patients initially presented with marked agitation , psychotic behaviour , dyskinesis , and intermittent seizures .
seizures were observed in two patients ( patients 2 and 3 ) and disappeared 23 weeks after symptom onset . after admission , these patients showed varied degrees of catatonia symptoms such as behavioural , motor , autonomic , and breathing abnormalities .
the patients were diagnosed with anti - nmdar encephalitis after antibodies to nmdars were found in their serum and cerebrospinal fluid ( csf ) . during this acute phase of the encephalitis , all three patients had catatonia with rigidity and tonic posturing in their extremities that was more severe on the left side .
the catatonic symptoms were relatively mild in patient 1 , were moderate in patient 2 , and were severe in patient 3 ( table 1 ) .
clinical improvements were obtained after methyl - prednisolone therapy in patient 1 , after methyl - prednisolone with electroconvulsive therapy ( ect ) in patient 2 , and after methyl - prednisolone , immunoglobulin , and ect in patient 3 .
fdg - pet image were acquired 67 weeks after the onset of clinical symptoms ( acute phase ) and follow - up pet studies were performed at 1123 weeks from the onset of symptoms ( recovery phase ; patient 1 at 11 weeks , patient 2 at 23 weeks , and patient 3 at 21 weeks ) .
none of the patients had clinical seizures the day before the pet scans . to compare the brain area of metabolic change
, the brain images were normalised with the statistical parametric mapping software package ( spm2 ) with a 12 mm full width at half maximum ( fwhm ) . for single - subject analyses , the scaled fdg - pet brain image of a patient
was compared voxel - by - voxel with corresponding images from the age - matched normal control groups .
one - sided , two sample t - tests for detecting areas of hypermetabolism and hypometabolism was done with false discovery rate ( fdr ) < 0.05 in the acute phase ( multiple comparisons with voxel size > 100 ) and uncorrected p < 0.001 in the recovery phase ( multiple comparisons with voxel size > 100 ) .
the clinical symptoms and pet findings from the three patients are summarised in table 2 .
the pet images in all three patients showed the various extent of increased metabolism in the right frontotempoparietal regions including the right orbitofrontal cortex , in the right insular cortex , in the bilateral basal ganglia ( more prominent on the right side ) , in the cerebellum , and in the left frontal cortex depending on the severity of catatonia .
by contrast , increased metabolism was observed in the brainstem and right thalamus of patients 2 ( fig .
1c ) , with the increase being more prominent in patient 3 . widespread decreased metabolism in the bilateral occipital cortex and the various extent of hypometabolism in the frontal lobe was observed in all three patients .
follow - up pet showed normal finding in two patients ( patient 1 and 2 ) who did not show catatonia or tonic rigidity , but , showed mild increased metabolism in the right basal ganglia in patient 3 who showed mild intermittent rigidity and tonic posturing in the left extremities without behavioural abnormalities ( fig .
the results in our patients revealed that the extent of the metabolic changes in the pet images was well correlated with the severities of catatonia accompanied by behavioural and motor abnormalities .
hypermetabolism was observed in the frontotemporoparietal regions and bilateral basal ganglia in the mild catatonic patient , whereas the severe catatonic patient displayed more widespread and intense metabolic changes in the above mentioned areas and hypermetabolism in the thalamus and brainstem .
these results were consistent with previous reports , which found that only right frontolateral hypermetabolism or occipital hypometabolism is observed in less severe cases7 and that wider metabolic changes in severe cases.8 but , until now there have been no reports about brainstem involvement in severe cases .
anti - nmdar antibodies cause a selective and reversible decrease in surface nmdars , which results in variable clinical symptoms that depend on the extent of the decrease.5 decreased nmdar provokes frontostriatal syndrome through inactivation of gamma - aminobutyric acid ( gaba ) ergic neurons , orofacial and limb movements through disinhibition of a brainstem central pattern generator , breathing abnormalities through direct effects on the medullary - pontine respiratory network , and autonomic manifestations such as hypersalivation , hypertension , hyperthermia , and cardiac dysrhythmia through decreased regulation of dopaminergic , cholinergic , and noradrenergic systems.5 the extent of the affected brain areas by anti - nmdar antibodies was well correlated with the severity of clinical symptoms and with the extent of hypermetabolic changes in our cases .
although catatonia may be caused by gabaergic abnormalities in the orbitofrontal cortex that lead to dysfunctional dopaminergic interactions between the motor / premotor cortices and the subcortical basal ganglia,9,10 the pathogenesis and anatomical substrates of catatonia remain poorly defined .
the behavioural , emotional , and affective symptoms may correlate with dysfunctions in orbitofrontal cortical activity .
furthermore , the motor symptoms may be mediated by dysregulation of cortical - subcortical circuits between the motor / pre - motor cortices and the basal ganglia.9 in addition , alterations in the brainstem may underlie the severe vegetative symptoms.9 in this study , patient 1 displayed mild catatonic symptoms such as irrelevant speech , and tonic rigidity without displaying mutism , autonomic abnormalities , and breathing abnormalities .
these findings were correlated with increased metabolism in frontotemporoparietal regions and in both basal ganglia without hypermetabolism in the thalamus or the brainstem .
patients 2 and 3 displayed more severe catatonic symptoms that included mutism , rigidity , tonic posturing , and autonomic dysfunctions , demonstrating diffuse hypermetabolism in the above mentioned areas and in the thalamus , and in the brainstem .
patient 3 showed more severe motor symptoms such as opisthotonic posture , orolingual dyskinesia , and breathing abnormalities than patient 2 .
the most prominent difference between patients 2 and 3 was that patient 3 showed increased brainstem hypermetabolism .
in contrast , the extent of the hypometabolic changes was not markedly different among these three patients even though patient 2 and 3 slowed slightly wide hypometablic changes compared to patient 1 . taken together , these data suggest that the severity of catatonic symptoms may be associated with the extent of increased metabolism rather than decreased metabolism .
interestingly , patient 3 showed intermittent tonic rigidity in her left extremities without any behavioural abnormalities during the follow - up period .
these findings suggest that tonic rigidity in catatonia is likely caused by hypermetabolism in the contralateral basal ganglia even though the statistical threshold of the second pet study was lower than the first study at acute phase .
a previous study reported a patient with marked limb rigidity that showed basal ganglia hypermetabolism.11 in addition , reduced n - acetylasparatate was observed in the basal ganglia of a patient in the acute phase of anti - nmdar encephalitis.12 the results of these studies are consistent with our findings . in conclusion , the results of the present cases revealed that the extent of cerebral hypermetabolic changes correlates with the severity of catatonia accompanied by behavioural , motor , autonomic , and breathing abnormalities in anti - nmdar encephalitis patients .
the behavioural abnormalities were correlated with diffuse fronto - tempro - parietal , especially orbitofrontal , hypermetabolism , and tonic rigidity was correlated with hypermetabolism in the basal ganglia .
in addition , hypermetabolism in the brainstem may provoke more severe clinical symptoms such as hypoventilation and autonomic dysfunctions .
Output:
| catatonia is one of the main symptoms of anti - n - methyl - d - aspartate receptor ( nmdar ) encephalitis .
however , it is unknown whether metabolic changes observed with 18f - fluorodeoxyglucose positron - emission tomography ( fdg - pet ) are correlated with the severity of the catatonic symptoms and clinical course .
three patients with anti - nmdar encephalitis showing variable degrees of catatonia were performed with fdg - pet scans during the acute and recovery phase .
pet findings showed hypermetabolism in the frontotemporoparietal regions and bilateral basal ganglia in the patient with mild catatonia , but more widespread hypermetabolic regions including the thalamus and brainstem were observed in the patients with more severe catatonia .
follow - up pet scans in one patient showed mild hypermetabolism in the right basal ganglia that correlated with mild rigidity and tonic posturing in the left extremities .
extent of cerebral metabolic changes correlates with the severity of catatonia accompanied by behavioural , motor , autonomic , and breathing abnormalities in anti - nmdar encephalitis . |
PubmedSumm118517 | ***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: hrthle cell carcinoma ( hcc ) is a distinct and rare subtype of well - differentiated thyroid cancers .
the aggressive nature of hcc stems from the higher propensity for multifocality , lymph node ( ln ) metastasis and distant metastasis compared to the other types of well - differentiated thyroid cancer .
unlike the more common papillary thyroid cancer , hcc can not be diagnosed on fine - needle aspiration ( fna ) . rather , fna typically yields the diagnosis of hrthle cell neoplasm .
the definition of a neoplasm differs in the literature , with some recommending the presence of greater than 50% hrthle cells 1 , 2 , while others use greater than 75% 3 , 4 as the cutoff .
regardless of the percent cellularity , the presence of capsular and/or vascular invasion is required to make the diagnosis of hcc on histopathology .
attempts have been made to identify clinical parameters that can accurately predict the malignant potential of hrthle cell neoplasms.2 however , tumor size has been shown to be predictive of malignancy in several studies.1 , 5 - 7 our group previously demonstrated that the risk of malignancy in a hrthle cell neoplasm was 55% for tumors > 4 cm and only 13% for tumors
4 cm.5 this finding is corroborated in other studies that found that between 44%8 and 65%1 of neoplasms
> 4 cm were malignant . determining the malignant potential of hrthle cell neoplasm is important because it can change the initial surgical approach from a lobectomy to a total thyroidectomy .
the aim of this study was to determine if tumor size correlated with ln metastasis in patients diagnosed with hcc .
we retrospectively analyzed the records of all patients who underwent a thyroid operation at the university of california , san francisco from february 1997 to september 2008 .
patients who were diagnosed with hrthle cell carcinoma on final pathology were used for analysis .
patient demographics , preoperative imaging results , intraoperative findings , and postoperative outcome data were collected .
the institutional review board at the university of california , san francisco , approved the study .
a fine needle aspiration ( fna ) of suspicious thyroid nodules and/or lymph nodes was performed for diagnosis .
an ultrasound ( us ) of the neck was performed to evaluate the thyroid gland and lymph node basins .
the type of surgical procedure was dictated by clinical parameters : a thyroid lobectomy was performed on patients with a thyroid neoplasm and no contralateral thyroid nodules or suspicious cervical lymphadenopathy , with a completion thyroid lobectomy if final pathology revealed hcc ; a total thyroidectomy was performed on patients with a thyroid neoplasm and contralateral thyroid nodules or suspicious cervical lymphadenopathy ; a total thyroidectomy and cervical lymph node dissection ( central and/or lateral ) was performed when suspicious lymphadenopathy was found preoperatively on ultrasound , or during the operation .
during the study period , 39 patients were diagnosed with hrthle cell carcinoma . the majority of patients with hcc were women and the mean age at diagnosis of all patients was 58.7 years ( table 1 ) .
the preoperative diagnosis included 31 ( 79% ) patients with hrthle cell neoplasm , 3 ( 7% ) with thyroid goiter , 2 ( 5% ) with hcc , 2 ( 5% ) with follicular cell neoplasm and 1 ( 2% ) with graves ' disease .
four patients had risk factors for thyroid cancer ; 1 had a family history of thyroid cancer , and 3 patients had a history of radiation exposure . at the initial operation , 22 ( 56% )
patients underwent a thyroid lobectomy , 14 ( 36% ) total thyroidectomy , and 3 ( 8% ) total thyroidectomy and lymph node dissection .
patients who underwent an initial thyroid lobectomy underwent a subsequent operation for a completion thyroidectomy .
of the 3 patients who received a lymph node dissection , 1 had ipsilateral central ln metastases identified intraoperatively and underwent a central ln dissection , and the other 2 had lateral ln metastasis identified on preoperative ultrasound and underwent an ipsilateral central and lateral ln dissection . though there was no gender difference between the two groups , patients with ln metastasis were older than those without ( figure 1 :
similarly , patients with ln metastasis had larger tumors than those without ( figure 2 : mean size 6 and 4 cm , respectively ) .
tumor size was predictive of lymph node metastasis as no patient with tumor < 5 cm presented with lymph node involvement ( 3/15 with > 5 cm cancer had node metastasis , 0/24 with < 5 cm cancer had node metastasis ) .
all patients with lymph node metastasis had widely invasive tumors with capsular invasion , vascular invasion and multifocal disease .
of the 36 tumors without ln metastasis , 9 ( 25% ) were moderately - to - widely invasive , 14 ( 39% ) had capsular invasion , 20 ( 56% ) had vascular invasion , and 4 ( 11% ) were multifocal
our group previously showed that the overall rate of malignancy in fna proven hrthle cell neoplasms was 21% and that 55% of these tumors
for example , it has been suggested that a total thyroidectomy , rather than a lobectomy , be considered for older patients with tumors larger than 4cm.8 in this series , we sought to determine if the size of the hcc tumor could predict the presence of ln metastasis . in our patient cohort ,
this is similar to other reported rates of 3% to 13%.3 , 9 others , however , have report higher rates of 18% to 25%.10 , 11 despite the associated risk of ln metastasis in patients with hcc , no studies have shown that hcc size predicts ln involvement .
patients who presented with ln metastasis had larger tumors than those who presented without ln metastasis .
interestingly , no patients with cancers < 5 cm presented with ln metastasis . on the other hand , 20% of patients with cancers
this study also demonstrates that all patients with ln metastasis had widely invasive and multifocal tumors .
this finding has been corroborated in another study that demonstrated that all seven patients with ln metastasis had widely invasive hcc.9 the presence of capsular invasion or vascular invasion , however , did not predict ln involvement . though hcc commonly affects women
more often than men , gender was not an associated risk factor for developing ln metastasis .
older age is considered a risk factor for malignancy in patients with hrthle cell neoplasms.8 similarly , we found that advanced age was a risk for the presence of ln metastasis in patients with hcc .
specifically , all of our patients who presented with ln metastasis were octogenarians ( figure 1 ) .
this finding suggests that older patients with large hcc are at risk for developing lymph node metastasis . in summary , as size has been shown to predict the malignant potential of hrthle cell neoplasms and this study demonstrate that size and age are also predictive of ln metastasis in patients with hcc .
our data suggest that consideration should be given to performing a prophylactic ipsilateral central neck dissection at the time of their initial operation in older patients with large tumors .
Output:
| introduction : hrthle cell carcinoma ( hcc ) is a rare tumor that tends to metastasize to the lymph nodes .
some studies have correlated size of hrthle cell tumors with the risk of malignancy .
whether the size of hcc correlates with the risk of lymph node ( ln ) metastases , to our knowledge has not been addressed.methods : a retrospective analysis was performed on all patients diagnosed with hcc on final pathology between 1997 and 2008 . the tumor size and lymph node status
was obtained for each patient .
the data were analyzed utilizing student 's t - test and the fisher 's exact test to calculate the two - tailed p-value.results : out of 39 patients diagnosed with hcc 3(8% ) had ln metastases ; 1 had ipsilateral central ln metastasis and 2 had ipsilateral central and lateral ln metastasis .
ln dissection was performed in patients with known metastasis ( 2 were evident on preoperative ultrasound and 1 intraoperatively ) .
patients with ln metastasis were older than those without ( mean age : 86.7 and 56.4 years , respectively ) , had larger tumors ( mean size : 6 and 4 cm ) and were commonly male ( 2 of 3 ) .
no tumor < 5 cm presented with lymph node involvement ( 3/15 with > 5 cm cancer had node metastasis , 0/24 with < 5 cm cancer had node metastasis).conclusions : similar to what has been found in patients with papillary thyroid cancer , older male patients with hrthle cell carcinomas greater than 5 cm are more likely to have lymph node metastasis .
our data suggest that these patients may benefit from a prophylactic ipsilateral central neck dissection at the time of their initial operation . |
PubmedSumm118518 | ***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: rhabdomyolysis , a syndrome of skeletal muscle cell damage , engenders the release of toxic intracellular materials into systemic circulation 1 .
the pathogenesis of rhabdomyolysis is based on an increase in free ionized calcium in the cytoplasm 1 .
prompt diagnosis requires routine monitoring of serum creatine kinase ( ck ) activity in a patient with a suggestive history or clinical features 1 .
serum concentrations of alanine ( alt ) and aspartate ( ast ) aminotransferases have been regarded as markers of liver injury 2 .
measurement of alt and ast enzymatic activity is still most commonly done to evaluate putative liver injury 2 .
blood concentrations of alt and ast reflect liver cell membrane damage , with subsequent leakage of intracellular enzymes into circulation , especially the cytosolic ones 2 .
transaminases are reliable predictors of individual components including type 2 diabetes and decreased hepatic insulin sensitivity , coronary heart disease , atherothrombotic risk profile , and overall risk of cardiovascular and metabolic disease 2 . therefore , routine testing of aminotransferases alt and ast is now regarded as an indicator of liver metabolic function 2 .
a 40yearold man diagnosed with schizophrenia at the age of 17 had functioned stably in his community for more than two decades .
he was admitted to our hospital because of auditory hallucinations , delusions , and chaotic and aggressive behavior . for 2 weeks
when admitted , he presented abnormal behavior , agitation , selftalking , selflaughing , and aggression in the quiet room .
at 165.8 cm height , his weight was 58.5 kg , implying his body mass index ( bmi ) as 21.3 kg / m .
physical examination revealed 147/105 mmhg blood pressure , 113 beats / min heart rate , and 36.3 c body temperature .
baseline tests such as those of serum electrolytes , urine examination , thyroid hormones , chest xray , brain ct , and electrocardiography all yielded normal results . results of the main initial laboratory evaluations are presented in the table 1 : serum ck , 6622 iu / l ; serum ast , 208 iu / l ; alt , 68 iu / l ; and serum myoglobin , 1644 ng / ml . on the 2nd day , he was diagnosed with rhabdomyolysis .
intravenous infusion containing 35 mmol / l sodium chloride with 20 mmol / l potassium chloride ( solita t3 ) was started at a rate of 100 ml / h , accompanied by restriction of oral fluids under physical restraint .
therefore , we were unable to prescribe it to the patient because of elevated concentration of serum creatine kinase
the individual value curve for ck , ast , alt , alkaline phosphatase ( alp ) , and glutamyl transferase ( ggt ) during hospitalization is shown in the fig .
1 . actually , ck fell rapidly on the 4th day , although ast and alt started to increase rapidly and mutually in parallel .
the respective values of ck , ast , alt , alp , and ggt on the 8th day were 715 , 388 , 582 , 212 , and 43
blood liver function tests were normal : total bilirubin , 1.02 mg / dl ; cholinesterase , 221 iu / l ; hepaplastin test , 73% ; and international normalized ratio ( inr ) of 1.36 .
viral serology tests for hepatitis b and c were negative ( table 1 ) . on the 15th day , ast and alt decreased rapidly . on the 15th day , risperidone therapy , at a dose of 4 mg / day , was started to treat his hallucinations and his chaotic and aggressive behavior . on the 19th day
on the 22nd day , ck was normal , but alp , alt , ast , and ggt were elevated as shown in the fig .
1 . subsequently , we changed to slowrelease paliperidone 6 mg / day to treat his hallucinations and because of difficulty swallowing risperidone . from the 28th day , because his liver damage was suspected to have occurred as an adverse effect of risperidone therapy , blonanserin 8 mg / day was used instead .
he was discharged in a stable condition with normal serum aminotransferases on the 67th day .
his psychiatric condition and his health condition have remained stable . selected laboratory parameters time course changes of serum enzymes in the patient : green line , creatine kinase ( ck ) ; blue line , aspartate transaminase ( ast ) ; red line , alanine aminotransferase ( alt ) ; yellow line , glutamyl transferase ( ggt ) ; and black line , alkaline phosphatase ( alp ) .
the schizophrenic patient showed sudden onset of rhabdomyolysis . the intermixed pattern of intrahepatic and extrahepatic causes of alt elevation is associated with respective clinicaltherapeutic events .
iu / l ) ratio > 3 , which , taken together with a normal alp and ggt indicate an extrahepatic source of transaminitis .
the most common causes of rhabdomyolysis are illicit drugs , medical drugs , muscular diseases , trauma , neuroleptic malignant syndrome , seizure , and immobility 4 .
his past medical , medication , and family histories , respectively , rule out potential drug abuse , behavioral peculiarities such as psychogenic polydipsia and polyphagia , and genetic myopathy .
systemic bacterial infection is unlikely in the absence of inflammation of the blood chemistry tests .
unfortunately , we failed to ascertain what occurred with this patient immediately before admission . because excessive physical activity is a major cause of rhabdomyolysis in psychiatric patients 1 , somewhat elevated ck concentration might result from his excessive physical activity and concurrent interruption of routine medication .
second , the intermixed pattern of intrahepatic and extrahepatic causes of alt elevation is associated with respective clinicaltherapeutic events . given shorter halflives of ck and ast and the resuscitative measures undertaken for treating rhabdomyolysis 2 , 4 , 5 , 6 , 7 , serum concentrations of ck and ast improved more rapidly than alt during the first few days , as shown in the table 1 and fig .
antipsychotic therapy started immediately after admission can be expected to cause liver dysfunction , which might explain the hepatotoxic pattern of overlapped elevation of alt more than ast on days 48 of hospitalization that might be completely unrelated to rhabdomyolysis .
this hypothesis is supported by a concomitant elevation of alp and ggt ( liver function biomarkers ) and a continuous decrease in ck ( rhabdomyolysis marker ) , as shown in the fig . 1 and table 1 .
consequently , this allegedly unusual and mysterious elevation of transaminases that is believed to result from psychotic rhabdomyolysis might reflect intermixed patterns of intrahepatic and extrahepatic causes of alt elevation associated with respective clinicaltherapeutic events .
two isoforms of alt are alt1 and alt2 . actually , alt1 and alt2 appear to have not only different tissue sources but also cellular localization , suggesting dissimilar biological roles in the pathogenesis of acute or chronic liver disease 2 .
alt1 is encoded by a gene of gpt1 located in chromosome 8 ( 8p24.3 ) , but alt2 is encoded by a different gene of gpt2 located in chromosome 16 ( 16q12.1 ) 2 .
alt1 , which is expressed primarily in liver 8 , and alt2 , which is expressed primarily in muscular tissue 9 , can not be discriminated using current biochemical tests measuring serum alt 2 .
if two isoforms of alt were applicable in clinical practice , then it might stimulate further insight into how these conflicting observations of seemingly unrelated clinical and biochemical events are explainable and reconciled . in conclusion , facts associated with this case support the emerging evidence that aminotransferases are surrogate biomarkers of liver metabolic function beyond the classical concept of liver cellular damage because their enzymatic activity might actually reflect key aspects of the physiology and pathophysiology of the liver function 2 .
Output:
| key clinical messagea schizophrenic patient showed rhabdomyolysis with idiopathic transaminitis .
the intermixed pattern of intrahepatic and extrahepatic alanine aminotransferase ( alt ) elevation is associated with respective clinicaltherapeutic events .
aminotransferases play a role as surrogate biomarkers of liver metabolic functioning beyond the obsolete classical concept associating alt elevation only with liver cellular damage . |
PubmedSumm118519 | ***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: traumatic macular holes can have various clinical courses : some close spontaneously , while others persist without treatment.1 recent papers have reported the efficacy of vitrectomy for treatment of traumatic macular hole.2,3 however , the role of vitrectomy is not well established .
recent studies have shown a higher closure rate of macular holes with internal limiting membrane ( ilm ) peeling than with the conventional method.46 ocular blunt trauma sometimes results in not only a macular hole but also choroidal rupture .
the choice of treatment is more controversial in such cases than when there is a macular hole only .
the authors present a rare case of severe chorioretinal rupture with closed globe injury that achieved a good outcome through early vitrectomy with ilm peeling .
a 22-year - old woman was hit in her left eye with a beer bottle .
initially , when she visited the emergency room , the eyelids were swollen , and the snellen visual acuity ( va ) was 30/20 in the right eye and 3/100 ( 2/20 when wearing 6.5 dioptors ) in the left eye , due to injury - induced high myopia , hyphema , and vitreous hemorrhage .
ophthalmoscopic examination revealed both a crescent - shaped retinal rupture near the macula three disc diameters ( dds ) in size and a choroidal rupture six dds in size that was over the vascular arcade .
subretinal hemorrhage near the disc , limited retinal detachment in the temporal fundus of the disc , and peripheral retinal edema were observed ( figure 1a and b ) .
fluorescein angiography revealed a window defect of the ruptured area , leakage in the temporal retina near the macula , and blocked fluorescence .
goldmann perimetry revealed expansion of marriott scotoma , a crescent - shaped scotoma within 20 , and a nasal peripheral visual field defect .
optical coherence tomography revealed rupture and subsidence of the retina and choroid , and a retinal detachment ( figure 1c ) .
the patient underwent 20-gauge pars plana vitrectomy 3 days after the injury . after removing the vitreous core ,
a posterior vitreous detachment was created , followed by ilm peeling over the vascular arcade using indocyanine green staining .
fluid - air exchange was performed , followed by filling the eye with 20% sulfur hexafluoride gas .
five days postoperatively , closure of the ruptured retina was confirmed ( figure 1b ) .
four months after surgery , va had improved to 12/20 when wearing 2.5 diopters , and myopia was decreased .
fluorescein angiography revealed late - phase staining at the site of the retinal rupture and a window defect at the site of the choroidal rupture .
optical coherence tomography revealed closure of the ruptured retina , but the choroid and retina showed subsidence , and the rpe layer had thickened ( figure 1d ) .
goldmann perimetry revealed a decrease of the central scotoma , but the nasal crescent - shaped scotoma had become slightly larger .
microperimetry ( mp-1 microperimeter ; nidek co , ltd , aichi , japan ) revealed that retinal sensitivity at the ruptured area and superior temporal region of the macula was 0 db ; however , the fixation point at the nasal region of the macula was detected with the mp-1 microperimeter ( figure 1e and f ) .
va had improved to 16/20 when wearing 1.0 diopters at 12 months post injury , and visual function was maintained for 48 months postoperatively .
recently , ilm peeling has been performed to increase the success rate of vitrectomy . in general ,
, there have been no reports on the treatment of large retinal ruptures caused by blunt trauma .
observation without treatment for 13 months following injury is the normal course for small traumatic macular holes , as spontaneous closure of traumatic macular holes is common .
however , in the current case , the retinal rupture was three dds in size and the choroidal rupture was six dds .
the authors considered that vitreous tamponade alone would not be able to close the retinal break , and therefore chose to perform vitrectomy soon after the injury .
the purposes of vitrectomy were to remove the vitreous traction to close the retinal break and to permit gas tamponade .
the width of the retinal break was large , one dd , so the ilm was removed to decrease tangential traction .
although , this case presented a severe retinal rupture and a choroidal rupture , favorable va of 16/20 was acquired .
yeung et al7 reported a closed globe injury with choroidal rupture , but final va in their case was poor : counting fingers to 20/60 .
miyake and ando8 reported that the visual outcome was poor unless vitrectomy was performed within 2 months of injury .
the good outcome in this case might have been because of the early surgical intervention to prevent scarring at the macula , and peeling the ilm to remove tractional force and cell proliferation . additionally , it was fortunate that the rpe atrophy was spared at the macular area . however , some visual field defect remained , because the nerve fiber layer was disrupted .
the mp-1 microperimeter was very useful in this case for checking and following the retinal sensitivity . as there have been reports of choroidal neovascularization after choroidal rupture
the results suggest that vitrectomy with ilm peeling early after injury can be considered for severe blunt chorioretinal rupture .
Output:
| the authors present a rare case of large chorioretinal rupture caused by blunt traumatic injury of the globe . a 22-year - old woman sustained a blunt injury to her left eye
. the best - corrected snellen visual acuity was 2/20 in her left eye , and hyphema and vitreous hemorrhage were noted .
the day after the injury occurred the vitreous hemorrhage had disappeared .
fundus examination revealed a crescent - shaped retinal rupture three disc diameters in size near the macula , and a choroidal rupture six disc diameters in size that was over the vascular arcade .
three days after the injury , vitrectomy with internal limiting membrane peeling was performed .
postoperative prone positioning was maintained for 4 days .
five days postoperatively , closure of the ruptured retina was confirmed .
the visual acuity improved to 16/20 4 months after surgery and this was maintained over a 48-month period . in conclusion ,
early vitrectomy with internal limiting membrane peeling after injury was effective for a case involving severe blunt chorioretinal rupture with closed globe injury . |
PubmedSumm118520 | ***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 rapid pace of progress made by laparoscopic surgeons , however , has resulted in some concern and criticism as the role of operative laparoscopy has continued to be redefined .
for instance , many conditions considered to represent absolute contraindications for laparoscopy only a short time ago are now accepted as indications for this method of intervention .
these conditions include obesity , severe adhesions , previous laparotomies , cancer , abdominal hernia , pregnancy , and bowel perforation with generalized peritonitis .
a growing experience with operative laparoscopy is also evident from the fact that few operations still necessitate laparotomy , for example , organ transplants and massive debulking .
complicated cases such as removal of large uteri or the presence of severe adhesions or endometriosis are now routinely performed with laparoscopic assistance .
similarly , certain operative complications such as injury to the ureter , or blood vessels can be safely treated laparoscopically by the experienced surgeon .
technology still exerts a strong influence on operative laparoscopy , as witnessed by the recent introduction of small diameter laparoscopes that offer good resolution and light intensity .
this technologic breakthrough has made laparoscopy suitable even for patients who can not withstand general anesthesia .
small diameter laparoscopy can be offered for emergency diagnosis and management of patients presenting with acute hemodynamic instability and suspected active intra - abdominal bleeding due , for instance , to an ectopic pregnancy .
small diameter laparoscopy is likely to be adopted as a critical bedside diagnostic tool , and even as an office procedure in certain settings , in the near future .
the concerns raised following the generally successful introduction of operative laparoscopy stem to a large extent from the very nature of surgical research .
the introduction of new forms of medical treatment is regulated by federal agencies demanding prolonged , multi - phase study schemes .
in contrast , new surgical procedures are usually developed by individual surgeons without controlled comparative research protocols and though randomization has been advocated in surgical trials , few surgeons view this as a realistic suggestion .
even experienced surgeons must undertake a number of operative procedures before they feel comfortable in performing that procedure .
thus , comparing new laparoscopic operations to conventional procedures demands completing a certain learning stage .
the challenge of introducing new surgical techniques is further complicated by the difficulty in recruiting a sufficient number of patients to provide adequate statistical power to reveal differences in outcome .
in addition , it can be difficult to gather a large , typically heterogeneous group of surgeons who are familiar enough with a new surgical procedure to lend validity to the study . if the surgeons differ in skill and technique when performing either the conventional or the laparoscopic operation , the validity of the results may be biased .
on the other hand , restricting randomized studies to a limited group of expert surgeons will usually limit this source of bias , but it will decrease the ability to generalize the results . randomizing the patients in
blocks - for each individual surgeon - may improve the ability to control for the effect of variation in surgical skill and experience .
these difficulties commonly result in simpler surgical procedures being studied first in a randomized fashion .
this occurred in the study of laparoscopic surgery , with simple procedures , such as insertion of trocars , first studied in a randomized fashion .
subsequently more complex procedures , such as hysterectomy , were the subject of randomized trials . the implementation of large multi - center studies , the gold standard of evidence based medicine , has been rarely utilized for laparoscopic surgery .
the implementation of complex trials is often curtailed by the difficulty in obtaining the necessary funding and medical insurers are very reluctant to approve financial coverage to a
the need to evaluate the outcome of some operations with a second - look laparoscopy is even less likely to be covered by managed care organizations .
the use of a placebo or a sham operation is especially important when the outcome is subjective improvement of symptoms , such as pelvic pain .
although laparoscopic sham procedures occasionally have been used with success in a blinded and randomized manner , few insurers currently agree to pay for a trial of blinded sham versus real procedures and it can be very difficult to persuade patients to do so . unlike the introduction of new drugs , little direct profit results from such studies .
major sources of funding , such as the pharmaceutical companies , are therefore less involved with surgical research , unless the use of specific new instruments is examined .
it is understandable that when the effects of treatment are large , and their value self - evident , randomized trials may not be necessary to confirm these observations .
the benefits of laparoscopy compared to laparotomy , however , fall mostly within the frame of improving quality of life and do not substantially affect survival .
for example , while the life - saving role of surgical treatment for ectopic pregnancy did not require a randomized trial to prove its merits , the benefits of using laparoscopy over laparotomy to treat ectopic pregnancies clearly justify such a controlled study . however , the obvious advantages of laparoscopy in terms of rapid recovery and superior cosmetic results led to strong patient demand and rapid adoption of these techniques into general practice .
thus , by the time randomized trials were designed , few patients were willing to undergo surgery using a large abdominal surgical incision .
even when two types of laparoscopic operations are compared , patient consent may not be readily given .
it has been very difficult to randomize patients to undergo either laparoscopic supracervical or total hysterectomy , since many patients have a clear opinion regarding what is best for them , despite the fact that the relative merits of both procedures have not yet been definitely proven .
the highly technical nature of laparoscopic surgery and the rapid rate with which new instruments are introduced , require a high intensity of surgical training . at a time when growing numbers of procedures are being performed on an outpatient basis
, few residency programs can adequately prepare their residents for independently undertaking advanced laparoscopic surgery .
the situation is further accentuated by the overall decreasing number of operations performed because of improved medications replacing surgical procedures , such as methotrexate for ectopic pregnancy , or the application of less invasive surgical procedures such as endometrial ablation instead of hysterectomy for menorrhagia . as the degree of training and experience
strongly correlate with complication rates , the success of laparoscopy is very much dependent on the surgeon 's skills .
future training programs must find a way to include participation in a substantial number of surgical procedures which is essential for acquiring proper technical skills and for gaining adequate knowledge of patient selection , preparation for surgery , and postoperative care .
many procedures can be simplified by combining laparoscopic surgery with either vaginal procedures or a minilaparotomy .
this hybridization reduces the need for intracorporeal suturing and lengthy removal of tissue from the abdomen .
many common gynecologic operations , such as myomectomy or cystectomy , can be easier to perform if the superior exposure provided by laparoscopy to explore the abdomen is first utilized .
the ovary or fibroid can then be grasped and an extracorporeal conventional procedure can be completed through a minilaparotomy incision .
laparoscopy has attracted more criticism than any other form of surgery , despite the fact that the difficulties in evaluating new surgical procedures are not unique to this approach .
the results of large , uncontrolled series currently attest to the efficacy , safety and practicality of all major forms of laparoscopic pelvic surgery .
the continuing acceptance of laparoscopy is likely to depend on better randomized trials as insurers will demand more concrete evidence of its superiority over conventional surgery .
laparoscopy has come to a point where the experienced surgeon can successfully perform almost every known surgical procedure .
for example , one of the most challenging surgical procedures is the management of extensive endometriosis of the pelvis , especially when it extends to the parametrium and involves the ureter and rectovaginal septum . in this instance
, a multidisciplinary team including gastrointestinal , genitourinary , and gynecologic ( pelvic ) surgeons are often required .
we believe as years go by and the experience of surgeons increases , laparotomy will be performed less and less .
future generations of surgeons will not have to learn laparotomy first and then progress to laparoscopy .
time will prove that learning operative laparoscopy is preferable to laparotomy and the complications of operative videolaparoscopy are less than those of laparotomy .
even most complications of operative videolaparoscopy will be managed by this method and not by laparotomy .
as acknowledged above , only a few exceptional operations , such as extensive tumor debulking , removal of giant tumors and organ transplants , will demand a large laparotomy exposure . however ,
even portions of these procedures can be assisted by the laparoscope , which may reduce the size of the incision .
extending the many benefits of minimal access surgery to an ever growing number of patients is greatly dependent on our ability to provide proper training in advanced operative laparoscopy .
this trend will continue until video - assisted operative laparoscopy replaces laparotomy in almost all cases .
in the united states , our best estimate suggests this reality will occur by the year 2020 .
Output:
| the continually changing definition of operative laparoscopy as well as the ever - widening boundaries of its use are discussed in this report .
it is important to prepare residents to adequately undertake advanced laparoscopic surgery as laparotomy is gradually replaced by laparoscopy for many routine procedures . since degree of training and experience strongly correlate with complication rates , more focus on laparoscopy during graduate education would be beneficial to residents in order to keep them up to date with the rapid development of this field . |
PubmedSumm118521 | ***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 77-year - old female visited our clinic with a chief complaint of painful swelling in the submental area which had begun 2 days ago .
the patient had been treated for pulmonary edema caused by asthma and aspiration pneumonia from 7 years ago , and she was currently being treated for pyelitis , cerebral infarction , dementia and herpes zoster .
clinical examination showed several root rests , gingival swelling on the entire dentition , redness and pus discharge in the upper and lower anterior teeth , induration , redness , and tenderness to palpation on the submental area . also , bilateral bone exposure on the lingual mandible suggested osteomyelitis .
clinical and radiographic examinations including panoramic radiograph were carried out . on the panoramic radiograph , several dental caries
were observed , as well as periapical abscess on the right maxillary lateral incisor and right maxillary first molar .
extraction sockets were also observed . ill - defined bony destructive change on the left mandibular canine area with sclerotic change of surrounding trabecular bone was found ( fig .
incision and drainage was carried out under local anesthesia and a drain was inserted lingually , however pus drainage was poor .
on the next day , dysphasia and dyspnea were intensified . soft tissue neck anteroposterior view and oxygen saturation was examined . on the radiographic image ,
immediate endotracheal intubation was carried out and the oxygen saturation was stabilized at 96% , with no other problem on vital sign .
blood test revealed high inflammation values with white blood cell at 18,110/mm and c - reactive protein at 33.23 mg / dl .
infusion and antibiotic treatment ( amoxicillin - potassium clavulanate , isepamicin sulfate , and metronidazole ) was carried out .
contrast - enhanced ct images showed non - enhanced low attenuated region with the irregular periphery of non - homogeneous enhancement on the right submandibular space ( fig .
3 ) . also , these findings were found similarly in the bilateral submental and the left submandibular spaces .
there was enhanced soft tissue swelling in the nasopharynx , oropharynx , and the inferior pharynx .
extraoral incision and drainage on the submental area was immediately carried out under general anesthesia .
after surgery , saline with povidone - iodine irrigation in the drain insertion area was carried out twice a day .
however , the follow - up contrast - enhanced ct revealed that pus had spread widely to the posterior area of the right sternocleidomastoid muscle , retropharyngeal space , parapharyngeal space , hyoid bone area , and prevertebral space ( fig .
4 ) . due to the increasing necrotizing area and the deep spread of the infection ,
the previous drains were removed and further submental necrotized area was excised under general anesthesia .
an incision was made 6 cm below the anterior border of the right sternocleidomastoid muscle , and the pus formation space was reached and irrigated .
drains were inserted from the superior border of the left clavicle to the left mandibular border , from the submental area to intraoral area and to the right mandible border , and from the anterior border of the right sternocleidomastoid muscle to the interclavicular area .
intraoral drains were inserted in the right submandibular area and in the right pterygomandibular space .
after the second surgery , saline with povidone - iodine irrigation in the drain insertion areas was continued twice a day .
another follow - up contrast - enhanced ct showed reduced pus formation in the submental area , right parapharyngeal space , and retropharyngeal space .
blood test resulted in decreased inflammation , however the edema in the airway and the pus formation around the hyoid bone were still found .
an incision was made on the hyoid bone area . when the hyoid bone was completely reached , a small amount of pus discharge was observed .
after vigorous irrigation , additional drains were inserted in the right sternocleidomastoid muscle incision area in the direction of the hyoid bone , the interclavicular area and above the right clavicle .
after surgery , the drains were irrigated with saline mixed with antibiotics ( ceftriaxone 1 g , hanmi pharm , seoul , korea ) twice a day .
5 ) showed that pus formation in the right submandibular and submental area had almost completely disappeared , as well as the parapharyngeal and the retropharyngeal space .
the edema in the airway was also reduced , therefore the endotracheal tube was removed .
appointment for treatment plans regarding the mandibular osteomyelitis that was observed on the follow - up ct was scheduled .
among odontogenic infections that lead to deep space abscess , mediastinitis and necrotizing fasciitis of the neck are known to be secondary complications which can be life threatening .
patients with odontogenic infection who require incision and drainage in the oral maxillofacial region are normally affected with more than one myofascial space .
generally , submandibular , submental , and parapharyngeal space are affected.3 when head and neck infection spreads to the fascia and the subcutaneous tissue , necrotizing fasciitis may occur and sometimes follow a deeper infection path .
the more caudal the infection spreads , the more likely the severe complications such as mediastinitis may occur .
infection spreads along the fascia and affects the subcutaneous tissues , myofascia , skin and muscles.4 this type of infection is very rare in head and neck region and odontogenic infection causes it even rarer .
the fatality rate was reported to be 20 - 75%.5 deep neck infection can also arise from infections of the teeth , glands , and neck lymph nodes , however odontogenic causes are few.6 such infections spread to the parapharyngeal and retropharyngeal space to obstruct the airway , or take an upper path to form brain abscess , or when it spreads along the carotid sheath , fatal long - term complications such as bleeding due to vessel damage may occur .
bonapart et al7 stated that the main routes of neck infection spreading to the mediastinum were the prevertebral space , which connected to the anterior part of the mediastinum , and the retropharyngeal and viscerovascular space , which lead to the posterior part of the mediastinum and the diaphragm . in this report
, the infection had spread to the parapharyngeal space and the prevertebral space , but not to the mediastinum . for evaluation of deep neck space infection , ultrasound , mri , and radiographic examinations such as soft tissue neck x - ray
the soft tissue neck x - ray is the most convenient method , and it is especially useful for evaluating the retropharyngeal space and the prevertebral space since it allows the measurement between the anterior part of the vertebrae and the posterior wall of the pharynx . in the present case , when the patient was displaying dyspnea , the soft tissue neck anteroposterior view allowed the evaluation of the airway obstruction and its following treatment .
however , using the soft tissue neck x - ray alone for the diagnosis , gives 33% of false negative rate , meaning that other imaging evaluation method is required for a more accurate clinical diagnosis.8 ultrasonography has been used to detect abscess cavities , although the anatomic detail provided by ct makes it superior in confirming the presence of an abscess.9 mri can provide more detailed anatomic structures , and can detect infected spaces which have been indefinable on ct images .
however , the high cost , time for image processing , and the cooperation required from the patients are the disadvantages.10 contrast - enhanced ct images clearly delineate the position and size of the lesion as well as its relationship with the adjacent anatomic structures . also , it is useful in evaluating any changes in the upper airway in patients with trismus or with parapharyngeal or retropharyngeal space abscess .
the images provide valuable information in deciding the method for maintaining the airway such as endotracheal intubation , cricothryoidotomy , or tracheostomy.11 on ct images , the attenuation level of space abscess is between that of water and soft tissues . when a contrast medium is used , a rim enhancement around the abscess area is observed .
swelling of the adjacent muscles signifies the spreading of inflammation in the surrounding area.12 in the present case , the contrast - enhanced ct was used to identify the spreading of pus into deeper spaces after initial treatment , and for guiding extensive incision and drainage under general anesthesia to prevent further expansion .
also , follow - up cts were used to evaluate the edema of the airway and to determine the timing for endotracheal extubation . for effective treatment of deep space abscess ,
early accurate diagnosis and its appropriate treatment mandatory , and for necrotizing fasciitis , absolute understanding of the anatomical structures in the infection area and active surgical treatment along with intensive antibiotic treatment is necessary . in our case , since the patient state was in severe , the urgent infection was treated with antibiotics for a long term , and sequestrectomy and decortication of the exposed bone in the oral cavity was sufficient for satisfying results instead of extensive mandibulectomy . in conclusion ,
when the infection spreads to the deep neck area , especially contrast - enhanced ct would be useful to observe every fascial space and to locate abscesses effectively in the head and neck area .
Output:
| the advent and wide use of antibiotics have decreased the incidence of deep neck infection .
when a deep neck infection does occur , however , it can be the cause of significant morbidity and death , resulting in airway obstruction , mediastinitis , pericarditis , epidural abscesses , and major vessel erosion . in our clinic , a patient with diffuse chronic osteomyelitis of mandible and fascial space abscess and necrotic fasciitis due to odontogenic infection at the time of first visit came .
we successfully treated the patient by early diagnosis using contrast - enhanced ct and follow up dressing through the appropriate use of radiographic images . |
PubmedSumm118522 | ***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: colorectal cancer screening is known to contribute to reduction of incidence and mortality of colorectal cancer through detection of precursor lesions of cancer or early stage cancer , and the five - year survival rate of colorectal cancer diagnosed early was reported to around 90% ( 1,2 ) . in addition , the screening has declined mortality of the cancer . in 12 to 18 years after beginning of cancer screening ,
the mortality rate of colorectal cancer became lower by 16% ( 3 ) and it was found to reduce mortality rate of persons aged 50 to 75 years ( 4 ) . in korea , 2007 annual report of korea central cancer registry showed that the incidence rate of colorectal cancer ranked third in males by recording 49.7 per 100,000 population and the rate recorded the fourth highest level or 33.9 per 100,000 population in females ( 5 ) .
in particular , the incidence rate of colorectal cancer had increased every year and its mortality rate also tended to rise ( 5,6 ) .
many researches insisted that because colorectal cancer had very long biological natural history as an advanced cancer ( 7 ) and long symptom - free interval but it could be treated through early detection , screening and preventive treatment were effective ( 8,9 ) . for the national cancer screening program to detect and treat cancer early and to decrease mortality of cancer in south korea , stomach , breast and cervix cancer screening have been conducted for medical aid beneficiaries , whose medical accessibility is weak , since 1999 . in 2002
the target population was extended to medical aid beneficiaries and a low - income bracket paying lower 20% premiums among the national health insurance subscribers . in 2003
, liver cancer screening was added and the target population became larger by including people paying lower 30% premiums among the total subscribers . in 2004 by adding colorectal cancer screening , the cancer screening program for five major cancer ( stomach , liver , colorectal , breast and cervical cancer ) was established ( 10 ) . since the range of target population was enlarged to medical aid beneficiaries and people paying lower 50% premiums among the people insured by national health insurance , the program has been maintained up to 2008 .
the national colorectal cancer screening began in 2004 , and males and females aged over 50 years take fecal occult blood test ( fobt ) every year and participants with a positive result undergo an additional screening such as colonoscopy and double - contrast barium enema test ( dcbe ) .
although studies on tests for colorectal cancer screening and their meaning and cost - effectiveness have been partially reported , researches on the current situation of the national colorectal cancer screening program are still insufficient .
in addition , we investigated the process of the colorectal cancer screening and characteristics of screening tests by analyzing participation rates according to test methods .
this study utilized the database of target population and participants of colorectal cancer screening of 2008 national cancer screening program .
the target population was adults aged over 50 years among medical aid beneficiaries and national health insurance subscribers .
for the subscribers , they or their dependants who paid lower 50% premiums based on those of november , 2007 ( monthly 67,800 or less than 67,800 won for employee insured and 56,500 or less than 56,500 won for self - employed insured ) , were included in this study .
when the data about the monthly premiums did not exist , the target population were selected by considering current premiums compared to those on the standard month ( 11 ) . according to the inclusion criteria , totally 7,522,452 were the total target population of colorectal national cancer screening program and out of them 4,640,365 were the target population of colorectal cancer screening in 2008 .
colorectal cancer is recommended to be screened every year and fobt was performed as a primary screening test by using fecal immunochemical tests ( reversed passive haemagglutination assay [ rpha ] or latex agglutination test ) or fecal porphyrin quantification . for the participants with a positive result in fobt , colonoscopy or dcbe test
when dcbe result had abnormal findings ( polypus , probably cancer , colorectal cancer and other diseases than cancer ) , colonoscopy was conducted additionally .
when colonoscopy found abnormal findings ( polypus , suspected colorectal cancer , colorectal cancer and others ) biopsy was utilized according to decision of a physician ( 11 ) . to analyze the current situation of colorectal cancer screening ,
the participants were defined as persons with at least one among a result of fobt , a result in colonoscopy , result in dcbe , a result of biopsy or a result of final outcomes in screening record . out of 985,148 with at least one of them in the record , 984,915 were recruited as participants in 2008 by excluding 111 ones aged less than 50 years , 101 ones thought as persons not screened without personal information and 21 already diagnosed cancer patients . in summary ,
the target population and the participants of colorectal cancer screening of the colorectal national cancer screening program in 2008 were 4,640,365 and 984,915 , respectively .
age was divided into subgroups by five years with the subjects aged over 50 years and the elderly aged 75 years was analyzed as a subgroup .
region was divided into 16 cities and or provinces by using the specific number of organizing public health centers .
the results of screening were classified based on contents of the result sheet reported to national health insurance cooperation . in the sheet ,
final outcomes of colorectal cancer were ' normal ' , ' need a follow - up ' , ' need diagnostic work - up for cancer ' , ' need treatment for cancer ' and ' other diseases than cancer ' . '
normal ' meant that a result of biopsy , colonoscopy or double - contrast barium enema test was normal or that fobt showed a negative result . '
need a follow - up ' was written when biopsy revealed inflammatory , hyperplastic or pathologic findings , low / high grade adenoma or dysplasia , when colonoscopy or double - contrast barium enema test found polypus or when fobt result was positive . '
need diagnostic work - up for cancer ' meant that colorectal cancer was suspected and inspection was needed immediately , and ' need treatment for cancer ' showed that colorectal cancer was diagnosed and treatment for it was necessary immediately . ' other diseases than cancer ' was written for other diseases not related with colorectal cancer .
the results of the screening were analyzed with chi square test by demographic variables such as gender , age , type of insurance and region and by screening tests like fobt , colonoscopy , dcbe and others .
fobt positive rate and participation rates of secondary screening tests were calculated with 95% confidence interval ( ci ) and all data analysis was conducted with sas version 9.1 ( sas inc . , cary , nc , usa ) .
this study utilized the database of target population and participants of colorectal cancer screening of 2008 national cancer screening program .
the target population was adults aged over 50 years among medical aid beneficiaries and national health insurance subscribers .
for the subscribers , they or their dependants who paid lower 50% premiums based on those of november , 2007 ( monthly 67,800 or less than 67,800 won for employee insured and 56,500 or less than 56,500 won for self - employed insured ) , were included in this study .
when the data about the monthly premiums did not exist , the target population were selected by considering current premiums compared to those on the standard month ( 11 ) . according to the inclusion criteria , totally 7,522,452 were the total target population of colorectal national cancer screening program and out of them 4,640,365 were the target population of colorectal cancer screening in 2008 .
colorectal cancer is recommended to be screened every year and fobt was performed as a primary screening test by using fecal immunochemical tests ( reversed passive haemagglutination assay [ rpha ] or latex agglutination test ) or fecal porphyrin quantification . for the participants with a positive result in fobt , colonoscopy or dcbe test
when dcbe result had abnormal findings ( polypus , probably cancer , colorectal cancer and other diseases than cancer ) , colonoscopy was conducted additionally .
when colonoscopy found abnormal findings ( polypus , suspected colorectal cancer , colorectal cancer and others ) biopsy was utilized according to decision of a physician ( 11 ) . to analyze the current situation of colorectal cancer screening ,
the participants were defined as persons with at least one among a result of fobt , a result in colonoscopy , result in dcbe , a result of biopsy or a result of final outcomes in screening record . out of 985,148 with at least one of them in the record , 984,915 were recruited as participants in 2008 by excluding 111 ones aged less than 50 years , 101 ones thought as persons not screened without personal information and 21 already diagnosed cancer patients . in summary ,
the target population and the participants of colorectal cancer screening of the colorectal national cancer screening program in 2008 were 4,640,365 and 984,915 , respectively .
demographic characteristics examined in this study were age , types of insurance and region . age was divided into subgroups by five years with the subjects aged over 50 years and the elderly aged 75 years was analyzed as a subgroup .
region was divided into 16 cities and or provinces by using the specific number of organizing public health centers .
the results of screening were classified based on contents of the result sheet reported to national health insurance cooperation . in the sheet , final outcomes of colorectal cancer were ' normal ' , ' need a follow - up ' , ' need diagnostic work - up for cancer ' , ' need treatment for cancer ' and ' other diseases than cancer ' . '
normal ' meant that a result of biopsy , colonoscopy or double - contrast barium enema test was normal or that fobt showed a negative result . '
need a follow - up ' was written when biopsy revealed inflammatory , hyperplastic or pathologic findings , low / high grade adenoma or dysplasia , when colonoscopy or double - contrast barium enema test found polypus or when fobt result was positive . '
need diagnostic work - up for cancer ' meant that colorectal cancer was suspected and inspection was needed immediately , and ' need treatment for cancer ' showed that colorectal cancer was diagnosed and treatment for it was necessary immediately . '
other diseases than cancer ' was written for other diseases not related with colorectal cancer .
the results of the screening were analyzed with chi square test by demographic variables such as gender , age , type of insurance and region and by screening tests like fobt , colonoscopy , dcbe and others .
fobt positive rate and participation rates of secondary screening tests were calculated with 95% confidence interval ( ci ) and all data analysis was conducted with sas version 9.1 ( sas inc . , cary , nc , usa ) .
when the current situation of colorectal cancer screening in 2008 was examined , 984,915 out of totally 4,640,365 target population participated in the screening with the participation rate of 21.2% in average ( table 1 ) .
the screening rate of national health insurance subscribers was higher than that of medical aid beneficiaries by recording 23.0% and 12.6% , respectively .
the rate of females was slightly higher than that of males by recording 21.9% and 20.5% , respectively . for age ,
the screening rate recorded the highest level or 27.5% in seniors aged 60 to 64 years and the lowest level or 7.8% in those aged over 75 years . for region , while the screening rate was the highest in busan and daejeon by recording 25.0% , it was the lowest in jeonnam by recording 14.6% .
when the results of colorectal cancer screening of the participants were investigated , 93.8% ( 924,080 ) , 2.0% ( 19,722 ) , 0.6% ( 5,867 ) 0.1% ( 509 ) and 3.5% ( 34,737 ) were found to be normal , need a follow - up , need a work - up for cancer , need treatment for cancer and be other diseases than cancer , respectively . out of the 984,915 fobt results ,
73,568 ( 7.5% ) and 911,347 ( 92.5% ) showed positive and negative results in fobt , respectively ( table 2 ) .
the positive rate was relatively slightly higher in medical aid beneficiaries than in national health insurance subscribers by recording 7.9% ( 95% ci , 7.8 to 8.1 ) and 7.4% ( 95% ci , 7.4 to 7.5 ) , respectively .
the positive rate of males was higher than that of females by recording 8.8% ( 95% ci , 8.7 to 8.9 ) and 6.4% ( 95% ci , 6.3 to 6.4 ) , respectively .
the positive rate of the elderly aged over 75 years showed the highest level or 9.1% ( 95% ci , 8.8 to 9.3 ) and for region the rate of jeonnam was the highest by recording 15.6% ( 95% ci , 15.2 to 15.9 ) .
when 73,568 participants with a positive result in fobt were analyzed according to age and region , adults aged 50 to 54 years accounted for the largest part or 26.3% while adults aged over 75 years did for the smallest part or 5.5% ( table 3 ) . for region , among adults aged 50 to 54 those in ulsan had the largest portion or 31.0% and those in jeju captured the smallest portion or 22.6% . on the contrary , among adults aged over 75 years those in jeju and ulsan accounted for the largest ( 9.9% ) and the smallest portions ( 3.0% ) , respectively .
the national cancer screening program provided colonoscopy or dcbe as a secondary screening test for participants with a positive result in fobt . out of 73,568 showing the positive result in fobt , 31,671 underwent a secondary screening test and the participation rate was 43.0% ( 95% ci , 42.7 to 43.4 ) ( fig .
8,554 underwent colonoscopy and dcbe as a secondary screening test with the participation rate of 31.4% ( 95% ci , 31.3 to 31.6 ) and 11.6% ( 95% ci , 11.4 to 11.9 ) , respectively , the colonoscopy rate was higher than that of dcbe .
the national cancer screening program recommended that persons with abnormal finding in dcbe took colonoscopy additionally . among 2,422 with abnormal findings in dcbe 198
( participation rate 8.1% ; 95% ci , 7.0 to 9.2 ) underwent colonoscopy . in a narrowed analysis
, it was 143 who had ' probably cancer ' or ' colorectal cancer ' among 198 dcbe abnormal people , and 24 took colonoscopy ( participation rate 16.8% ; 95% ci , 10.7 to 22.9 ) out of 143 ( data not shown ) .
the program recommended that persons with abnormal findings in colonoscopy to have biopsy , and 9,973 out of 15,926 with abnormal findings in colonoscopy underwent biopsy ( participation rate 62.6% ; 95% ci , 61.9 to 63.4 ) . among 558
observed to have ' probably cancer ' or ' colorectal cancer ' , 500 took biopsy ( participation rate 89.6% ; 95% ci , 87.1 to 92.1 ) ( data not shown ) .
results of colonoscopy and dcbe were compared by designating the participants showing a positive result in fobt and undergoing each of the two tests as 100 ( fig .
2 ) . ' normal ' accounted for 31.8% and 71.5% in the results of colonoscopy and dcbe , respectively , so the latter fraction was two times higher than that in the former one .
the fractions of ' polyp ' were 41.2% and 5.3% in the results of colonoscopy and dcbe , respectively , and those of ' probably cancer ' were 1.2% and 1.5% in the results of colonoscopy and dcbe , respectively . '
colorectal cancer ' was observed in 1.2% and 0.2% of the participants undergoing colonoscopy and dcbe , respectively , and the fraction of the former test was higher than that of the latter test .
when the current situation of colorectal cancer screening in 2008 was examined , 984,915 out of totally 4,640,365 target population participated in the screening with the participation rate of 21.2% in average ( table 1 ) .
the screening rate of national health insurance subscribers was higher than that of medical aid beneficiaries by recording 23.0% and 12.6% , respectively .
the rate of females was slightly higher than that of males by recording 21.9% and 20.5% , respectively . for age ,
the screening rate recorded the highest level or 27.5% in seniors aged 60 to 64 years and the lowest level or 7.8% in those aged over 75 years . for region , while the screening rate was the highest in busan and daejeon by recording 25.0% , it was the lowest in jeonnam by recording 14.6% .
when the results of colorectal cancer screening of the participants were investigated , 93.8% ( 924,080 ) , 2.0% ( 19,722 ) , 0.6% ( 5,867 ) 0.1% ( 509 ) and 3.5% ( 34,737 ) were found to be normal , need a follow - up , need a work - up for cancer , need treatment for cancer and be other diseases than cancer , respectively .
out of the 984,915 fobt results , 73,568 ( 7.5% ) and 911,347 ( 92.5% ) showed positive and negative results in fobt , respectively ( table 2 ) .
the positive rate was relatively slightly higher in medical aid beneficiaries than in national health insurance subscribers by recording 7.9% ( 95% ci , 7.8 to 8.1 ) and 7.4% ( 95% ci , 7.4 to 7.5 ) , respectively .
the positive rate of males was higher than that of females by recording 8.8% ( 95% ci , 8.7 to 8.9 ) and 6.4% ( 95% ci , 6.3 to 6.4 ) , respectively .
the positive rate of the elderly aged over 75 years showed the highest level or 9.1% ( 95% ci , 8.8 to 9.3 ) and for region the rate of jeonnam was the highest by recording 15.6% ( 95% ci , 15.2 to 15.9 ) .
when 73,568 participants with a positive result in fobt were analyzed according to age and region , adults aged 50 to 54 years accounted for the largest part or 26.3% while adults aged over 75 years did for the smallest part or 5.5% ( table 3 ) . for region , among adults aged 50 to 54 those in ulsan had the largest portion or 31.0% and those in jeju captured the smallest portion or 22.6% . on the contrary , among adults aged over 75 years those in jeju and ulsan accounted for the largest ( 9.9% ) and the smallest portions ( 3.0% ) , respectively .
the national cancer screening program provided colonoscopy or dcbe as a secondary screening test for participants with a positive result in fobt . out of 73,568 showing the positive result in fobt , 31,671 underwent a secondary screening test and the participation rate was 43.0% ( 95% ci , 42.7 to 43.4 ) ( fig .
1 ) . as 23,117 and 8,554 underwent colonoscopy and dcbe as a secondary screening test with the participation rate of 31.4% ( 95% ci , 31.3 to 31.6 ) and 11.6% ( 95% ci , 11.4 to 11.9 ) , respectively , the colonoscopy rate was higher than that of dcbe .
the national cancer screening program recommended that persons with abnormal finding in dcbe took colonoscopy additionally . among 2,422 with abnormal findings in dcbe 198
( participation rate 8.1% ; 95% ci , 7.0 to 9.2 ) underwent colonoscopy . in a narrowed analysis , it was 143 who had ' probably cancer ' or ' colorectal cancer ' among 198 dcbe abnormal people , and 24 took colonoscopy ( participation rate 16.8% ; 95% ci , 10.7 to 22.9 ) out of 143 ( data not shown ) .
the program recommended that persons with abnormal findings in colonoscopy to have biopsy , and 9,973 out of 15,926 with abnormal findings in colonoscopy underwent biopsy ( participation rate 62.6% ; 95% ci , 61.9 to 63.4 ) . among 558
observed to have ' probably cancer ' or ' colorectal cancer ' , 500 took biopsy ( participation rate 89.6% ; 95% ci , 87.1 to 92.1 ) ( data not shown ) .
results of colonoscopy and dcbe were compared by designating the participants showing a positive result in fobt and undergoing each of the two tests as 100 ( fig .
2 ) . ' normal ' accounted for 31.8% and 71.5% in the results of colonoscopy and dcbe , respectively , so the latter fraction was two times higher than that in the former one .
the fractions of ' polyp ' were 41.2% and 5.3% in the results of colonoscopy and dcbe , respectively , and those of ' probably cancer ' were 1.2% and 1.5% in the results of colonoscopy and dcbe , respectively . '
colorectal cancer ' was observed in 1.2% and 0.2% of the participants undergoing colonoscopy and dcbe , respectively , and the fraction of the former test was higher than that of the latter test .
the target population of colorectal cancer screening in national cancer screening program in 2008 was totally 4,640,365 and their participation rate was averagely 21.2% .
fobt positive rate out of the participants was approximately 7.9% and males , the elderly aged over 75 years and medical aid beneficiaries recorded relatively higher positive rates compared to females , other age groups and people insured health insurance , respectively .
for secondary screening rate of the participants with a positive result in fobt , the rate of colonoscopy was higher than that of dcbe .
that fobt was conducted as a primary screening test of colorectal cancer in the national cancer screening program in korea , which is similar with the national colorectal cancer screening program in england , japan and finland operating ( 8) , and persons showing a positive result in fobt underwent colonoscopy and dcbe ( 12 - 14 ) .
colorectal cancer screening program has been operated since 2004 and we have been reporting our program results in a monograph every year .
target population of colorectal cancer screening tended to increase from 2.26 million in 2004 to 3.27 million in 2005 , 4.40 million in 2006 and 4.34 million in 2007 ( 15 ) .
the target population of a current colorectal cancer screening conducted in 2008 was about 4.60 million and out of them 0.98 million participated in the screening by recording the rate or 21.2% .
the level was slightly lower than 25.7% or 1.73 million out of 6.73 million target population of colorectal cancer screening shown by a report ( 16 ) of national health insurance cooperation in 2008 investigating the total beneficiaries of national health insurance .
in addition , even though a direct comparison is hard to be performed , the participation rate of fobt or colonoscopy within 10 years was 50 to 60% in the u.s . in 2006 and the participation rate of fobt every two years or of colonoscopy within five years recorded 28 to 53% in canada in 2008 ( 14 ) .
so south korea needs more efforts to encourage the colorectal cancer screening rate in the national cancer screening program . in comparison of participation rates according to demographic characteristics ,
the rates were even by gender and age but the rate of seniors aged over 75 years reduced sharply . as the screening rate of national health insurance subscribers was two times higher than that of medical aid beneficiaries ,
this finding suggested that types of insurance could mean economic differences and socio - economic differences could lead to differences in screening rates .
however , because various factors such as comorbidity , accessibility of medical institutions for screening , educational background and recognition on diseases were not considered , a direct interpretation on correlation between economic levels and screening rates had some limitations in this study . in the meantime
, the results of colorectal cancer screening showed that medical aid beneficiaries and older recipients recorded higher rates of additional tests , so the screening of the vulnerable needed to be encouraged . among the participants of a primary colorectal cancer screening , fobt positive rate was about 7.5% .
as this study did not include national health insurance subscribers paying higher 50% premiums and private health examination , it could not represent the total people in south korea . despite these limitations ,
the positive rate was compared with the results of national cancer screening in foreign countries to determine the level of south korea roughly . in the screening of japan conducted with about 4.00 million adults aged over 40 years in 1995 ,
the pilot study of england reported in 2004 ( 13 ) showed that the colorectal cancer screening rate was approximately 59.2% but the fobt positive rate was about 1.6% .
as other studies in korea , a randomized clinical trial in gumi found that the fobt positive rate of the general public was around 1.0 to 2.4% ( 7 ) , and it was said that the positive rate of persons visiting health examination centers of hospitals from january , 2004 to april , 2005 was around 1.8% ( 17 ) .
the difference in fobt positive rates of the national screening program and community - based studies was thought to be caused by considering that the national screening program was conducted by hospitals and clinics around the nation . in this study ,
the regional distribution of fobt positive rate showed relatively higher deviation from 4.2 to 15.6% and the rate of jeonnam was outstandingly high .
when the rates were stratified according to region and age , the positive rate of jeonnam was higher than that of other regions but there was no significant increase by age and no specific correlation according to region and age in the distribution of positive rates . therefore , the deviation was considered to be caused by properties of health examination institutions . however , it is the third year of the quality control the national cancer screening program including fobt tests by the ministry of health and welfare , national cancer center of korea and with academic societies .
we expect that the discrepancy of quality of the fobt tests between institutions may diminish and the quality overall to be increased afterward . for gender
, males recorded 1.4 times higher positive rate or 8.8% than females and for age the elderly aged over 65 years showed a high positive rate by recording 8.1 to 9.1% . although this study could not determine correlation between older age and higher positive rate of fobt and between older age and higher incidence rate and mortality rate of colorectal cancer , it showed at least that the tendency of higher fobt positive rate at older age was same with the tendency of incidence of colorectal cancer by age in south korea ( 5,6 ) .
the participants with a positive result in fobt were recommended to undergo colonoscopy or dcbe and the participation rate of colonoscopy was about 2.7 times higher than that of dcbe by recording 31.4% and 11.6% , respectively . additional analysis on difference in participation rates of the two secondary tests by gender , age , region and types of insurance was performed although its results were not presented as results . according to the analysis , colonoscopy rate was higher in males ( 32.1% ) and national health insurance subscribers ( 32.2% ) than the average rate or 31.4% but dcbe rate was higher in females ( 12.0% ) and medical aid beneficiaries ( 13.1% ) than the average rate or 11.6% .
in addition , colonoscopy rate was decreased at older age by recording 17.2 to 37.1% and dcbe rate did not show a tendency according to age by recording 10.5 to 12.9% .
for region , colonoscopy rate was higher in 14 regions except two ones ( gwangju and gangwon ) and its deviation was 19.2 to 54.7% .
these results suggested that gender , types of insurance and age affected preference to or recognition on more invasive colonoscopy needing longer examination time . the difference in participation rates of secondary screening tests by region was observed and it was considered to be caused by the difference in the real condition of medical institutions and medical circumstances .
future studies were necessary to determine that clearly . according to a study assuming markov model in terms of cost - effectiveness of colorectal cancer screening tests ( 18 ) , as a colonoscopy screening was effective in reducing mortality rate compared to others and showed a high cost - effectiveness .
a research performed in south korea also insisted that colonoscopy was cost - effective ( 9 ) . as a secondary test
was recommended based on these results , the participation rate of colonoscopy was considered to be high . in addition , persons with abnormal findings in dcbe were recommended to undergo colonoscopy in the screening process , so the participation rate of colonoscopy was higher
. colonoscopy rate out of persons with abnormal findings in dcbe and biopsy rate out of persons with abnormal findings in colonoscopy recorded 8.1% and 62.6% , respectively , and the rates of persons found to have ' probably cancer ' or ' colorectal cancer ' were higher than the former ones by recording 16.8% and 89.6% , respectively .
like this , as abnormal findings included ' polypus ' , ' probably cancer ' , ' colorectal cancer ' and ' other diseases than cancer ' , high rates of ' polyps ' and ' other diseases than cancer ' were considered to provoke reduced participation rate of secondary tests in total participants with abnormal findings . in particular , the rate of persons showing a positive result in fobt but not taking secondary test recorded a high level or 57.0% . that was considered to be because this study analyzed only the data of the national cancer screening program , and if cases undergoing secondary tests through private health examination or private medical sector were included the secondary screening rate was expected to become higher .
moreover , even though persons were recommended to undergo a secondary screening test , low recognition on colonoscopy or dcbe and inconvenience of taking it were thought to increase the rate of not attending secondary screening .
this study found that the secondary colorectal cancer screening rate was low although the national program provided free secondary test for persons with a positive result in fobt and that needed to be dealt with properly . among persons with a positive result in fobt , those observed to have cancer in secondary tests such as colonoscopy and dcbe accounted for approximately 1.2% and 0.2% , respectively , and those done to have ' probably cancer ' were 1.2% and 1.5% , respectively . considering that fobt positive rate showed a large deviation by region and its average was higher than those in previous studies , the result suggested that more efforts to improve the sensitivity of fobt were necessary .
foreign studies also reported that the sensitivity of fobt was lower by recording 30 to 50% ( 8) . in future
, it is needed to supplement fobt and to enhance policies to increase the effect of the national colorectal screening based on cost - effectiveness studies using national data on colonoscopy and dcbe as secondary screening tests .
this study was conducted to investigate the results of the national cancer screening program and to assess outcomes of colorectal cancer screening by analyzing the colorectal cancer screening in the national cancer screening program in 2008 . in future ,
more efforts to increase the colorectal cancer screening rate need to be continued and specialized advertisement strategies according to age , gender and region are also necessary .
also , a faithful participation such as higher participation rates of secondary tests should be guided and high - quality screening should be provided in all health examination institutions through quality control or education .
Output:
| purposethis study aims to investigate the current situation of national colorectal cancer screening by analyzing participation rates , positive rates of screening methods and screening rate of secondary screening tests in colorectal screening of the national cancer screening program in 2008.materials and methodswith database about target population and screened individuals of the national cancer screening program , the results of target population and participants of colorectal cancer screening in 2008 were analyzed . among adults aged over 50 years of medical aid and beneficiaries of national health insurance paying lower 50% premiums in the total subscribers ,
4,640,365 were target population of colorectal cancer screening and the data of 984,915 undergoing fecal occult blood test ( fobt ) as a primary screening were analyzed.resultsthe colorectal cancer screening rate was 21.2% and the rates of national health insurance subscribers , females and the elderly aged 60 - 64 years were higher than those of others .
the recipients with a positive result in fobt recorded approximately 7.5% .
medical aid beneficiaries ( 7.9% ) , males ( 8.8% ) and seniors aged over 75 years ( 9.1% ) showed higher positive rates than the average one .
out of the fobt positive recipients , 43.0% took a secondary screening and the rate undergoing colonoscopy ( 31.4% ) was higher than that of doing double - contrast barium enema test ( 11.6%).conclusioncolorectal cancer screening rate of medical aid beneficiaries and people paying lower 50% premiums among national health insurance subscribers , was different according to demographic characters ( gender , age and types of health insurance ) .
this finding meant that screening for the vulnerable needed to be encouraged by considering socio - demographic characters .
additionally , more efforts were necessary to increase the secondary screening rate of people with a positive result in primary one . |
PubmedSumm118523 | ***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: every one 's job , as a source of providing life needs , a factor of creating identity and
social relationship , is considered as the most important reasons of tenseness .
occupational stress is a physical and mental response emerged through interaction of an
individual with working environment and mismatching his or her work needs with his or her
abilities and demands .
this tenseness occurs in all jobs , but this issue receives especially
much more attention and importance in the jobs when they are dealing with human
health .
one of the important issues
affecting on professors performance and their efficiencies is a mental pressure resulting
from their gradual burnout .
mental pressure is considered as a great impact on teachers '
job , particularly on teaching - learning process , and constantly included physical , emotional
and attitudinal burnout that is often created by consuming extra energy that professors use
to encounter and adapt themselves with these pressures .
creativity reduction , reluctance to work , lack of concentration on work , easily irritated
and an aggressiveness towards coworkers , lack of self - confidence , extreme tiredness coming
from work and increasing mistakes are the outcomes of stress and mental work pressure and
finally lead to unproductivity and inefficiency in any organization . according to cordes and dougherty 's view , a series of such stressful occupational factors
cause the occupational burnout that is one of the main and significant consequences of
occupational stress .
occupational burnout is a psychological process which is the result of
a long - term pattern of unsafe and unsound interaction between an individual and his or her
workplace or atmosphere .
he described
occupational burnout as a mood of tiredness and exhaustion resulting from laborious working
without any motivations .
they
describe it as a psychological syndrome consisting of three dimensions of feeling burnout or
emotional tiredness ( a feeling of tiredness resulted from working with others ) ,
depersonalization ( indicating an interpersonal dimension of occupational burnout that a
person becomes reluctant to his personal responsibilities and aggressive and careless to
clients in his workplace ) , and reduction of personal efficiency ( the employee feels that his
or her work is not productive ) .
maslash and liter consider some effective factors as the causes of occupational burnout
such as the less and more amount of work , less and more control level over the work , low
reward , discrimination in workplace , lack of suitable social relationship , and the conflict
among the values of the workplace .
these factors cause a lot of problems for family , social , individual and organizational
life that the most important of them are as follow ; absence , leaving the workplace , lateness
or tardiness behavior different psychological complaints , changing job , and interpersonal
conflict with colleagues .
nowadays , occupational burnout is a common problem in all the systems of the health care ,
in another words , based on the available census , one in seven person gets occupational
burnout at the end of the day . keeping up with the importance of the issue , investigating the process of burnout and
occupational stress has taken a lot of attentions in recent years so that a large number of
researches have been done in iran and all over the world .
for example , saberiand badri gargari in the different works studied teachers ' occupational burnout
and zeighami & shakerinia investigated the relationship between stress
and nurses ' occupational burnout .
data extracted from different studies that has been done
recently by using maslash's occupational burnout questionnair different jobs indicated an
increasing outbreak of the occupational burnout in the most of these job groups .
, research showed that the amount of occupational burnout was
low in faculty members based on the dimensions of emotional fatigue and depersonalization ,
but about half of the faculty felt a reduced personal accomplishment in their
jobs .
the academic members , due to their educational and researching duties , consume a lot of
mental energy and it is thought that they are among the groups exposed to harm of
occupational burnout .
so concerning the negative effects of occupational burnout and a
pressure on personal accomplishment and physical and mental health of individuals ,
consequently , the reduction of quality , efficiency , and outcomes of their occupations , and
also regarding the limited number of studies investigating the outbreak of occupational
stress and its relationship with academic 's occupational burnout , therefore the aim of this
study was to determine the occupational stress outbreak and its relationship with burnout
syndrome in the academic members of lorestan university of medical science
the participants included
111 academic members taking their internship period , or those were in their service
obligation , contracted , formal , formal experiment , and permanent employment status .
the
participants were selected by multistage sampling from medicine , nursing , health , and
paramedic colleges affiliated lorestan university of medical sciences .
the first
section contained personal and occupational characteristics of the participants such as age ,
gender , marital status , work experience , employment status , the college , administrative and
managing responsibility , native or non - native employee , academic rank , and basic and
clinical sciences .
it contained 9 questions in dimension of emotional tiredness , 8
questions in the decrement of personal accomplishment dimension , and 5 questions in
depersonalization dimension that they were considered as the three dimensions of
occupational burnout .
this tool had been designed to evaluate the frequency and the
intensity of the three dimensions of occupational burnout .
the frequency of related feelings
were measured by a seven - point scale ( i.e. never , daily , several times a week , weekly ,
several times a month , monthly , and several times a year ) and the intensity of these
feelings was graded by six- point likert scale ( very low , low , considerable , fairly high ,
high , and very high ) .
having added the scores extracted from the questions of each three
dimension , two final scores were obtained , one for the frequency scale and the other for the
intensity scale ; it should be said by referring to this rule that as the sum of scores in
the emotional tiredness and depersonalization sections is more and the sum of the decrement
of personal accomplishment scores is less , occupational burnout will be more , therefore the
scores of these sections can not be added .
if the scores of emotional tiredness dimension were less than 17 , between the range of
18 - 29 , and more than 30 , it would be represented as low , average , and extremely occupational
burnout respectively . in depersonalization dimension ,
the scores less than 5 , between 6 - 11 ,
and more than 12 , respectively indicated low , average , and severe occupational burnout . in
the decrement of personal accomplishment dimension
, the scores more than 40 , between 34 - 39 ,
and less than 33 were respectively considered as low , average , and severe occupational
burnout . in iran ,
several studies have confirmed the validity and reliability of this tool and alfa
cronbach coefficient for the whole test was r=0.83 and for each subscale of emotional
tiredness was r=0.88 , for personal accomplishment r=0.76 and for depersonalization r=
0.79 .
the reliability of the questionnaire used in this research was also obtained by
coefficient of cronbach 's alfa ( r=0.78 ) .
the third section of the research was osipow 's standard job stress questionnaire that
contained six dimensions including role overload , role insufficiency , role ambiguity , role
boundary , responsibility , physical environment ; each of these dimensions was graded based on
the likert 's 5- point scale ( i.e. , never , sometimes , often , usually , more often ) that
represented of 1 to 5 points respectively . according to the obtained scores , the individuals
were divided into the following groups : without stress , normal , average stress , and severe
stress .
this questionnaire was investigated and evaluated by many iranian researches
studying job stress and the results of various studies showed that the mentioned
questionnaire is reliable and useful to investigating job stress .
data collections of this questionnaire were through attending in different
departments and handing it in anonymous . in order to take ethical considerations into
account ,
the aim of the research was explained to the participants and their personal and
private information was kept confidentially and the principle of trustworthy was highly
regarded in this study .
analysis was done by spss ( version 13 ) , using statistical tests such
as qui square , kruskal - wallis , mann whitney tests , pearson correlation coefficient , and
descriptive statistics like mean and standard deviation .
according to the results , the average age of the studied subjects ( departments ) was 41.38
years old and the average of their work experience was 10.5 year .
70% of the participants
were male , 87% were married , 46.3% had a formal experiment and or permanent employment ,
58.5% were native , 48% having msc and phd education with administrative responsibilities ,
61.8% were assistant professors , and 63.6% teaching in different grades in basic sciences .
members of 158 members the faculty were students and at the time of the study were absent .
in spite of frequent attendance of 22 persons to fill out the questionnaire , they decided
not to take part in the research . finally , 111 questionnaires were filled out and returned
by the participants .
based on the findings , the mean and the standard deviation of the
scores were 14.07 ( 8.23 ) for emotional tiredness , 38.59 ( 7.36 ) for personal accomplishment ,
and 3.14 ( 5.62 ) for depersonalization .
72.1% of the studied subjects in emotional tiredness
dimension , 56.8% in decrement of personal accomplishment dimension , and 81.1% in
depersonalization dimension had a low level of scores .
the results indicated that the half
of participants in the decrement of personal accomplishment dimension were moderate to
severe situation , but , the most of them the level of emotional exhaustion and
depersonalization of participants were at low ( table
1 ) .
the results of the research showed that the total score of job stress in 3.9 percent of
men without stress , 96.1% with a low stress , and average and severe amount of stress in men
were not observed .
in addition , 91.2% of women with low stress , 8.8% with average , and the
amounts without stress and severe level were also not reported ; in the end , the above
findings indicates that 20.7% of the studied subjects were without any stress , 79.3% of them
had a low level of job stress , and the severe and average level of stress were not observed
in this study ( table 2 ) .
the results showed that
there was a positive correlation between job stress and burnout dimensions in terms of
frequency and intensity of emotional exhaustion , intensity and frequency of
depersonalization and frequency of decrement of personal accomplishment ( r=0.375 , p=0.001 ) .
it means as job stress get more in the studied subjects , with respect to the amount of
occupational burnout , will have a higher level of it .
but there was no correlation ( p=0.452 ,
r= 0.072 ) between job stress and the intensity of decrement of personal accomplishment
( table 3 ) .
regarding to the findings , there was no
significant relationship between jobs tress and occupational burnout with personal and
occupational variables of the studied subjects such as gender , marital status , employment
status , the college they served , administrative and managing responsibility , and academic
rank .
besides , no significant relationship was seen between the dimensions of occupational
burnout such as emotional tiredness and decrement of personal accomplishment , and totals
score of job stress with age and work experience .
but there was a negative correlation
between depersonalization dimension and age and work experience .
so as their age and work
experience were more , the level of depersonalization was lower ; and the individuals had a
better situation in the viewpoint of depersonalization . from the results it can be
understood that there was a significant relationship between occupational burnout in
intensive and frequent aspects of emotional tiredness , the frequency of depersonalization ,
and the frequency of personal accomplishment among the faculty busy working in different
grades of basic and clinical sciences ; that is , occupational burnout in the aspect of
intensity and frequency of emotional tiredness and frequency of depersonalization was lower
in the faculty working in basic science grades than the individuals working in the clinical
science grades , and the personal accomplishment was more in the frequency , but there was no
significant relationship between the total score of job stress and the grade of
teaching .
no relationship was observed between occupational burnout ( except in the aspect of
personal accomplishment frequency ) and the score of job stress with their educational
levels .
the frequency of personal accomplishment in post specialists was at the lowest level
and had the highest amount of occupational burnout among experts , phd and msc , and
professional doctors , the personal accomplishment with a slight difference within these
groups had respectively been increased ( tables 4 and
5 ) .
emotional tiredness ( et ) , decrement of personal accomplishment ( dpa ) , and
depersonalization ( d ) emotional tiredness ( et ) , decrement of personal accomplishment ( dpa ) ,
depersonalization ( d )
according to the results , the occupational burnout among the academic members of lorestan
university of medical sciences was more than the average level in emotional tiredness
dimensions while the personalization was less than the average level .
the results of
shanafel et al.,study on the doctors of
faculty , in the department of internal medical science of rochester , minnesota , showed that
the most of the participants were at a low level from occupational burnout point of view in
the depersonalization dimension , while the decrement of personal accomplishment dimension
was at high level , which was in line with this research .
, results concerning the occupational burnout of the educational
principalsand saberi 's et al .
it seems that the spiritual and valuable dimension of education is an
important factor for individuals to adapt themselves with job stresses coming from
education - research duties .
individuals ' interest , reputation , and social position can be
considered as the effective factors of occupational burnout as well .
stress measurement of the studied subjects put emphasis on this point that the faculty did
not have average and severe occupational stress .
,
findings who studied mental pressure of the faculty in isfahan university of medical
sciences .
they reported the job stress less than the average level.probably , because the task of faculty members
is to promote knowledge and research in the community and it was relevant to their expertise
and interest led to them feel less stress .
the results showed a strong and positive correlation ( p<0.001 ) within all components of
occupational burnout except the intensity of personal accomplishment and job stress .
it
means that the more job stress in the subjects , the higher level of burnout .
this result is
in line with zeighami and asgharzadeh 's findings concerning the positive correlation between
job stress and occupational burnout of nurses . by investigating the relationship of the six dimensions of occupational burnout and the
total score of stress with individuals ' variables such as age and work experience
, it can
inferred that individuals were at a better level with respect to their depersonalization and
its amount , as their ages and work experience increased .
another research also depicted that
work experience , as a result of aging , has a great effect on understanding and reduction of
burnout .
they stressed that aging and work experience lead to increasing the
adaptive mechanisms and stabilizing individuals in educational places ; and consequently
decrease the occupational burnout .
the results of this study showed no significant relationship between individuals ' marital
status and burnout and job stress .
our findings was similar to a research done in turkey
concerning the marital status and the different dimensions of burnout , no significant relationship was seen between
occupational burnout and employment status of the studied units while the total score of job
stress in formally permanent employed , formally experimental employed , internship and
contracted employed groups indicated an increasing growth respectively .
this finding is in
line with the research findings done by beker et al .
, in concerning the faculty 's job
satisfaction in which the job satisfaction was at the highest level in groups employed
formally and permanently .
there was no difference between occupational burnout and job stress among the academic
members in respect to the college they work .
they showed the
different amount of job stress in various colleges ; on the other hand , showing more
frequency of mental pressure in the colleges that the faculty members were highly involving
with students .
the result of the present study showed that there was no difference between occupational
burnout and job stress in the studied subjects with respect to being native or non - native
.
for individuals , being non - native , means being far away from their family can be a source of
creating anxious and mental pressure .
so , if this pressure were continuous and severe , it
would have a considerable impact on different aspects of individuals ' job . a research in the
u.s .
indicated that there was a meaningful relationship between these two variables and
occupational burnout . with regard to having administrative responsibilities , there was no difference between
occupational burnout and job stress .
occupational burnout in emotional tiredness and
depersonalization dimensions of the academic members who were busy working in the sections
of basic sciences was less than those working in clinical sections .
it seems that a high
percentage of the faculty members in clinical groups not only had educational
responsibilities but also had a vital role in treatment .
hence , they were exposed to the
occupational burnout resulted in both educational services and treatment affairs .
therefore ,
such a higher occupational burnout , regarding emotional tiredness and depersonalization
dimensions , can be both emerged in the forms of anxiousness resulted in job and being
reluctant to their clients that such signs were justifiable in these groups .
the amount of
occupational burnout with regard to the decrement personal accomplishment dimensions in the
groups belonging to basic sciences could be explained by this reason that the faculties of
basic sciences were under a less pressure of their workplace and clients ' expectations in
comparison to the clinical group members ; consequently , they experienced the decrement of
personal accomplishment . the results of beker et al .
, showed that job satisfaction score
clinical faculty members more than in comparison with basic science faculty members and
those administrative posts . in general ,
as it was mentioned before in investigating the individual and occupational
variables such as marital status , holding an administrative responsibility , being native or
non - native , academic rank , and the college the faculties work , no significant relationship
was observed with occupational burnout , it seemed that the low number of sampling in the
research was one of the reasons .
the results of the current research indicated that the amount of job stress and
occupational burnout is at an acceptable level in the academic members of medical sciences
in lorestan university , but it is advised not to ignore evaluating periodically and take
action to have interfering approaches if necessary in order to modify and control stress and
burnout which are destructive to preserving dynamic life of an organization .
however , by
applying some strategies to decrease stress and determining stress resources , we can improve
their psychological health of academic members .
limitations including small sample size , no response to the distributed questionnaires
from some professors , and using the self - reporting methods to collect data which may
decrease the generalization of the results . finally , it is suggested to do research with a
higher volume of sampling in a vast geographical scope along with qualitative and
meta - analytical studies .
we thank all the faculty members of lorestan university of medical sciences for their
kindness and attendance in this research .
Output:
| introduction : burnout syndrome is one of the consequences
and the results of occupational or job stress emerged in the form of emotional exhaustion
feeling , depersonalization and decrement personal accomplishment . the aim of this study
was to determine the occupational stress and its relationship with burnout syndrome in the
academic members of lorestan university of medical sciences .
methods : this descriptive cross - sectional survey was
conducted on 111 of the faculty members via multistage sampling .
data were collected by
the questionnaire of maslach burnout inventory ( mbi ) , and osipow occupational stress
inventory ( osi- r ) .
data were analyzed by using descriptive statistics as well as
analytical statistics such as chi square , kruskal - wallis , mann whitney tests and pearson
correlation coefficient .
results : the results showed that the most of the
participants had a low level of burnout three dimensions including emotional burnout
( 72.1% ) , depersonalization ( 81.1% ) , and the decrement of personal accomplishment ( 56.8% ) .
moreover 79.3% of samples had a low occupational stress , but there was a meaningful
relationship between occupational stress and dimensions of burnout syndrome with an
exception for the intensity of decrement of personal accomplishment .
conclusion : academic members were in an appropriate
condition concerning burnout syndrome and occupational stress .
however by applying some
strategies to decrease stress and determining stress resources , we can improve their
psychological health of academic members . |
PubmedSumm118524 | ***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: supplementary note s1 , data s1 , tables s1s5 , and figures s1 and s2 are available at molecular biology and evolution online ( http://www.mbe.oxfordjournals.org/ ) .
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| y chromosomes have long been dismissed as graveyards of genes , but there is still much to be learned from the genetic relics of genes that were once functional on the human y. we identified human x - linked genes whose gametologs have been pseudogenized or completely lost from the y chromosome and inferred which evolutionary forces may be acting to retain genes on the y. although gene loss appears to be largely correlated with the suppression of recombination , we observe that x - linked genes with functional y homologs evolve under stronger purifying selection and are expressed at higher levels than x - linked genes with nonfunctional y homologs .
additionally , we support and expand upon the hypothesis that x inactivation is primarily driven by gene loss on the y. using linear discriminant analysis , we show that x - inactivation status can successfully classify 90% of x - linked genes into those with functional or nonfunctional y homologs . |
PubmedSumm118525 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
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the input is a biomedical literature
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the output is the summary of an input biomedical literature in six sentences
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Input: the extracellular matrix ( ecm ) is the noncellular component present within all tissues and organs ; it is produced mainly by a heterogeneous population of fibroblasts and provides essential physical scaffolding for the cellular constituents as well as biochemical cues that are required for tissue morphogenesis , differentiation , and homeostasis .
the ecm is composed of water , proteins , and polysaccharides ; each tissue has an ecm with a unique and different composition and a distinct topology .
cell adhesion to the ecm is tissue specific and is mediated by ecm receptors , such as integrins , discoidin domain receptors , and syndecans .
the ecm includes the interstitial matrix and the basement membrane , of which the interstitial matrix is present between cells , whereas the basement membrane is a thin , sheet - like deposition of ecm that surrounds cells ( e.g. , muscle cells ) or underlies cells ( e.g. , epithelial cells ) .
the basement membrane is composed of two layers : a basal lamina and a fibrillar reticular lamina [ 2 , 3 ] .
adhesion mediates cytoskeletal coupling to the ecm and is involved in cell migration ; the ecm is also a highly dynamic structure that is constantly being remodeled , both enzymatically and nonenzymatically , and its molecular components are subjected to various types and numbers of posttranslational modifications .
the ecm is composed of two main classes of macromolecules : proteoglycans ( pgs ) and fibrous proteins .
pgs are composed of glycosaminoglycan ( gag ) chains covalently linked to a specific protein core .
the three main families are small leucine - rich proteoglycans ( slrps ) , modular proteoglycans , and cell surface proteoglycans .
pgs occupy the majority of extracellular interstitial space within the tissue in the form of a hydrated gel .
pgs have a wide variety of functions that reflect their unique buffering , hydration , binding , and force - resistance properties .
collagen is the most abundant fibrous protein within the ecm and constitutes up to 30% of the total protein mass of a multicellular animal .
this protein constitutes the main structural element of connective tissues and also provides tensile strength , regulates cell adhesion , supports chemotaxis and migration , and directs tissue development .
elastin provides recoil to tissues that undergo repeated stretch . a third fibrous protein , fibronectin ( fn ) , is intimately involved in directing the organization of the interstitial ecm and also plays a crucial role in mediating cell attachment and function .
additionally , fn is important for cell migration during development and has been implicated in cardiovascular disease and tumor metastasis .
laminins and collagen type iv form independent networks that are connected by nidogen and perlecan .
every mammalian host is in constant danger of infection caused by pathogens , such as viruses , bacteria , fungi or parasites .
host defense against these pathogens requires a well - regulated inflammatory response marked by leukocyte migration into the site of infection , destruction of the microorganisms , resolution of inflammation , and , finally , healing and repair of the tissue architecture . generally speaking
indeed , on an evolutionary scale , most parasites have developed adaptive mechanisms to evade host immune system responses .
some parasites evade the host 's immune response by hiding intracellularly , such as toxoplasma and plasmodium species , and certain others evade the cell immune response completely including extracellular parasites such as entamoeba histolytica , free - living amoebas , and trichomonas vaginalis .
parasites engage a plethora of surface and secreted molecules to attach to and enter mammalian cells .
many of these molecules are involved in triggering specific signaling pathways , both in the parasite and the host cell , that are critical for parasite entry and survival .
several important advances have been achieved in identifying factors that are critical to parasite virulence and the pathogenesis of the diseases they cause . among the most widely studied of these factors are parasite - derived proteases .
parasitic proteases can play a variety of roles in establishing , maintaining , and exacerbating an infection .
most of the human protozoan parasites invade , migrate , and reside within a variety of tissues and organs , whether they are intracellular or extracellular parasites .
interestingly for some parasites it has recently been reported the induction of ecm proteases in host cells . connective tissue and basement membranes represent major barriers to parasite invasion , dissemination , and access to essential nutrients .
e. histolytica is the causal agent of amoebiasis in humans and is responsible for an estimated 35 to 50 million cases of symptomatic diseases and approximately 100 000 deaths annually , mainly in the developing world .
parasite excystation in the small intestine produces eight trophozoites per cyst , which then colonize the large intestine .
once e. histolytica trophozoites are normally established in the human colon , the infection has variable outcomes , including such manifestations as asymptomatic colonization , diarrhea , dysentery , invasive colitis , liver abscesses , or metastatic invasion .
parasite destruction of host cells appears to be the basis of disease ; invasive disease pathologies , such as colitis and liver abscesses , are associated with tissue invasion and massive host tissue destruction .
for example , flask - shaped ulcers , a hallmark of amoebic colitis , is characterized by severe damage to enteric cells as well as the migration to the lamina propria and blood vessels .
it has been proposed that for the initial contact or adhesion , surface carbohydrates on the target cell are recognized by specific molecules ( lectins ) .
one of the more studied amoebic lectins is the gal / galnac lectin , which mediates the binding to host carbohydrate determinants that contain galactose and/or n - acetyl - d - galactosamine ( galnac ) .
the subsequent cell lysis occurs through the insertion of pore - forming proteins ( amoebapores ) into the host cell membranes , which allows a massive influx of extracellular ca combined with the release of amoebic proteases at the site of contact , with the subsequent degradation of the substrate .
once the targets are partially digested , the amoeba internalizes the cell debris and substrate fragments by phagocytosis .
in contrast , the interaction of trophozoites with extracellular matrix ( ecm ) components results in the proteolysis and destruction of the connective tissue .
these proteases have been demonstrated to act on a variety of host substrates in vitro [ 2125 ] .
at least some of these proteases are secreted , and a few have been characterized as surface localized ; hence , they have the potential to contribute to host tissue breakdown in vivo .
an in vitro model was developed to analyze the interaction of e. histolytica trophozoites with ecm proteins .
the assays quantitatively monitored the adhesion of trophozoites to purified fn - covered surfaces and the breakdown of this protein under diverse experimental conditions .
the data showed specificity in the binding and the occurrence of structural and biochemical events in the amoebas that participate in and promote the adhesion to the substrate and the later degradation .
a putative amoebic fibronectin receptor with a molecular weight of 37 kda was found [ 27 , 28 ] .
another protein of 140 kda was found , with similarities to -integrin family that together with the 37-kda protein recognizes fibronectin and produces cytoskeletal changes in the amoebae .
the adhesion to fibronectin triggers proteolytic enzyme release , which facilitates the local degradation of the substrate [ 27 , 28 , 30 ] .
certain of these secreted proteases show similarities to cathepsin b and might generate fragments with chemotactic and chemokinetic properties that are able to promote binding as well as locomotion of trophozoites .
collagen is a major component of the basal lamina and the ecm components of the intestine .
there are three collagen - binding proteins described in e. histolytica , with molecular weights of 105 , 56 , and 30 kda , that recognize mainly collagen type i ; the 30 kda protein has collagenolytic activity .
antibodies raised against the 30 kda molecule inhibit the binding of trophozoites to collagen .
several of the proteolytic activities related with ecm degradation are summarized in table 1 and figure 1 .
an amoebic collagenase activity was first described by muoz et al . ; this study showed that this protein of e. histolytica was a membrane - bound enzyme that digests native collagen type i and type iii at neutral ph and 37c .
three major fragments of 75 , 50 , and 25 kda were obtained from collagen type i when this protein was incubated with e. histolytica trophozoites for 3 h. after this incubation period , smaller fragments of collagen were found , possibly due to the action of other proteolytic enzymes . the collagenase activity was found mainly in electron - dense granules in e. histolytica .
these granules were induced and secreted in response to the incubation of collagen type i with trophozoites of e. histolytica in vitro . in another study ,
one specific collagenase activity with a molecular weight of 72 kda was found in e. histolytica crude extracts .
this activity was found in electron - dense granules and could be related to the actin cytoskeleton function because one cytoskeleton - altered amoeba ( bg-3 ) derived from the pathogenic hm1-imss strain had less collagenase activity .
collagen type i incubation not only promotes collagenase activity but also increases the secretion of other proteases ( mainly cp ) , and , together with ca , is able to induce the activation of several amoebic genes related to certain virulence factors , such as amoebapore c and cysteine protease 5 , along with the stress - induced protein hsp70 and the ribosomal protein l27a . in a recent study , chvez munguia et al
there is evidence supporting the role of the extracellular cysteine proteases of e. histolytica as virulence factors .
cp purified from axenized e. histolytica cleaves collagen , elastin , fibronectin , and laminin [ 21 , 24 , 34 , 6163 ] .
cp - a5 and cp - b9 cysteine proteases possess gelatinase activity in vitro [ 34 , 36 ] and may have a role during tissue invasion .
hou et al . has shown that promature cp - a5 binds to colonocyte and triggers cytokine secretion . in a recent work using 3d collagen matrix determined that amoebic cps are responsible for the collagenase activity and that these enzymes have an important role during cell migration through a three - dimensional collagen scaffold .
e. histolytica trophozoites combine cell shape deformation and protease activity in order to overcome physical constraints , suggesting that e. histolytica 's particular mode of migration explains its ability to overcome various environment constraints to rapidly invade human tissues . in this work
, the authors also hypothesize that cp5 promotes inflammation and the secretion of host metalloproteases ( mmp ) that contribute to the ecm destruction .
finally , the collagenolytic activity of e. histolytica has been correlated with its virulence when compared among different strains of e. histolytica [ 6567 ] or with other virulence factors . in all the studies
the study of e. histolytica proteases is an interesting field to be explored in the future as drug targets to inhibit the migration and invasion of this parasite .
g. intestinalis ( also known as giardia lamblia and giardia duodenalis ) is a major contributor of diarrheal diseases in humans .
an estimated 200 million people have symptomatic giardiasis worldwide , and children under 5 years are at particular risk .
although g. intestinalis infection is not invasive , parasites adhere to the brush border microvilli lining on the small intestine surface , leading to a reduction in their height , accompanied by decreased expression and activity of several digestive enzymes located in the intestine .
adhesion to ecm could be important for colonization , since trophozoite attachment was demonstrated to be even more effective to type i collagen than to the apical surface of confluent madin darby canine kidney ( mdck ) cells in vitro .
giardia releases products that may contribute to pathogenesis , such as proteases , although they have not been well characterized yet [ 74 , 75 ] .
there are only three reports regarding the collagenolytic activity using zymograms ( table 1 , figure 1 ) .
williams and coombs explored intracellular proteases present in lysates of trophozoites and observed collagen degradation by a group of low molecular mass proteases ( 3065 kda ) , plus one of 120 kda .
in contrast , coradi and guimaraes in 2006 demonstrated that the hydrolysis of collagen type i by trophozoites lysates was associated with a broad enzymatic activity , from > 116 to 18 kda .
[ they used five strains isolated and axenized in brazil and the reference strain portland 1 . ] in all strains , the major proteolysis zones were visualized at [ 90- to 18-kda ] region , mainly the bands detected at 66 , 45 , 30 , and 18 kda and a diffuse zone ranging from 35 to 18 kda .
the significance of these differences in the enzymatic activity remains to be determined , and it would be interesting to identify if it correlates with strain virulence . a subsequent study showed that these proteases are in fact secreted by trophozoites , since excretory / secretory products display collagenolytic activity in the same molecular range , mainly the activities of 145 , 96 , and 82 kda bands .
inhibition assays showed that the main proteolytic activity against collagen type i in excretory / secretory products is due to cp .
the fact that trophozoites contain and/or release collagenases could be of special importance in giardiasis pathogenesis , particularly when it comes to alterations in the intestinal epithelium . additional research is required to confirm this hypothesis , from the identification of the genes encoding for these collagenases to the use of animal models to test their contribution to the infection .
are able to cause several diseases in humans , which are associated with immunocompromised patients in the case of granulomatous amoebic encephalitis and with contact lens wearers in the case of keratitis .
more than 30 cases of acanthamoeba keratitis were identified recently from the chicago ( illinois ) area alone .
it is estimated that as of august 2006 more than 5000 cases of acanthamoeba keratitis have occurred in the united states . because acanthamoeba keratitis is not a reportable disease in the united states ,
the name of this protozoan comes from the presence of spine - like structures on its surface .
this amoeba has a simple life cycle with two stages , a vegetative stage , or trophozoite , and a resistant stage , or cyst .
parasite adhesion to target cells or tissues is a necessary step to invade the host ; this step is mediated by a 130 kda mannose - binding protein ( mbp ) , which is a surface - expressed protein .
other adhesins include a laminin - binding protein of 28.2 kda and a 55 kda protein that was found to bind to laminin in the pathogenic strain a. culbertsoni .
furthermore , a. polyphaga binds to the ecm proteins collagen type iv , laminin and fibronectin , and calcium enhances this binding . in these interactions , amoebas exhibit a stronger attachment to the basal membrane components laminin and collagen iv .
the adhesion to these molecules leads to secondary responses , such as phagocytosis and toxin production , that result in host cell death via the phosphatidylinositol 3-kinase ( pi3k ) pathway .
additionally , acanthamoeba has been shown to display plasminogen activator activity , which can trigger host mmp leading to the degradation of basement membranes .
acanthamoeba also possesses hydrolytic enzymes , such as elastases , phospholipases , serine proteases [ 8689 ] , cp [ 86 , 89 ] , and contact metalloproteases .
there are many proteases in acanthamoeba that are able to degrade certain components of ecm proteins ( table 1 , figure 1 ) .
described the presence of a collagenolytic enzyme that digested collagen shields and purified collagen in vitro .
collagen is one of the major components of the cornea , so keratitis is directly linked to the collagenolytic activity .
more importantly , in vivo studies demonstrated the pathogenic features of this parasite product , as a. castellanii - conditioned medium produced lesions that resembled amoebic keratitis .
the use of nonspecific protease inhibitors and ethylenediaminetetraacetic acid - na ( edta - na ) with acanthamoeba - conditioned medium completely blocked the degradation of collagen shields , and the use of edta - na in vivo also blocked amoebic collagenase activity .
mitro et al . also described the collagenolytic activity of a. polyphaga - conditioned medium on the substrates azocoll and gelatin ( both denatured type i collagen ) and native collagen type i. they concluded that a. polyphaga secretes multiple proteases of the serine , cysteine , and metalloprotease types and that all the proteases can contribute to the collagenolytic effect .
kong et al . described the purification of a secretory serine protease of a. healyi .
the purified protease had a molecular weight of 33 kda , a ph optimum of 8.0 , and a temperature optimum of 40c .
the protease activity is inhibited by phenylmethylsulfonyl fluoride ( pmsf ) and diisopropylfluorophosphate ( difp ) serine protease inhibitors . na et al . purified a secreted protease from a. castellanii of approximately 12 kda in molecular weight .
this molecule was a chymotrypsin - like serine protease that could degrade various protein substrates , such as collagen , fibronectin , laminin , secretory iga , igg , plasminogen , fibrinogen , hemoglobin , and rabbit corneal protein .
the researchers also used the purified protein to test cytopathogenicity toward hep2 cells , which resulted in the loss of viability within 12 h. the cytopathogenic events were completely inhibited when the protease was pre - treated with pmsf before being added to the hep2 cells .
the purified 33 kda protease had a ph optimum of 8.5 and a temperature optimum of 37c .
this protease is able to degrade collagens type i and iv , fibronectin , fibrinogen , hemoglobin , albumin , igg , and iga .
furthermore , kim et al . reported that this 33 kda protease could be purified from different acanthamoeba strains with different degrees of virulence .
identified two proteases of 130 and 150 kda from an acanthamoeba isolate capable of inducing granulomatous encephalitis .
the 130 kda protease was inhibited by pmsf , suggesting that it is a serine protease , whereas the 150-kda protease was inhibited by 1 , 10-phenanthroline , suggesting that it is a metalloprotease .
these proteases degrade ecm components , such as collagen i and iii ( major components of collagenous ecm ) , elastin , and plasminogen as well as casein and hemoglobin .
ferreira et al . characterized secreted elastase activities in the conditioned medium of acanthamoeba polyphaga .
these activities are in the range of 70130 kda , and they have an optimal ph of 7.5 ; additionally , they are inhibited by pmsf , antipain , chymostatin , and 1 , 10-phenanthroline , and partially reduced by elastinal and edta .
this study demonstrates that amoebic trophozoites secrete elastase activities and suggests the high - molecular - weight serine proteases as possible elastase candidates .
finally , de souza carvalho et al . described the partial biochemical characterization of extracellular proteolytic enzymes secreted by acanthamoeba spp .
different enzymatic patterns of collagenases were observed , varying between single and multiple collagenase activities .
low - molecular - weight serine proteases were secreted by the trophozoites and were associated with a more severe clinical course of the keratitis .
consequently , acanthamoeba proteolytic enzymes could be related to the degree of virulence and clinical manifestations of disease in human keratitis .
more studies are necessary to comprehend the importance of the proteases of this parasite in the diseases caused by acanthamoeba spp . and also to design protease inhibitors as drugs to target acanthamoebic proteases .
are free - living amoebae that are found worldwide in warm fresh water and that feed mostly on bacteria .
naegleria spp . are amoeboflagellates that could transform from the trophozoite form into a flagellate if nutrients are limited .
species of naegleria have been known for over a century , but it was only approximately 40 years ago that one species , called naegleria fowleri , was found to cause primary amoebic meningoencephalitis ( pam ) in human .
n. fowleri is a pathogen with a worldwide distribution ; because the organism lives and multiplies in warm water , most cases of pam occur in tropical regions .
however , it is almost always fatal , with only approximately 5% of patients surviving , and it affects mostly children .
pam affects the central nervous system ( cns ) , progresses rapidly , and is commonly fatal . in experimental animals , the amoebae gain access to the cns by crossing the olfactory bulbs [ 97 , 98 ]
once there , the trophozoites divide rapidly and cause inflammation associated with tissue destruction , leading to death in a few days . the pathogenic mechanisms involved in the tissue invasion and destruction
are poorly understood . however , various in vitro studies suggest the presence of many virulence factors that could be involved in the pathogenesis of pam .
these factors include the presence of adhesins , pore - forming proteins [ 100 , 101 ] , phospholipases , contact - dependent lysis , elastase , and secreted proteases with cytopathic effects [ 45 , 104 ] .
reported that n. fowleri possesses an integrin - like molecule that binds to immobilized fibronectin .
this protein was described as being an -integrin subunit and has a role in cytotoxicity .
described the interaction of n. fowleri with human collagen i. recently , jamerson et al .
compared the adhesion to collagen and fibronectin by the pathogenic n. fowleri strain and the nonpathogenic n. lovaniensis , finding greater adherence of n. fowleri to fibronectin .
cervantes - sandoval et al . found several differences between pathogenic n. fowleri and nonpathogenic n. gruberi in the expression of mannose and fucose glycoconjugates .
n. fowleri presents higher levels of surface glycoconjugates that contain -d - glucose and terminal -l - fucose residues than n. gruberi .
these differences could be related to the adherence to different substrates , and , therefore , they could also be related to the pathogenesis of n. fowleri .
partially purified a secreted protease activity of 30 kda with two isoforms ( table 1 , figure 1 ) .
the biochemical properties of these two forms of n. fowleri protease activity were indistinguishable , suggesting that they might be posttranslationally modified isoforms of the same gene product .
this activity was abolished by trans - epoxysuccinyl - leucylamido(4-guanidino)butane ( e-64 ) and leupeptin , cysteine protease inhibitors .
trophozoites or secreted protease activities were able to degrade mainly collagen and elastin ecm proteins ; this effect was inhibited by zfa - fmk , a specific cysteine protease inhibitor .
described proteolytic activities from n. fowleri and n. gruberi that are able to degrade azocoll at 37c .
more studies are needed to elucidate whether specific proteases from n. fowleri can degrade specific ecm proteins , such as collagens type i and iv , fibronectin , elastin , and laminin .
the study of naegleria virulence factors is still scarce ; therefore , many studies have to be done in the future pointing out especially to the role of amoebic proteases in the invasion to the cns .
it is also necessary to develop new drugs against this parasite , and some of these drugs could target mainly cps .
t. vaginalis is a flagellated protist that is responsible for the most prevalent nonviral sexually transmitted infection ( sti ) , with an annual estimate of 174 million new infections worldwide .
the parasite is capable of causing severe vaginal , ectocervical , prostatic , and urethral inflammations , and it is linked with sterility , pelvic inflammatory disease , adverse pregnancy outcomes , postnatal complications , and cervical cancers [ 109113 ] . furthermore , t. vaginalis also contributes to the hiv pandemic , along with other stis , by boosting the efficiency of virus transmission [ 109 , 111 , 114 , 115 ] .
the trophozoite attaches to the mucosal surfaces of the lower urogenital tract and divides by longitudinal binary fission .
t. vaginalis survives long term in the varying and adverse acidic environment of the vagina through various successful mechanisms .
after cytoadherence , t. vaginalis transforms to an amoeboid structure with increased cell - to - cell surface contact , forming cytoplasmic projections that interdigitate with target cells .
the interactions of t. vaginalis with mucins , vaginal epithelial cells , and ecm molecules persist in a non - self - limiting fashion .
the parasite readily attaches to surfaces with immobilized fibronectin and binds to fibronectin in a highly specific receptor - mediated fashion .
interestingly , the enzyme glyceraldehyde 3-phosphate dehydrogenase ( gapdh ) was found to be a surface - associated fibronectin - binding protein of t. vaginalis .
gapdh was upregulated by iron ; accordingly , higher levels of binding to fn were observed for organisms grown in an iron - replete medium .
unknown surface proteins and carbohydrates appear to mediate parasite binding to immobilized laminin . just as happened with fibronectin , t. vaginalis adhesion proteins that mediate cytoadherence
were found not to be involved in laminin binding [ 117 , 119 ] .
t. vaginalis encodes an impressive repertoire of candidate proteases , with almost 450 genes , making t. vaginalis one of the richest protease - containing protozoans in nature [ 120 , 121 ] .
an in silico search for possible surface - bound candidates to degrade ecm molecules showed that in the genome draft , 122 t. vaginalis entries are transmembrane proteases ( tps ) .
these proteases are better known in the human system , where they fulfill multiple functions , including degrading ecm proteins and cell - cell and cell - ecm adhesion , and are thought to be important in neoplastic , inflammatory , and infection sites [ 121 , 122 ] .
gp63 in leishmania are involved in binding to host cells and degradation of various host proteins , including proteins from the immune system and ecm proteins [ 121 , 123 ] .
in addition to these in silico inferred proteases that are possible candidates to degrade ecm , there are three reports of t. vaginalis cp activities degrading components of the ecm : cp30 , cp39 , and cp65 .
the cp30 fraction was obtained by performing a binding assay of total t. vaginalis proteins to fixed hela cells and then collecting the eluted proteins .
these hela - binding proteins are able to degrade collagen iv and fibronectin , but not laminin 1 , in the region corresponding to 30 kda , by the zymogram technique . using a gelatin two - dimensional ( 2d ) zymogram
, the researchers determined that the protease activity belonged to a cysteine protease , as it was inhibited by e-64 , and they detected two spots in this mw region ; however , this fraction was not tested again with ecm substrates . using a polyclonal antibody raised against the entire 30 kda hela - binding fraction separated by 1d gels , they located the cp30 fraction at the t. vaginalis surface and in the cytoplasm ; they also inhibited t. vaginalis adhesion to hela cells .
furthermore , t. vaginalis isolates with low levels of cytoadherence had little or none of the 30 kda protease activity .
the researchers also found that the cp30 fraction is immunogenic and is secreted by t. vaginalis in vitro ( culture media ) and in vivo ( vaginal washes ) .
interestingly , parasite cells grown in contact with hela cells appear to release higher levels of the cp30 fraction . because the researchers were working with a fraction ,
it is not possible to know whether a single protein is responsible for all the detected activities : gelatinase , collagenase , fibronectinase , immunogen , adhesin , surface protein , cytosolic protein , and secreted protein .
it is important to emphasize that cp30 was active on collagen iv and fibronectin only at a ph of 4.5 and 5.0 ; beyond this ph , no cp30 activity was detected , indicating that the in vitro optimal conditions for cp30 activity are consistent with the environmental conditions found in the urogenital tract of women .
for example , the vaginal ph in healthy women ranges from 4.0 to 5.0 and in women with ongoing trichomoniasis from 4.4 to 7.0 [ 46 , 125 ] .
thus , cp30 could degrade certain ecm proteins in the first step of infection , when the vaginal microenvironment is acidic .
the cp39 fraction was studied using the same strategy and showed almost the same behavior as the cp30 fraction , with the exception that more substrates were tested , and it was found that this fraction degrades collagen i , ii , and v in addition to collagen iv and fibronectin .
the 39 kda protease band is formed by only one spot in a 2d gelatin zymogram , with an mw of 37.5 kda and a pi of 4.9 ; the protein was identified by mass spectrometry .
tvcp39 had the motifs typical of a novel clan ca , family c1 , cathepsin l - like cps [ 126 , 127 ] .
the antibody against the purified recombinant protein did not recognize the original 37.5 kda protease in total protease - rich extracts .
instead , it recognized two spots of 28 and 24 kda with pi 5.0 , which were identified by mass spectrometry as part of the tvcp39 cytotoxic protease .
the authors concluded that the antibody can not identify the mature protease , probably due to posttranslational modifications such as n - linked glycans . using this antibody ,
it was observed that tvcp39 is located on the surface of the parasite and is secreted during active infection [ 47 , 127 ] supporting the role of tvcp39 as a potential biomarker for trichomoniasis in vaginal secretions .
additionally , tvcp39r binds to the surface of hela cells and protects them from trichomonal cytotoxicity , probably by competing with the native tvcp39 for the binding sites on hela cells .
sommer et al . showed that the cp30 fraction composed of tvcp4 , tvcp39 , and , in smaller proportion , tvcp3 was able to induce apoptosis in human vaginal epithelial cells ( hvecs ) .
the initiation of apoptosis is correlated with protease activity , as the specific cysteine protease inhibitor e-64 inhibited both activities . whether the mechanism involved in the cellular damage by tvcp39 is through induction of programmed cell death as was identified for the entire cp30 fraction requires further investigation .
the cp65 fraction was studied using the same strategy as for the cp30 and cp39 fractions , and it showed almost the same behavior , degrading collagen iv and fibronectin .
subsequently , they determined the proteolytic activity and the corresponding protein pattern in 2d gel electrophoresis to identify the tvcp65 protein spot and the coding partial gene .
the partial sequence was identified as a typical clan ca , family c1 , and cathepsin
the antibody against the purified recombinant protein recognized tvcp65 in total lysates of t. vaginalis and on the parasite surface .
the recombinant fragment of cp65 binds hela cells and prevents the native cp65 binding . in the case of tvcp65 ,
the partial gene was identified previous to the release of the t. vaginalis genome draft , so the entire gene was not obtained . remarkably , a recent study of the t. vaginalis degradome also showed , in the 2d zymogram , proteolytic activity in the 6370 kda regions , which might be related to this previously described tvcp65 protease .
the cps identified suggested that these high - mw spots are formed by two strongly bonded cp with mws between 34.6 and 33.7 kda , that are resistant to the denaturing and reducing conditions used during the 2d procedure [ 120 , 126 , 130 ] .
all three fractions identified genes coalescing in some way in the 30 kda region , which is in agreement with the findings in the t. vaginalis degradome ; most of the 27 proteolytic spots detected in 2d zymograms are encoded by only nine distinct genes identified with theoretical mws in the 30 kda region ( tvcp1 , tvcp2 , tvcp3 , tvcp4 , tvcp4-like , tvcp12 , tvcpt , tvlegu-1 , and another legumain - like cysteine protease ) .
therefore , there may be three different proteases that are actually within the same mw range of 30 kda and that behave differently in zymograms because of their different processing stages , posttranslational modifications , or dimerization .
alternatively , the signals may all correspond to the same protease , and further research would clarify this question .
moreover , after the protease genes of fractions cp30 , cp39 , and cp65 were identified , the ability to degrade ecm proteins was not tested for each one , so it remains to be determined which one of these proteases is responsible for ecm protein degradation . because the secreted fractions cp30 , cp 39 , and cp65 were able to degrade several types of collagens , they might also be the molecules involved in the cervical softening observed before labor , or preterm labor in women with trichomoniasis [ 47 , 48 , 132 , 133 ] .
further research should be performed to corroborate the role of such proteases in the tissue damage that occurs during trichomoniasis .
t. brucei is a protozoan parasite responsible for thousands of infections every year of african trypanosomiasis , with two variants : in animals , the disease is known as nagana , and in humans it is known as sleeping sickness or human african trypanosomiasis ( hat ) .
the transmission vectors are the tsetse flies that inoculate t. brucei parasites into the blood of its mammal host .
trypanosomiasis presents two stages : first , trypanosomes are observed in the hemolymphatic system , producing fever , splenomegaly , adenopathies , endocrine disarrays , and cardiac and neurological or psychological disorders . in this stage , trypanosomes multiply rapidly , infecting the spleen , liver , lymph nodes , skin , heart , eyes , and endocrine system . in the later stage , trypanosomes are distributed in the cns , leading to several sensory , motor , and psychic disorders , and culminating in death [ 134 , 135 ] . to reach the inner tissues in its host ,
the parasite t. brucei secretes proteases into the ecm ( table 1 , figure 1 ) , such as the 40 kda neutral metalloprotease that permits the parasite to move and migrate by degrading collagen , fibronectin , and laminin .
this activity is inhibited by edta , ethylene glycol tetraacetic acid ( egta ) , phenanthroline , and tetracycline .
the gp63 zinc metalloprotease , the most important matrix metalloproteinase ( mmp ) in the parasite , is a surface enzyme that was first reported in leishmania .
this enzyme performs several functions in different stages of the trypanosome life cycle , and the development of specific inhibitors provides new treatments for this parasitic disease . in the later stages of the disease ,
when the trypanosomes cross the blood - brain barrier ( bbb ) , the extracellular release of metalloproteases and cell adhesion molecules from t. brucei contributes to the bbb disruption by the modification of the ecm components , and these molecules can be used as markers for early diagnosis of the disease progression from the first to the second stage .
this information is important because the treatment differs between the two stages and is more complicated in the case of the later stage of the disease .
a prolyl oligopeptidase gene ( poptc ) homolog in t. brucei has been identified , poptb , and the secondary structure has been obtained .
recombinant poptb shows a structural composition similar to pop from t. cruzi and similar sensitivity to inhibitors .
associated proteases participate in the process of traversal across the bbb , as the t. brucei cp , brucipain , and cathepsin b ( tbcatb ) .
tbcatb is upregulated in vivo , suggesting the participation of this protein in the parasite internalization .
cp can activate a class of g protein - coupled receptors ( gpcrs ) known as protease - activated receptors , or pars .
the participation of par-2 in a calcium - mediated signaling pathway allows the trypanosomes to cross into the cns [ 17 , 52 ] .
gene - specific rnai can be induced in bloodstream parasites in an experimental model of trypanosome infection .
induction of rnai targeting tbcatb transcripts , led to reduced protease activity in vivo rescuing mice from a lethal t. brucei infection , as it was observed in previous in vitro rnai experiments . in the murine model of infection ,
trypanosomes expressing tbcatb rnai did not present splenomegaly , and parasites were not detected in blood , due to the inability of parasites to effectively enter into other tissues .
this constitutes an important evidence of the role of t. brucei proteases in the degradation of ecm proteins and also in the colonization and invasion of different organs in the host .
this protozoan parasite causes human chagas disease , a chronic and debilitating condition affecting 10 million people from mexico to argentina and chile .
t. cruzi is transmitted either by an insect vector that has access to the host via breaches in the skin or through mucosal membranes , mainly the conjunctival or gastric mucosa .
it is an obligate intracellular parasite that disseminates from the initial infection sites to the heart and smooth muscle , with several rounds of invasion , growth , and egress from infected cells during the acute infection .
very little is known regarding the early interactions between the parasite and its host that facilitate the establishment of the infection .
t. cruzi is also transmitted through blood transfusion , organ transplantation , ingestion of contaminated food or fluids , and congenital or sexual transmission .
vertical transmission of t. cruzi can not be prevented , but with early detection and treatment it can be cured with 100% success . during congenital t. cruzi infection ,
this result provides evidence that the parasite induces reorganization of the ecm in a way that regulates the inflammatory and immune responses of the host . in this context , the parasite load and the immunological status of both mother and fetus , which influence the probability of congenital transmission of t. cruzi , are determinants for the infection . in the infective process , collagen , heparan sulfate , and laminin are destroyed by the parasite , but interestingly , fibronectin is not affected , so the selective destruction of the ecm could be part of the invasion mechanism . at the site of primary infection ,
the metacyclic trypomastigotes infect local macrophages , fibroblasts , and mesenchymal tissues , but the infection of distant tissues after dissemination through the blood vessels is unknown .
several pieces of evidence have shown that t. cruzi interacts with host ecm components , not only producing the breakdown products that play an important role in parasite mobilization and infectivity but also altering the presence of cytokines and chemokines , allowing the escape of the parasite from the inflammatory and immune responses . during tissue invasion ,
t. cruzi interacts with different elements of the ecm , facilitating the internalization into different cells in the underlying connective tissue .
adhesion is very important for the parasite , which presents various surface molecules , such as the gp85 fibronectin receptor and gp83 , that bind to human cells to regulate the expression of laminin , needed to enter the host cell [ 143 , 144 ] .
these glycoproteins that bind to collagen , laminin , and fibronectin allow the parasite to permeate and migrate into the ecm barrier .
a recent study of the human ecm interactome of t. cruzi and its gp83 ligand shows that this interaction is important for understanding the molecular pathogenesis of the infection and could lead to novel approaches to intervention in chagas disease .
a prerequisite for host cell invasion is that t. cruzi must cross the ecm barriers . through mechanisms that are not well understood
the more obvious explanation for the decrease of ecm is that the parasite destroys the ecm by the secretion of proteases .
several products with characteristics of proteases were studied in this parasite ; they include cps , serine proteases , and metalloproteases ( table 2 , figure 2 ) .
gp57/51 , cruzain or cruzipain , a cysteine protease of the papain family , is the best characterized protein in t. cruzi .
it is synthesized during all developmental stages of t. cruzi , but in a regulated manner , and amastigotes and trypomastigotes contain 10-fold lower levels than epimastigotes .
the enzyme is present in lysosomes and reservosomes , and certain isoforms are associated with the plasma membrane , whereas others are secreted into the medium and are capable of degrading collagen , fibronectin and highly antigenic proteases [ 147 , 159 , 160 ] .
the crystal structure of the protein shows a unique active site feature , which suggests that the design of specific inhibitors could reduce parasitemia and infection with no effect on mammalian cells .
cruzipain is inhibited by organomercurial reagents such as e-64 , tosyl - l - lysinechloromethyl ketone ( tlck ) , and cystatins , such as peptidyl diazomethane [ 159 , 162 ] , or by the 2,3,5,6,-tetrafluorophenoxymethyl ketone inhibitor , which totally eliminates t. cruzi parasites .
cruzipain is structured as one catalytic domain , with high sequence identity with cathepsin s , and a long c - terminal domain , characteristic of the cp in trypanosomatids .
the mature enzyme is encoded by several arranged genes containing repeated units encoding the pre - proenzyme form with the c - terminal extension [ 160 , 164 ] .
previous studies have demonstrated that infection can be treated in cell , mouse and dog models by the inhibition of cruzipain [ 165 , 166 ] .
gp63 , or penetrin is a surface protease that promotes adhesion to heparin , heparan sulfate , and collagen
. this molecule could play a very important role in host cell invasion after migration through the ecm .
it is localized on the surface , promoting the selective adhesion of trypomastigotes in a saturable way and promoting adhesion and spreading of fibroblasts .
although it has not been determined whether this protease degrades ecm proteins , it is very important for t. cruzi binding to the ecm and for host cell invasion .
it catalyzes the cleavage of several ecm components , such as collagen types i and iv and fibronectin and is localized inside a vesicular compartment close to the flagellar pocket , which suggests that its secretion and local action on ecm components are required for infection .
it acts as a regulator of parasite infection and pathogenesis of chagas disease , with a molecular mass of 97 kda in cellular extract and an 85 kda polypeptide in both cellular and secreted parasite extracts .
these proteins were recognized by an anti - mmp-9 polyclonal antibody that localized them on the surface of t. cruzi .
mmps of the family of zinc - dependent peptidases that regulate ecm - eukaryotic cell interactions can be involved in normal matrix remodeling or pathological tissue destruction .
the gelatinases mmp-2 and mmp-9 are important in many physiological and pathological processes in mammals .
30 kda cathepsin b - like protease is another cysteine protease identified and produced in all forms of t. cruzi parasites that degrades human type i collagen .
pathogenoproteomics is the study of the interactions among host , vector , and parasite , which aims to understand infections with particular attention to the proteases in the secretome of trypanosomes as important molecules for virulence and pathogenicity , just as cps are known to play an indispensable role in the biology of parasitic organisms and suspected to act as a major pathogenic factors in mammalian hosts .
specific interactions between t. cruzi and ecm components play an important role in parasite distribution , mediating basement membrane and ecm degradation as well as adhesion to and invasion of host cells . the ecm - binding sites on the t. cruzi surface
the complete genome of t. cruzi is still unknown , and several proteases have been identified , although most of them have not been biochemically well characterized .
cruzipain is the best characterized protease , and it has been proposed as a virulence factor in chagas disease due to its participation in the invasion of mammalian cells . in this regard , the treatment of t. cruzi - infected mice with specific protease inhibitors resulted in their effective rescue from lethal infection , and parasitological cure of most of them .
these results are very hopeful , since they clearly indicate that proteases could be considered as valid targets for chemotherapy in chagas disease .
in fact , efforts to develop new drugs for chemotherapy have been recently shown to be effective for the treatment of chagas disease in animal models .
leishmania are kinetoplastid dimorphic protozoan parasites of vertebrate macrophages that cause the chronic sandfly - borne disease leishmaniasis .
it is estimated that 1.5 to 2 million children and adults develop symptomatic disease each year , resulting in more than 70,000 deaths ( primarily from visceral leishmaniasis ) and an infection prevalence of 12 million people .
different species of leishmania are responsible for a spectrum of human diseases , ranging from the self - healing cutaneous forms caused by l. major , l. tropica , and l. mexicana to the more severe mucocutaneous disease caused by l. braziliensis and finally to the most severe form , the visceral disease caused by l. donovani .
leishmania develops within the midgut of the sandfly vector as flagellated promastigote stages that transform through a number of physiological states , culminating in the nondividing , metacyclic promastigotes that are preadapted for life in the mammalian host .
metacyclic promastigotes are injected into the skin when female sandflies take a blood meal and are phagocytosed by a variety of host cells , including neutrophils , dendritic cells , and macrophages that are equipped to clear invading microbes
. however , internalized promastigotes differentiate into nonflagellated amastigotes that can replicate within lysosome - like compartments , or parasitophorous vacuoles , within these cells .
leishmania surviving intracellularly produce multiple effects in phagocytes , including inhibition of the respiratory burst , prevention of apoptosis , inhibition of chemotaxis in both macrophages and neutrophils , and suppression of the th1-type protective response .
in addition , during the intracellular life of leishmania , this protozoan requires a repertoire of adaptations to assure entry - exit from the cell as well as to thwart innate immune mechanisms and prevent clearance .
these adaptations include the invasion and destruction of host tissues and the penetration of host vascular systems , enabling the parasites to migrate to sites specific for their growth and development . concerning the interplay between leishmania species and ecm
, several studies suggest that this interaction occurs through protease secretion and expression of ecm - binding proteins on the surface of the parasite [ 156 , 157 , 178180 ] .
. identified , isolated , and characterized an l. donovani promastigote surface protein that binds with high affinity ( kd in the nanomolar range ) to laminin , a major adhesive glycoprotein of the ecm and basement membrane .
in addition , a prominent laminin - binding protein of 67 kda was identified on the promastigote surface . in the process of tissue invasion
, there is likely an association of the parasite with the host epithelial cell surface via a receptor - adhesion - like interaction .
importantly , several authors have indicated that ecm components provide a mechanism of adherence for different human pathogens , such as candida albicans , paracoccidioides brasiliensis , and trichomonads , that express laminin - receptor - like molecules that mediate cellular attachment to eukaryotic host cells .
concerning proteolytic activity against the ecm , several researchers reported the degradation of collagen and fibronectin by promastigotes of l. amazonensis . importantly (
table 2 , figure 2 ) , mcgwire found that promastigote migration through the ecm is enhanced by a 63 kda glycoprotein , a zinc - dependent metalloprotease ( syn . gp63 or leishmanolysin ) .
they used a matrigel assay , where approximately 40% of the gp63 expressing promastigotes had migrated into the lower chamber at 12 h after inoculation , while only 7% of gp63-deficient had migrated at the same time . additionally , purified leishmanial gp63 from stationary - phase promastigotes was effective in digesting collagen type iv and fibronectin .
after incubation with gp63 , it began a digestion of the proteins into smaller units that became a smear of smaller proteins of less than 15 kda .
interestingly , the patterns of digested fibronectin observed by sds - page differed somewhat depending on the source of gp63 used , and cell - associated gp63 appeared to digest fibronectin into larger subunits than did purify gp63 .
finally , laminin appeared to be resistant to digestion by gp63 , as it remained intact as protein subunits regardless of the conditions used for incubation .
in addition , when gp63 was inactivated by preincubation with a zinc chelator , orthophenanthroline , this metalloprotease did not degrade fibronectin .
importantly , it was found that leishmanolysin is able to facilitate complement inactivation in serum , participating in the interaction with the host macrophages and in intraphagolysosomal survival [ 179 , 182 ] . following this line of research , kulkarni et al
. showed that both promastigotes and amastigotes of leishmania species ( l. amazonensis , l. major , l. donovani ) can bind directly to soluble fibronectin and laminin and that promastigotes express a distinct surface protein of ~60 kda that binds both ecm proteins .
the results presented strongly indicate that the protein(s ) that bind fibronectin and laminin are distinct from leishmanolysin . because fibronectin and laminin bound to parasite surface proteins of nearly identical molecular weights , it is likely that they may bind the same surface receptor .
importantly , a rapid and extensive surface proteolytic degradation of fibronectin by promastigotes of multiple leishmania species was found .
fibronectin was cleaved into 10 to 13 fragments that ranged in size from 240 to 25 kda , and complete degradation occurred by 24 h for all parasite lines . additionally , leishmania - degraded fn decreased the production of reactive oxygen intermediates by parasite - infected macrophages and affected the accumulation of intracellular parasites .
the authors suggest that the binding of fn and laminin via this receptor may increase the proximity of surface - localized leishmanolysin to fn , resulting in its enhanced degradation .
these results support the idea that cutaneous leishmania species express a receptor protein functionally analogous to the microbial surface component recognizing adhesive ecm molecules . furthermore
, multiple leishmania species can extensively degrade fn in a rapid manner using surface leishmanolysin , which suggests that this process is functionally conserved and may contribute to the pathogenesis of different forms of leishmaniasis .
it is likely that the binding of ecm proteins , such as fn , to the cell surface receptor may lead to signal transduction within parasites , resulting in changes in gene expression that facilitate further parasite invasion or stage transformation .
some studies reported the participation of ecm domains that may be potentially important for the activity of macrophages in innate immunity . interestingly
, kulkarni found several fragments that encompassed nearly the entire fn protein being degraded at the extreme n- and c - terminal ends .
smaller fragments of ~60 and 25 kda were each composed of two and three comigrating fragments of the same size , respectively .
one of the 60 kda fragments encompassed the region of fn containing the rgd domain , and the 28 and 25 kda fragments overlap and encompass the fn ics domain .
it is possible that the proteolytic degradation of fn by leishmania may expose this region for interaction with macrophages in these assays and that the interaction of macrophages with this or other fn fragments may lead to their deactivation .
currently , only a limited number of drugs are available for treating severe cases of cutaneous , mucocutaneous , and visceral leishmaniasis , although none is optimal due to their toxicity or teratogenicity , expense , requirements for hospitalization , and/or the widespread emergence of drug resistance [ 183185 ] . as an alternative strategy ,
there is still great potential for the discovery and design of potent inhibitors that selectively target gp63 to block or reduce leishmania infection by favoring the functional activation of the macrophage . in the case of the intracellular leishmania parasite ,
small molecule protease inhibitors might mimic amino acids or purines for which the parasite has a specific uptake mechanism .
furthermore , homologous host proteases are generally present in lysosomes , a less accessible subcompartment within mammalian cells .
because the ultimate goal of invading leishmania is to become intracellular , mcgwire proposes that enhanced migration at the site of inoculation may promote parasite binding to and phagocytosis by macrophages .
furthermore , migration through the ecm and basement membrane may facilitate the access of parasites to the blood or lymph circulation for dissemination to distant sites [ 178 , 180 ] , where they may parasitize tissue macrophages . supporting this hypothesis ,
gp63-deficient parasites have shown to have diminished virulence in mice [ 188 , 189 ] .
in fact , many different roles have been assigned to this protein , such as ( i ) evasion of complement - mediated lysis , ( ii ) facilitation of macrophage phagocytosis of promastigotes , ( iii ) inhibition of natural killer cellular functions , ( iv ) resistance to killing by antimicrobial peptide , ( v ) degradation of macrophage and fibroblast cytosolic proteins , and ( vi ) promotion of survival of intracellular amastigotes .
the multiple functions of this protein make difficult the assessment of ecm degradation impact in the parasite virulence .
therefore , additional studies are necessary , using more controlled conditions , such as mice expressing collagen and fn mutated in the cleavage site of gp63 , where we can dissect only the ecm degradation role of gp63 .
additional research would be the use of green - fluorescent protein ( gfp ) and gp63-deficient leishmania to precisely track them when invading at the beginning of the infection , instead of late infection measures such as parasite burden or lesion sizes which reflect more complex phenomena [ 188 , 189 , 191 ] .
this parasite has a worldwide distribution and is considered to be one of the most successful on earth [ 192 , 193 ] .
the tissue cyst - forming coccidium t. gondii can probably infect all warm - blooded animals ( mammals and birds ) and humans , with the cat being the only definitive host . although up to one third of the human world population is infected with t. gondii , most infections are asymptomatic .
primary infection is usually subclinical , but in some patients , cervical lymphadenopathy or ocular disease can be present .
infection acquired during pregnancy may cause severe damage to the fetus . in immunocompromised patients , reactivation of latent disease can cause life - threatening encephalitis [ 192 , 194 ] . within the feline intestinal epithelium , the parasites go through a sexual cycle , resulting in oocyst shedding . in its intermediate hosts , such as humans ,
the parasites go through a sexual cycle , and infection is mainly acquired by ingestion of food or water contaminated with oocysts or by eating undercooked or raw meat containing tissue cysts .
the wall of these cysts is digested inside the host stomach , and the released bradyzoites will invade the small intestine . within the small intestine , they transform into tachyzoites , the rapidly growing , disease - causing form .
tachyzoites , which can infect most nucleated cells , replicate inside a parasitophorous vacuole and egress , leading to cell death and rapid dissemination to neighboring cells .
this slowly replicating form of the parasite resides inside cysts that localize mainly in the skeletal muscle and the brain for the life of the host [ 197199 ] .
a hallmark of t. gondii infections is passage of parasites across restrictive biological barriers - intestine , bbb , blood - retina barrier , and placenta during primary infection or reactivation of chronic disease .
traversal of cellular barriers permits the rapid dissemination of parasites to gain access to biologically restricted organs .
this process involves active parasite motility and tightly regulated interactions between host cell receptors and parasite adhesins that facilitate paracellular transfer .
infected murine macrophages express less alpha4 and alpha5 integrin and are less adhesive to fn , laminin , or collagen during early infection , and adoptively transferred infected immature dendritic cells ( dcs ) show diminished expression of beta2 integrin .
thus , t. gondii may alter the adhesive interactions of leukocytes , evade the host immune system , and disseminate to immunoprivileged sites , suggesting that parasites use murine macrophages , monocytes , and dcs as trojan horses to disseminate in the organism while avoiding immune attack .
moreover , to reach these immunoprotected sites , t. gondii must control how these trojan horses degrade the ecm proteins potentially with proteases such as mmps .
infection of murine macrophages from the cell lineage raw 264.7 with the rh strain produced an increase in cellular migration through a 3d matrix ( matrigel ) , and the presence of mmp inhibitor i drastically decreased the migration .
this observation demonstrates in vitro how t. gondii induces the macrophages ' machinery of invasion to achieve dissemination using mmps ( table 3 , figure 2 ) .
surprisingly , it was demonstrated that t. gondii ( rh strain ) infected human monocytic cells ( thp-1 ) have decreased prommp-9 ( progelatinase b ) secretion and expression .
mmp-9 is a secreted metalloprotease that is central in the migratory molecular complex , suggesting that this metalloprotease is fundamental for the migration of infected macrophages .
opposite to what bauche observed , seipel observed that t. gondii infection increased the secretion of an active mmp-9 form [ 214 , 215 ] .
confirming what seipel reported , recent research has shown that t. gondii gpis induce the production of mmp-9 in human macrophage - like thp-1 cells via a tlr2/4 in a tnf-dependent mechanism .
the secretion of mmp-9 requires an intermediary step , through docking at the cell surface .
shed cd44 , serine urokinase - type plasminogen activator receptor ( upar ) , and 41 or v3 integrins form a complex at the cell surface and function as a docking structure for prommp-9 . in cancer
metastasis , these molecules are often secreted as a multiprotein complex [ 216 , 217 ] .
further experiments demonstrate the presence of soluble cd44 , suggesting that t. gondii promotes shedding of cd44 , mediating the secretion of mmp-9 , as observed in other pathological and physiological conditions [ 217 , 218 ] .
schuindt showed in rh - infected raw 264.7 macrophages by immunoprecipitation assays that mmp-9 , cd44 timp-1 , and upar were secreted as a multiprotein complex by infected macrophages .
these data suggest that similar events to those observed in metastatic cells might take place during macrophage harboring of t. gondii .
the major physiological activators of prommp-2 ( progelatinase a ) are members of the mt - mmp ( membrane - type mmp ) family , and for mt1-mmp , this process involves the action of tissue inhibitor of matrix metalloprotease ( timp-2 ) .
timp-2 ( a physiological prommp-2 inhibitor ) forms a complex with active mt1-mmp that serves as a cell surface receptor for prommp-2 . t.
however , t. gondii infection did promote the expression and accumulation of a 60 kda active form of mt1-mmp [ 204 , 205 ] .
mt1-mmp was originally identified as an activator of mmp-2 and was later shown to degrade various ecm components , including collagen types i , ii , and iii , fn , laminin , and proteoglycans .
moreover , it was demonstrated that proteolysis of the ecm by mt1-mmp stimulates focal adhesion turnover , which regulates integrin - generated signal transduction and subsequent cell migration [ 220 , 221 ] .
mt1-mmp is also involved in cell - cell and cell - matrix interactions and cd44 shedding , along with adam10 [ 223 , 224 ] .
integrin v3 is fundamental for crossing the bbb , and it is also able to regulate the binding of 21 to fn and the conversion of pro-v to the mature v subunit .
this conversion is achieved by mt1-mmp in breast carcinoma cells but is usually performed by proprotein convertases ( pcs ) . just as occurs in carcinoma cells , the mt1-mmp pathway might be a preferential pathway for processing prointegrin subunits in t. gondii - infected macrophages . furthermore , t. gondii metalloproteases could also play a role in processing prointegrin subunits .
there are few in vivo studies on this topic , and they have shown that mmp-2 and mmp-9 are elevated in the intestine of t. gondii - infected mice .
it was shown that il-23 is essential in the development of small intestinal immunopathology by inducing local mmp-2 upregulation .
additionally , using knockout ( ko ) mice and inhibitors , it was demonstrated that mmp-2 but not mmp-9 is an essential downstream mediator of immunopathology in t. gondii induced ileitis , suggesting that mmps could be involved in tissue remodeling / repair , at the small intestine during t. gondii peroral infection . in a recent clinical study ,
increased concentrations of mmp-12 and elastin degradation products were detected in the serum of pregnant women infected with t. gondii .
co - immunoprecipitation of mmp-12 with elastin suggested that mmp-12 might mediate the pathological degradation of elastin in pregnant women with toxoplasmosis [ 210 , 227 ] .
this is an exciting new field for t. gondii and for other parasites , and the utilization by intracellular parasites of part of the migratory molecular complex appears to be a common practice observed in several physiological and pathological mechanisms involving migration , which may facilitate the access of infected leukocytes to immunoprivileged sites in the host [ 204 , 205 ] .
this parasite produces the illness named malaria and affects one million people every year , with the most vulnerable population being children under 5 years of age in africa .
the parasite is widespread in tropical and subtropical regions , including much of sub - saharan africa , asia , and the americas .
malaria is a mosquito - borne infectious disease of humans that results from the multiplication of plasmodium parasites , first within hepatocytes , resulting in tens of thousands of parasites that burst from the hepatocyte .
parasites inside red blood cells cause symptoms that typically include fever and headache , in severe cases progressing to coma or death . the mechanisms leading to severe malaria , of adhesion and release of bioactive products , are not entirely understood .
once malaria sporozoites enter the bloodstream , they infect hepatocytes , where they are able to replicate extensively .
the ability of the parasite to arrive and colonize the liver is directed by two proteins , the circumsporozoite ( cs ) protein and the thrombospondin - related adhesive protein ( trap ) , which recognizes the heparan sulfate proteoglycans and thrombospondin in the ecm , respectively .
as was previously reported , phagocytosis of trophozoite / hemozoin by adherent human monocytes stimulates the production of tnf- and other proinflammatory cytokines , inducing the synthesis of mmps .
once parasite adhesion is established , several host - derived enzymes , such as mmp-9 and timp-2 , increased in patients with severe malaria .
other studies have revealed an increase in mmp-8 with no difference in mmp-9 levels and the participation of the timp-1 and -2 .
therefore , mmps and timps are involved in the pathogenesis of malaria ( table 3 , figure 2 ) .
mmps are important for the disease and the resolution phases of acute and chronic inflammatory processes , facilitating entry into the tissues . in toxoplasma and plasmodium parasites ,
mmp-9 activation is a specific step for trophozoite / hemozoin - fed monocytes , it is dependent on tnf- production and is inhibited by using anti - tnf- antibodies or by the pharmacological inhibition of this protease .
host - derived enzymes induced by parasites may cause immunopathological conditions that could be relevant in the pathogenesis of malaria and toxoplasmosis , either as proteolytic enzymes that degrade the ecm or as effectors and regulators of the immune response [ 212 , 213 ] .
the participation of these proteases has already been described in different inflammatory diseases such as bacterial meningitis , sepsis , tuberculosis , multiple sclerosis , and bbb dysfunction . in this
regard , studies on mmp ko animals , human genetic , and epigenetic as well as biochemical studies using natural or synthetic inhibitors of these mmp will provide a better understanding of the pathophysiology of these parasitic diseases .
one example is the therapeutic potential of the antibodies produced against the activated forms of mmp-2 and -9 has been reported in murine models of inflammatory bowel disease .
the dysregulated mmps are targets for the inhibitory antibodies in a resembling way when timps were used , with the consequent diminishment of the infection .
another strategy is the use of specific inhibitors of mmp to produce brain damage attenuation in infant rats after pneumococcal meningitis . to increase the understanding of the specific role of these proteases , mmps
interestingly , in these studies , an important equilibrium between proteolytic and anti - proteolytic activity of mmps , was observed besides , the possibility to find an effect on the proteolytic compensation by different mmps or other classes of proteases .
these results confirmed the necessity of further investigation to elucidate the role of mmp in infectious diseases .
traditional physiological functions of mmps were the modulation and regulation of ecm , but , presently , these proteases have been related with the disease development .
their participation in cancer metastasis , chronic inflammation , and tissue damage has permitted to establish that mmps contribute to the generation of protein species with hugely differing activities .
mmps and timps impact disease development and , therefore , could be relevant as future targets for adjuvant intervention and offer a new chance to control pathogenic mechanisms in malaria and toxoplasmosis .
the host - parasite relationship is a complex phenomenon that is mediated by virulence factors from the parasite as well as exacerbated responses from the host .
parasite destruction of ecm might involve the participation of many types of protozoan parasite proteases : cps , serine proteases , and mmps .
for many of these parasites , the identity of the ecm proteases is unknown , because the reports refer only to proteolytic activities of certain molecular weight ranges .
therefore , it is important to identify each gene responsible for such proteolytic activity to have a better understanding of the parasite pathogenesis .
once the gene has been identified , it is important to use parasites in which protease genes are deleted , or overexpressed .
this will be of great value to elucidate the actual role of parasite proteases as virulence factors in migration and invasion of the host tissues .
parasites migrating through interstitial tissue or a basement membrane are confronted with three - dimensional tissue structures of complex and varied physicochemical properties . in this context , it is necessary to challenge parasite protease activities using in vitro and in vivo models of complex substrates such as 3d synthetic ecm ( matrigel ) as in vitro assays or isolated endothelial basement membranes , collagen - rich interstitial tissue , and provisional wound matrix as examples of in vivo models . on the other hand ,
the participation of host cells in the invasion and migration of parasites is of relevant importance , because they can be persuaded by parasites like e. histolytica and acanthamoeba to increase the production of mmps .
furthermore , host cells like the macrophages are used by intracellular parasites , like t. gondii and plasmodium , as trojan horses to invade tissues in a way that resembles metastatic behavior of cancer cells .
the study of proteases and their inhibitors is relevant to the search for new therapeutic targets or treatment strategies , or to improve the early diagnosis of human parasitic diseases and increase the power of the drugs used in treating these diseases .
Output:
| parasitic protozoa are among the most important pathogens worldwide .
diseases such as malaria , leishmaniasis , amoebiasis , giardiasis , trichomoniasis , and trypanosomiasis affect millions of people .
humans are constantly threatened by infections caused by these pathogens .
parasites engage a plethora of surface and secreted molecules to attach to and enter mammalian cells .
the secretion of lytic enzymes by parasites into host organs mediates critical interactions because of the invasion and destruction of interstitial tissues , enabling parasite migration to other sites within the hosts .
extracellular matrix is a complex , cross - linked structure that holds cells together in an organized assembly and that forms the basement membrane lining ( basal lamina ) .
the extracellular matrix represents a major barrier to parasites .
therefore , the evolution of mechanisms for connective - tissue degradation may be of great importance for parasite survival .
recent advances have been achieved in our understanding of the biochemistry and molecular biology of proteases from parasitic protozoa .
the focus of this paper is to discuss the role of protozoan parasitic proteases in the degradation of host ecm proteins and the participation of these molecules as virulence factors .
we divide the paper into two sections , extracellular and intracellular protozoa . |
PubmedSumm118526 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
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the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: psoriasis is a common , chronic , t - lymphocyte - mediated inflammatory skin condition characterized by scaly erythematosus plaques on body surfaces , which affects nearly 2%3% of the world s population in all geographic regions.1 the prevalence rates reported from africa and asia varied from no cases detected to estimates below 0.5%.2 psoriasis lesions have a predilection for nails , scalp , genitalia , extensor surfaces , and the lumbosacral region.1 to date , extradermatic manifestations of psoriasis have been well characterized . also emerging associations between psoriasis and other systemic diseases such as obesity ,
diabetes mellitus , depression or addiction , cancer , chronic inflammatory bowel disease , arthritis , and cardiovascular diseases ( cvd ) have been reported.36 some authors pointed out that psoriasis patients require education about their increased cvd risk factors .
there is a need to train dermatologists about the risk factors of systemic diseases , which should be examined regularly in diseased patients.7 cvd risk has been shown to be higher in younger patients and those with more severe psoriasis.4,5 since psoriasis is associated with smoking and alcohol intake , the increase in cvd and mortality among psoriatic patients is thought to be compounded by the cumulative effect of traditional risk factors for cvd.1 however , a cohort study showed that severe psoriasis is found to be a significant independent risk factor for cardiovascular mortality even after adjusting for traditional cvd risk factors.8 although the increased prevalence of myocardial infarction varies with age and disease severity , it remains significantly elevated after controlling for traditional cardiovascular risk factors.5 association of cvd and psoriasis is controversial . in some studies , the risk of cvd has been reported to be higher in patients with psoriasis.1,5,917 however , in some other reports in overall examination and considering the whole psoriatic patients the risk of cvd , transient ischemic attacks , or cerebrovascular accidents remained unchanged between psoriatic patients and controls.18 furthermore , no association between psoriasis and metabolic syndrome has been observed in korean psoriatic patients.19 another considerable finding is the lack of significant difference of the ischemic heart disease risk between psoriatic patients and controls in a large population - based dutch cohort.20 on the basis of a retrospective and cross - sectional study , the prevalence of papulosquamous diseases such as psoriasis and lichen planus was reported 15 per 10,000 population in rural areas of hamadan , iran.21 one major question to be considered is whether iranian patients of psoriasis are susceptible to metabolic syndrome risk factors and cvd . here , we have studied the associations of cvd and metabolic syndrome risk factors with psoriasis in a population of iranian psoriatic patients .
a case - control study of age- and sex - matched individuals with 55 psoriatic patients and 55 controls was performed .
histopathologically confirmed psoriatic patients with 20 years of age or older visited the department of dermatology , including both in- and out - patients , farshchian hospital , hamadan , iran ; between march 2011 and march 2013 were entered the study .
control group consisted of the healthy individuals accompanying the patients at the department of dermatology between march 2011 and march 2013 , with no history of immunodeficiency , immunosuppressive medications , and dermatologic diseases .
a written informed consent was signed by every patient following explanation of the nature of the study .
information regarding the smoking status and alcohol consumption , and medical problems including cvd , hypertension , diabetes , and hyperlipidemia , were recorded .
in addition , family history of cvd ; and duration , extent , and severity of psoriasis , height , weight , and blood pressure ( bp ) were measured for all subjects .
a fasting blood sample ( 3 cc ) was obtained from each participant and underwent centrifugation at 3,000 rpm for 10 minutes to separate serum .
the serum was then analyzed by chemical assay kits ( pars azmoon , tehran , iran ) with hitachi 902 auto analyzer to measure triglyceride ( tg ) , high - density lipoprotein ( hdl ) , and low - density lipoprotein ( ldl ) .
the following values were considered normal : tg < 200 mg / dl ; cholesterol total < 200 mg / dl ; ldl < 160 mg / dl ; hdl > 35 mg / dl in men ; and hdl > 45 mg / dl in women ; fasting blood glucose ( fbs ) < 126 mg / dl .
this study was approved by the national research council of the islamic republic of iran and was performed with the approval of the ethics human research review committee of the hamadan university of medical sciences .
first , we used chi - square test and student s t - test to determine the statistical significance of the differences of age , sex , smoking , obesity , cvd , hypertension , diabetes , hyperlipidemia , and metabolic syndrome between the patients with psoriasis and the controls .
the mean and standard deviation were used to report the data . in the second step ,
chi - square tests and logistic regression analysis were used to determine the risk factors for those significant differences of first step .
odds ratios ( or ) and the level of significance ( p - values ) are reported .
all these statistical investigations were performed by spss ( windows version 16.00 ; spss inc . ,
chicago , il , usa ) . a p - value of < 0.05 was considered as statistically significant .
a case - control study of age- and sex - matched individuals with 55 psoriatic patients and 55 controls was performed .
histopathologically confirmed psoriatic patients with 20 years of age or older visited the department of dermatology , including both in- and out - patients , farshchian hospital , hamadan , iran ; between march 2011 and march 2013 were entered the study .
control group consisted of the healthy individuals accompanying the patients at the department of dermatology between march 2011 and march 2013 , with no history of immunodeficiency , immunosuppressive medications , and dermatologic diseases .
a written informed consent was signed by every patient following explanation of the nature of the study .
information regarding the smoking status and alcohol consumption , and medical problems including cvd , hypertension , diabetes , and hyperlipidemia , were recorded .
in addition , family history of cvd ; and duration , extent , and severity of psoriasis , height , weight , and blood pressure ( bp ) were measured for all subjects .
a fasting blood sample ( 3 cc ) was obtained from each participant and underwent centrifugation at 3,000 rpm for 10 minutes to separate serum .
the serum was then analyzed by chemical assay kits ( pars azmoon , tehran , iran ) with hitachi 902 auto analyzer to measure triglyceride ( tg ) , high - density lipoprotein ( hdl ) , and low - density lipoprotein ( ldl ) .
the following values were considered normal : tg < 200 mg / dl ; cholesterol total < 200 mg / dl ; ldl < 160 mg / dl ; hdl > 35 mg / dl in men ; and hdl > 45 mg / dl in women ; fasting blood glucose ( fbs ) < 126 mg / dl .
this study was approved by the national research council of the islamic republic of iran and was performed with the approval of the ethics human research review committee of the hamadan university of medical sciences .
first , we used chi - square test and student s t - test to determine the statistical significance of the differences of age , sex , smoking , obesity , cvd , hypertension , diabetes , hyperlipidemia , and metabolic syndrome between the patients with psoriasis and the controls . the mean and standard deviation were used to report the data . in the second step , chi - square tests and logistic regression analysis were used to determine the risk factors for those significant differences of first step .
odds ratios ( or ) and the level of significance ( p - values ) are reported .
all these statistical investigations were performed by spss ( windows version 16.00 ; spss inc . ,
chicago , il , usa ) . a p - value of < 0.05 was considered as statistically significant .
the mean age of individuals in psoriatic patients was 47.3 ( 18.4 ) and in control group was 45.16 ( 15.9 ) . in patients group ,
65.5% of cases ( n=36 ) and in control group 64% ( n=35 ) were male .
no significant difference was observed for age and sex between groups . in psoriatic patients , 85% ( n=47 ) had plaque type , 2% ( n=1 ) had guttate type , 9% ( n=5 ) had plaque and guttate type , and 4% ( n=2 ) had pustules and guttate type .
smoking status was significantly ( p=0.03 ) different between cases ( n=32 ; 58.2% ) and controls ( n=9 ; 16.4% ) .
body mass index ( bmi ) of cases ( 26.364.71 ) was significantly ( p=0.02 ) higher than patients ( 24.63 ) .
interestingly , ldl and tg of psoriatic patients were significantly higher ( ldl , p=0.01 ; tg , p<0.001 ) compared with controls .
in addition , we observed that systolic and diastolic bps of cases were significantly higher ( systolic bp , p<0.001 ; diastolic bp , p=0.003 ) compared with controls .
although the mean of fbs and hdl levels was higher in cases as compared with controls , these differences were not statistically significant .
multivariate logistic regression analysis was performed to analyze the association between psoriasis and risk factors of cvd and metabolic syndrome ( table 2 ) . in final logistic regression model ,
the results of the analysis revealed that psoriasis was associated with systolic hypertension and elevated ldl and tg .
patients with psoriasis had an increased prevalence of systolic hypertension ( or 1.07 , 95% confidence interval [ ci ] 1.021.33 ) .
a significant relationship ( p=0.02 ) was found between smoking status and psoriasis ( or = 2.2 ; ci% 95=1.13.2 ) . also tg and psoriasis ( or = 1.02 ; ci% 95=11.34 ) showed a significant association ( p=0.005 ) .
the other considerable finding was the significant relationship ( p=0.03 ) between ldl and psoriasis ( or = 1.04 ; ci% 95=11.09 ) and in psoriasis the level of ldl was fourfolds higher .
this study was performed in a population of iranian psoriatic patients to find out the association between cvd risk factors and psoriasis .
we observed that serum tg and ldl are significantly higher in psoriatic patients , which augmented the risk of cvd independent of disease severity .
in addition , we found that systolic bps in patients were significantly higher than controls .
these findings , in addition to increased smoking , describe a considerable alarm for cardiovascular events in iranian psoriatic patients .
the comparisons between cases and controls revealed no significant difference between bmi of cases and controls . in accordance with our findings ,
herron et al found no significant difference between bmi of 500 female psoriatic patients and controls.22 conversely , madanagobalane and anandan found a significant difference in bmi between 118 south indian psoriasis vulgaris patients and 120 controls.23 total cholesterol of psoriatic patients was not significantly higher compared with controls in our study .
this finding was not in agreement with the previous study performed by pietrzak et al in which there was a significant difference between total cholesterol of psoriatic patients and controls.24 in addition , yaghmaei and fekri found a significant difference between total cholesterol of psoriatic patients ( 177.65 mg / dl ) and controls ( 170.21 mg / dl).25 dreiher et al conducted a study that included 10,669 psoriatic patients and 22,996 controls .
it revealed that psoriasis was associated with tg and hdl but the association was not statistically significant for total cholesterol or ldl.26 increasing evidence supports that psoriasis exfoliative lesions contain higher levels of cholesterol and lower free fatty acid concentrations compared with normal skin , accordingly in active phase of psoriasis in which shedding of skin ( exfoliation ) occurs , abundant cholesterol levels are lost that can increase the stimulation of the cholesterol synthesis.27 however , farshchian et al in their study on psoriasis showed that lipid profile in iranian patients with psoriasis did not differ compared with controls.28 tg levels of psoriatic patients in our study were significantly higher ( p<0.001 ) compared with controls , which is in line with the study of seishima et al29 and yaghmaei and fekri.25 furthermore , azizzadeh et al have found a significant difference between tg of psoriatic patients ( 152 mg / dl ) and controls ( 114 mg / dl ) while they did not find a significant correlation between serum lipid profile and onset age of disease.30 moreover , madanagobalane and anandan found a significant difference in tg levels between 118 south indian psoriasis vulgaris patients and 120 controls , but did not find a significant difference between hdl or bp of patients and controls.23 in a study of 479 korean psoriatic patients and controls performed by kim et al between 1999 and 2009 , a significant difference in tg was found ; while other indexes of metabolic syndrome such as obesity , bp , fbs , and hdl were not significantly different between patients and controls.19 it is of particular importance to note that ldl of psoriatic patients was significantly higher ( p=0.01 ) than controls in our study , which is line with the findings of azizzadeh et al.30 however , yaghmaei and fekri found no significant difference for ldl between cases and controls.25 we did not find significant difference between hdl of patients and controls , which agrees with the studies of madanagobalane and anandan23 and kim et al.19 in addition , mallbris et al found no significant difference between hdl of cases and controls.31 however , shahidi et al found significantly lower levels of hdl in psoriatic patients than controls.32 a survey showed that decreased hdl was the main biological abnormality in tunisian psoriatic patients.33 our study investigated the risk of psoriasis and smoking , showing a significant relationship so that smoking increased the psoriasis risk nearly twofolds .
more studies are needed to confirm this association as a causal relationship ; meanwhile , it has been surveyed in some studies with probable confirmed associations . to provide an example , herron et
they reported that smoking 20 cigarettes daily increases the risk of psoriasis threefolds , but such an effect has not been observed for obesity and bmi.22 naldi et al showed that smoking was strongly associated with pustular psoriatic lesions.34 ashkevari et al found a significant association between smoking and psoriasis , and smoking was noted to increase the psoriasis risk nearly twofolds.35 in addition , gelfand et al observed a significant association between smoking and psoriasis.36 from a pathophysiological point of view , epidermal cell proliferation , differentiation , angiogenesis , and cellular immune system are seemed to be involved . moreover , cholinergic receptors of cigarette nicotine on keratinocytes stimulate inflow of calcium and cell differentiation .
furthermore , smoking and cigarette nicotine may influence immune process in skin of psoriatic patients.37 on the basis of the findings of the present study , smokers with psoriasis should be encouraged to quit smoking .
our study showed a significant difference between alcohol consumption of psoriatic patients and controls in univariate analysis , while it was not confirmed in final model of logistic regression . despite controversial findings regarding alcohol consumption and psoriasis risk
, a recent meta - analysis showed that there is a significant association between psoriasis and alcohol consumption.38 altogether , the biologic role of alcohol in psoriasis requires further studies .
meta - analysis of armstrong et al on observational studies elucidated that the risk of systolic hypertension is two times higher in psoriatic patients as compared with normal population , and also the more severe psoriasis develops , the more hypertension risk increases.39 in addition , cohen et al observed an association between psoriasis and hypertension and suggested routine screening for hypertension in psoriasis patients.40 while madanagobalane and anandan reported no differences in bp of psoriatic patients and controls.23 fbs levels of psoriatic patients and controls were not significantly different in the present study , which is in accordance with the study of kim et al.19 however in some studies , such as ahlehoff et al41 and pereira et al,42 a significantly higher fbs was observed in psoriatic patients as compared with controls . in a german cross - sectional study ,
psoriasis was significantly associated with type 2 diabetes and myocardial infarction.43 the small sample size could be considered as on of the limitations of the present study .
in addition , the data of smoking and alcohol consumption habit might be underreported due to the cultural issues .
in summary , the serum tg and ldl are significantly higher in cases resulted in increased risk of cvd independent of disease severity .
in addition , we found the elevated bp of psoriatic patients compared with controls , which intrigues cardiologists and internists regarding screening and education of these patients for self - assessment of bp .
the significant difference between smoking of cases and controls indicates that smoking might be an independent risk factor for psoriasis .
patients should be encouraged to quit smoking for a better prognosis of the disease . however , more comprehensive studies with larger sample sizes are required .
generally , the data in the present study are sufficient only for the suggestions , because recommendation of these screenings requires data from longitudinal prospective study .
Output:
| backgroundpsoriasis is a common chronic inflammatory skin disease .
there is overwhelming evidence on the higher risk of cardiovascular diseases in patients with psoriasis as a result of hyperlipidemia , which is more common in these patients.objectivesthe aim of this study was to elucidate the association between the cardiovascular risk factors and psoriasis.methodsin a cross - sectional study , 55 patients with psoriasis and 55 matched ( sex and age ) controls were entered the study at the department of dermatology between march 2011 and march 2013 .
blood samples were obtained following 14 hours fasting status and serum levels of triglyceride , cholesterol , high - density lipoprotein , and low - density lipoprotein were determined using standard laboratory methods , and other variables such as sex , age , smoking , alcohol consumption , and the type of disease were recorded.resultsour findings showed that levels of triglyceride , low - density lipoprotein , and smoking were significantly higher in psoriatic patients when compared with controls , whereas the level of high - density lipoprotein and cholesterol was not significantly different between two groups .
body mass index of psoriatic patients was not significantly higher than controls .
patients with psoriasis also had an increased prevalence of hypertension.conclusionour findings further verify lipid abnormalities in psoriatic patients .
psoriasis is associated with higher rate of hypertension , which may be resulted in increasing the risk of cardiovascular diseases in these patients .
thus , serum lipid profile and blood pressure in all patients with psoriasis , regardless of disease severity , deserve consideration to be checked . |
PubmedSumm118527 | ***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: traumatic head and brain injuries , including penetrating head injuries , are the leading cause of morbidity and mortality in young people.1,2 however , in some patients these head injuries do not affect neurological function , even if the foreign body is retained in the brain parenchyma.27 when no neurological deficits are presented and no foreign body is visible during inspection , these cases are sometimes wrongly classified as a mild head injury .
furthermore , existing guidelines in the treatment of mild cranial traumas do not include protocols for neuroimaging examination.810 secondary infection , brain edema , and hematomas can result in a fatal clinical course and death with medicolegal consequences.3,4,11,12 in 1997 , a series of patients presented with transcranial stab wounds ; it was discovered that those with retained knife blades were shown to be at high risk for secondary morbidity and mortality.7 guidelines do not currently exist for this group of patients , or for the necessary neuroimaging examinations or surgical approaches required to treat these individuals .
we therefore present a special case of a penetrating head injury that was initially overlooked , and discuss the diagnostic and therapeutic procedures that were used within the context of the existing guidelines.9
a 19-year - old patient suffered from a head injury due to an assault that occurred from behind .
he was admitted to an emergency department to have a dressing applied to a small occipital laceration .
clinical examination revealed no loss of consciousness , nausea , vomiting , or any other neurological deficit ; however , a hard and bloody eschar was noted on his scalp in the occipital region ( figure 1 ) .
inspection of the wound conducted prior to the intended suturing demonstrated a foreign metallic body in the wound that could not be removed .
the patient was admitted into our emergency unit , and cranial computerized tomography ( ct ) was performed , revealing a knife blade penetrating the cranial bone .
additionally , ct angiography demonstrated the foreign body touching , or potentially penetrating , the bridging veins and the superior sagittal sinus ( figure 2 ) , which appeared to be patent . at that time , and in view of the neuroimaging results , it was unclear as to whether the knife had harmed the sinus , and if removal of the knife blade would provoke massive bleeding . in view of the possibly lacerated dorsal part of the sinus , we decided to perform a surgical intervention .
consequently , we performed a craniotomy that extended beyond the superior sagittal sinus while the knife blade remained in situ ( figure 3 ) .
after vertical elevation of the bony fragment , only marginal bleeding from the sinus occurred .
the sinus leakage was covered with autologous material . to remove the knife blade from the bone , parts of the bone had to be removed .
the remaining bone fragment was replaced and fixed with titanium clamps ( figure 4 ) . due to suspected inflammation , antibiotics were prescribed for 5 days following the procedure .
no neurological deficits occurred , and there were no clinical or laboratory signs of inflammation .
postoperative neuroimaging revealed only minor intraparenchymal bleeding , but no other morphological changes ( figure 4 ) .
traumatic head and brain injuries are significant causes for morbidity and mortality , especially in young people .
classification of these traumas depends on their underlying mechanisms , their clinical presentation , and pathological neuroanatomical changes.10 in order to provide better treatment and to reduce possible secondary damages , many guidelines have been developed , which are mostly related to severe head injuries.9 for patients with head injuries , but presenting with or without mild neurological deficits , standard practices remain unclear.13 existing guidelines do not currently recommend neuroimaging for diagnostic purposes among this group of patients , and at best they suggest monitoring patients overnight for observation.9 although it is advised that a ct scan of the cerebrum be performed in patients with suspected open or depressed skull fracture,9 our patient would not have received any radiological diagnostics due to his inconspicuous clinical status and his negligible wound .
however , this approach could have medicolegal consequences , as reported previously.4 thus , good practice suggests that every patient with an open wound be inspected carefully a claim that should be self - evident . if there is any risk of existing penetrating or depressed skull trauma , ct imaging should be performed , even in patients with a glasgow coma scale sum score of 14 or 15.14 previous studies have demonstrated that in up to 14% of patients with a glasgow coma scale of 14 , ct scans showed intracranial lesions.15,16 additional ct angiography should be performed in penetrating injuries with hematomas or suspected vascular lesions.8 performing additional diagnostics may lead to therapeutic intervention . without surgical removal of the foreign body
, our patient would have been at increased risk for morbidity and mortality7 due to bleeding from the sagittal sinus , increasing intracranial pressure , or infections of the open wound .
nevertheless , surgical removal of the foreign body may itself provoke secondary parenchymal and vascular injuries.7,17 for instance , a neuroimaging - based approach allows for the reconstruction of the local anatomical structures,57,18 thus minimizing the risk of surgically induced secondary brain injuries .
many guidelines exist on how to handle different kinds of traumatic brain injuries.810,13,14,16,19 considering the great variability of trauma mechanisms and possible associated neurological deficits , each patient should be treated individually .
if the cause of the trauma is not obvious , the patient should be admitted into a neurosurgical unit for adequate surgical treatment.9 unclear neurological status should indicate that neuroimaging ( eg , ct ) is necessary , especially in children,19 and that additional imaging ( eg , ct angiography , mri ) should be performed if needed . reducing
the risk of a neurological deficit is of the highest priority for the patient , and thus a diagnostic ct scan may be warranted .
Output:
| objectivein young people , traumatic head and brain injuries are the leading cause of morbidity and mortality . in some cases ,
no neurological deficits are present , even after penetrating trauma .
these patients have a greater risk of suffering from secondary injuries due to secondary infections , brain edema , and hematomas .
we present a case report which illustrates that brain injuries that do not induce neurological deficits can still result in a fatal clinical course and death , with medicolegal consequences.clinical presentationa 19-year - old patient was admitted to hospital suffering from a head injury due to an assault .
he reported that he was attacked from behind .
medical examination showed no neurological deficits , and only a small occipital wound .
neuroimaging of the cranium revealed that a knife blade was penetrating the cranial bone and touching the superior sagittal sinus.interventionafter removing the foreign body , magnetic resonance imaging showed that the superior sagittal sinus remained open.conclusionwe want to stress that possible problems can arise due to the retention of objects in the cranium , while also highlighting the risk of superficial clinical examination . |
PubmedSumm118528 | ***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 clinical replacement of lost natural teeth by osseointegrated implants has represented one of the most significant advances in restorative dentistry . since their introduction in the 1970s , endosseous oral implants have become an integral part of reconstructive dentistry .
initially , implant therapy was predominantly intended for the fully edentulous patient . in recent years , however , the partially dentate patient has also become a candidate for implant placement . in such patient ,
this blend of teeth and implants is , in particular , critical in the periodontally susceptible patient in whom the submarginal biofilms may harbor putative periodontal pathogens which may also be involved in the processes associated with the resorption of the bony support for the implant .
one of the key factors for the long - term success of oral implants is the maintenance of healthy tissues around them .
effect relationship between bacterial plaque accumulation and the development of inflammatory changes in the soft tissues surrounding oral implants has been developed .
if this condition is left untreated , it may lead to the progressive destruction of the tissues supporting an implant ( peri - implantitis ) , which may compromise its future and ultimately lead to its failure .
an implant patient must always be enrolled in a supportive therapy program that involves recall visits at regular intervals .
the aim of the present 1-year study was to assess and compare the peri - implant status after the placement of prosthesis in partially edentulous subjects to the periodontal status of adjacent teeth which served as control teeth .
a total of 25 participants with 28 implant supported crowns ( median age 30 years ) , irrespective of sex , were recruited from a list of consecutive implant patients treated at a postgraduate section of the department of periodontics , faculty of dental sciences , king george 's medical university , lucknow .
the inclusion criteria were systemically healthy patients with good oral hygiene , implant supported single crown , restorative suprastructures provided satisfactory fit , and adjacent control teeth periodontally healthy .
exclusion criteria were patients with deleterious habits such as smoking , chewing tobacco , patients with parafunctional habits such as bruxism , clenching , and grinding subjects with overhang crown margins on implants carious exposed control teeth .
the suprastructures consisted of 28 single cemented crowns that were seated postsurgically . for all patients ,
after the insertion of suprastructure , full mouth oral prophylaxis was performed and meticulous scaling and root planing were performed on adjacent teeth which served as control .
preventive measures such as high level of plaque control with the help of toothbrush using bass technique supplemented by long - term application of antiseptic mouthwash ( 0.2% chlorhexidine ) was advised to the patients .
the patients were asked to report after 1 , 3 , 6 , 9 , and 12 months for clinical evaluation .
the clinical examination was carried out by a single examiner after the placement of crowns at an interval of 1 , 3 , 6 , 9 , and 12 months and included the assessment of the following parameters at four aspects of each implant and adjacent teeth .
the patients were motivated to maintain good oral hygiene as a part of supportive periodontal therapy . the modified plaque index ( mpli ) according to mombelli et al .
1987 , the bleeding score according to the muhlemann index ( 03 ) modified by mombelli et al . , calculus score , and probing pocket depth ( ppd ) .
for each period , the implants and control teeth were compared by analysis of variance followed by dunnett 's test . a two - tailed ( = 2 ) , probability ( p ) value < 0.05 was considered to be statistically significant , p < 0.01 highly significant and p > 0.05 not significant .
ms excel ( ms office 972003 ) and graphpad prism ( version 5 , graphpad software , inc .
, 7825 fay avenue , suite 230 , la jolla , ca 92037 usa ) were used for the analysis .
for each period , the implants and control teeth were compared by analysis of variance followed by dunnett 's test . a two - tailed ( = 2 ) , probability ( p ) value < 0.05 was considered to be statistically significant , p < 0.01 highly significant and p > 0.05 not significant .
ms excel ( ms office 972003 ) and graphpad prism ( version 5 , graphpad software , inc .
, 7825 fay avenue , suite 230 , la jolla , ca 92037 usa ) were used for the analysis .
table 1 lists the overall means of the clinical parameters assessed at four aspects around each implant and control teeth and shown graphically by line diagrams in figure 1 .
comparison of periodontal parameters between implants and natural teeth ( a ) modified plaque index .
( e ) gingival recession during the study period , the mpli , modified bleeding index ( mbli ) , calculus score , ppd , and recession decreased from 1 month to 12 months in both implants and in control teeth .
the mean mpli , mbli , and calculus score were comparatively high in control teeth than implants in all assessed periods [ table 1 ] .
the mean mpli in implant was 3.21 0.40 in the 1 month which reduced to 0.93 0.19 in the 12 month [ figure 1a ] .
the mean mbli was comparatively high in control teeth than implants in all assessed periods .
the mean mbli in implant was found to be 5.07 0.21 in the 1 month which reduced to 0.96 0.17 in the 12 month . in mesial teeth , it was found to be 4.29 0.22 in the 1 month which reduced to 1.43 0.15 in the 12 month . in distal teeth , the mean was found to be 4.96 0.36 in the 1 month which reduced to 1.57 0.22 in the 12 month [ figure 1b ] . in the present study , the mean ( standard error [ se ] ) ppd in implants was 2.90 0.10 in the 1 month which reduced to 2.37 0.11 in the 12 month .
the mean ( se ) ppd in mesial teeth was found to be 2.55 0.07 in the 1 month which reduced to 2.12 0.05 in the 12 month . in distal teeth , the mean ppd was 2.32 0.09 in the 1 month which reduced to 2.01 0.09 in the 12 month [ figure 1c ] .
the mean level of calculus score was comparatively high in control teeth than implants in all assessed periods [ figure 1d ] .
recession was slightly higher in control teeth than implants throughout the study period , but it was not statistically significant ( p > 0.05 ) [ figure 1e ] .
during the course of the study , the mpli decreased from 1 month to 12 months in both implants and in control teeth .
the mean mpli was comparatively high in control teeth than implants in all assessed periods . on comparing , the mean mpli of implants and control teeth in all assessed periods did not differ significantly ( p > 0.05 ) except mesial teeth at 1 month , which is significantly ( p < 0.05 ) high in mesial teeth ( 4.61 ) than implant ( 3.21 ) [ table 1 and figure 1a ] . our results are seen in accordance with the studies of machtei et al .
2006 in which he found that pi was significantly higher in teeth than implants ( 1.2 vs. 0.8 ) .
the amount of plaque accumulation and the signs of inflammations were even lower around the implants compared to control teeth .
this may reflect a greater attention to the implant sites during home care procedures or a different association of implants to plaque accumulation .
the tight recall schedule and high motivation among the patients had a substantial influence on plaque control .
like mpli , mbli also decreased from the start of the study to the end of the study in both implants and control teeth .
the mean mbli was comparatively high in control teeth than implants during the study period . on comparing , the mean mbli of implants and control teeth in all assessed periods did not differ significantly ( p > 0.05 ) except distal teeth at the 9 month . in this period ,
the mean levels of control teeth were significantly high ( p < 0.05 or p < 0.01 ) than implants [ table 1 and figure 1b ] .
1997 in which he found that the mean mbli was 0.35 in implants and 0.44 in control teeth . however , juodzbalys and wang et al . 2007 reported that mbli remained unchanged at 1-year follow - up .
the rather low values of mbli around implants appear to confirm that patients investing in implant therapy and suprastructures in general were cooperative and performed good oral hygiene .
however , a slight increase in mbli was noticed in distal , which could be due to less attention toward control teeth compared to implants .
a significant difference was observed between implants and control teeth with respect to mean ppd .
ppd decreased in both implants and control teeth throughout the study period . according to the study of adell et al .
1990 , peri - implant probing depth up to 3 mm around implants was considered
in our study , ppd in implants was found to be 2.90 in the 1 month which reduced to 2.37 in the 12 month .
less than 3 mm of probing indicated that there was no progressive peri - implant connective tissue destruction around implants .
increased ppd was reported to be an important indicator , suggesting a high risk of infection developing in the implant mucosa .
an increase in ppd was not observed with time in the present study , indicating that the implant mucosa was kept in a healthy condition from the beginning of the study .
the ppd in control teeth in all the assessed periods was significantly ( p < 0.05 or p < 0.01 ) low as compared to respective implant except mesial teeth at the 9 month and 12 month [ table 1 and figure 1c ] .
1997 also found deeper probing depth around implants than teeth ( 2.55 mm at implants/2.02 at teeth ) .
in contrast , increased ppd was observed to be associated with a high risk of inflammation . because of patients ' good oral hygiene maintenance as indicated by the decreased mpli , the calculus score also decreased during the course of the study except at the 12 month in implants where calculus score was slightly increased from 0.25 to 0.36 . the mean level of calculus score was comparatively high in control teeth than implants in all assessed periods [ table 1 and figure 1d ] .
the present study therefore emphasizes that an implant patient must always be enrolled in a supportive therapy program that involves recall visits at regular intervals .
long - term studies can be done for bacterial monitoring around different dental implant system , and various immunological parameters of teeth and different dental implant platforms should also be investigated .
the detained results suggested that the tight recall schedule and high motivation among the patients had a substantial influence on plaque control ; therefore , the present study emphasizes that an implant patient must always be enrolled in a supportive therapy program that involves recall visits at regular intervals .
Output:
| introduction : nowadays , dental implants permit consideration of as one of the most reliable therapeutic modalities during the establishment of any prosthetic treatment plan . in numerous clinical situations , implants can clearly contribute to a notable simplification of therapy , frequently enabling removable prostheses to be avoided , keeping it less invasive with respect to remaining tooth structure .
the aim of the present study was to clinically assess the peri - implant and periodontal conditions after the placement of crowns in partially edentulous patients.materials and methods : twenty - five participants with 28 implant supported crowns were recruited in the study . after the insertion of suprastructure , meticulous scaling and root planing were performed on adjacent teeth which served as control .
the clinical examination was carried out by a single examiner after placement of crowns at an interval of 1 , 3 , 6 , 9 , and 12 months and included the assessment of modified plaque index ( mpli ) , bleeding score , calculus score , probing pocket depth ( ppd ) , and recession on the four aspects of each implant and adjacent teeth.results:the mpli , modified bleeding index ( mbli ) , calculus score , ppd , and recession decreased from 1 month to 12 months in both implants and in control teeth .
the mean mpli , mbli , and calculus score were comparatively high in control teeth than implants .
ppd was found to be more on implants than in control teeth .
recession was slightly higher in control teeth than implants throughout the study period , but it was not statistically significant.conclusion:an implant patient must always be enrolled in a supportive therapy program that involves recall visits at regular intervals . |
PubmedSumm118529 | ***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: parry - romberg syndrome ( prs ) also known as " progressive facial hemiatrophy "
is characterized by a progressive but self - limited atrophy of the skin and
subcutaneous tissue on one side of the face .
prs was first reported by
parry and then described as a syndrome by romberg .
there is a progressive
wasting of subcutaneous fat , sometimes accompanied by the atrophy of skin ,
cartilage , bone , and muscle .
it overlaps
with a condition known as linear scleroderma " en coup de sabre " . in most of the instances
atrophy is usually
confined to one side of the face and cranium ; however it may occasionally spread to
the neck and one side of the body .
the onset is insidious and the condition
usually manifests in the first or the second decade of life with skin changes
resembling scleroderma .
progression of the disease is rapid in the
two to ten years following onset and then stabilizes .
it is usually accompanied by neurological complications like
trigeminal neuralgia , migraine , seizures and changes in the eyes and hair [ 11 - 13 ] .
partial seizures have found to be most common neurological complication . in a survey conducted worldwide 11% of the
patients with prs had coexistent epilepsy .
many theories
have been postulated to explain this rare disease like autoimmunity , trigeminal
theory and etc .
the disease is common in females and the male to female
ratio is 3 : 2 .
there are no published trials of the treatment , however
the restorative plastic surgery which includes fat or silicone implants ,
flap / pedicle grafts , or bone implants can be used .
radiographically , the
teeth on the involved side appear small and usually have short roots .
authors herein present a case of a rare and an uncommon case of parry - romberg
syndrome .
a 31 year old female patient reported to the department of oral medicine and
radiology , ab shetty memorial institute of dental sciences , nitte university ,
deralakatte , mangalore , karnataka , india , with the complaint of multiple root stumps
in the maxillae and the mandible since six months .
on general , a physical examination facial asymmetry was detected due to the hollowing
of cheek and chin on the left side ( figure
1 ) , the left eye was depressed in the socket ( enophthalmos ) along with
deficient eyebrows ( figure 2 ) , the malar
hypoplasia , atrophy of facial skin and upper lip on the left side .
loss of the
subcutaneous fat with prominent bony ridges on the ipsilateral side was observed
when compared to the normal side .
there was a deviation of nose and the angle of mouth to the affected
side .
pigmentation was noticed on the left side of the forehead and the chin region .
there was a atrophy of
temporalis , buccinator , masseter muscles and prominent zygomatic arch on the left
side ( figure 4 ) .
the ear on the left side was
pulled towards the front giving it a bat ear appearance . clinical photograph showing marked asymmetry of the face .
the further evaluation patient gave a history of trauma ( fall ) from approximately
4 - 5 feet above the ground , when the patient was six months old .
the patient also noticed brownish discoloration of the skin near the forehead
followed by shrinkage of the left side of the face when she was thirteen years of
age .
the patient visited a local physician , who suggested cosmetic correction for
the same , but could not carry out the treatment because of financial reasons .
the intraoral examination revealed the atrophy of tongue on the left side and angular
cheilitis on the same side .
the teeth examination revealed multiple root stumps and decayed teeth
( figure 5 ) .
based on the clinical features , a diagnosis of parry - romberg syndrome was made .
routine blood investigations were carried out which revealed all values within
normal limits . as a part of radiographic investigations an orthopantomogram , paranasal sinuses view
and a posterior - anterior cephalogram was made .
the orthopantomogram revealed
thinning of the body of mandible , smaller condyle and the coronoid process , shorter
roots of teeth on the left side , when compared to the right side ( figure 6 ) .
orthopantomography showing thinning of the body of mandible , smaller condyle
and the coronoid process , shorter roots of teeth on the left side when
compared to the right side .
the paranasal sinus x - ray examination showed smaller frontal and maxillary sinus on
the left side when compared to the right side ( figure 7 ) .
paranasal sinuses radiograph showing hypoplastic maxillary sinus on the left
side when compared to the right side .
the posterior - anterior cephalograms revealed asymmetry of the jaws ( figure 8) . posterior - anterior cephalogram showing asymmetry of the jaws . as a part of treatment all the teeth of fewer prognoses were extracted and a
removable partial denture was fabricated .
there is no definitive treatment for this condition but an attempt to use alloplastic
implants can be done to improve facial disfigurement .
similar treatment was
suggested to the patient , but the patient could not make it up for a logistic
reasons .
the patient was reviewed for a period of six months and no progressive
changes have occurred .
it is characterized by a slow and
progressive unilateral atrophy of the facial tissues , including muscles , bones and
skin .
the condition is more often found in female population and has
predilection for the left side of the face , which is seen in presented herein case
.
more than an aesthetic concern , this
disease brings several functional and psychological problems due to asymmetry of the
face .
the main feature is hemiatrophy of
the facial tissues , typically fat , but variably skin , other connective tissue , and
sometimes bone .
the prevalence rate is estimated to be at least 1 per
700.000 in the general population .
characteristically , the atrophy progresses slowly during many years and then
becomes stable as in our case .
the extension of atrophy is frequently limited to on one side of the face , and the
ipsilateral involvement of body is rare ( 23 to 10% of cases were described as being
bilateral ) . in the case
the most important features of
this disease are enophthalmos , the deviation of mouth and nose to the affected side ,
and the unilateral exposition of teeth ( when lips are involved ) , which were also found in our case
.
clinically , the skin can be dry and hyperpigmented , which is also seen in presented case .
some patients present a
demarcation line between normal and abnormal skin , known as " coup de sabre " ( french
term which means " cut of the sword " ) which is not seen in our
case .
another important feature is ocular involvement and the most frequent
manifestation is the enophthalmos , due to fat loss around the orbit , as was observed
in our patient [ 11 - 13,21,27 ] .
thinning of the ear due to atrophy of the
fat around it , alopecia on the involved side was a manifestation registered in our
patient .
the neurological complications ,
such as trigeminal neuralgia , facial paresthesia , severe headache and contralateral
epilepsy can also be present , but were not diagnosed in our case .
our
patient also presented with atrophy of the tongue on one side in consistent with the
findings mentioned by da silva - pinheiro tp et al . .
radiographically , the teeth of patients with prs have short roots and appear small ,
when compared to the uninvolved side .
these features could not be seen as the patient had multiple
root stumps on the affected side ( figure
5 ) .
the treatment is usually based on reposition of adipose tissue that was lost due to
atrophy .
autogenous fat grafts , cartilage grafts , silicon injections and prostheses ,
bovine collagen and inorganic implants are some alternatives to aesthetic correction
of the atrophy .
the treatment modalities
mentioned , resolve just momentarily the good appearance , whereas all the structure
projected in the cosmetic surgery is lost with time , due to gravity action , and the
patient usually requires new intervention .
panfacial volumisation with autologous fat is an excellent tool for
replacing volume and restoring contour to the aging face .
our patient was suggested treatment using alloplastic
implants to improve the facial appearance , but could not make up for financial and
logistical reasons .
parry - romberg syndrome is an uncommon condition , which manifest as atrophy of one
side of the face . in most cases , parry - romberg syndrome appears to occur randomly
for unknown reasons .
we hereby
are presenting a case of parry - romberg syndrome with classical features .
Output:
| referencesbackgroundthe purpose of this report is to present a rare entity of parry - romberg
syndrome .
this poorly understood degenerative condition is characterised by
atrophic changes affecting one side of the face .
the cause of these changes
remains obscure.methodsthe authors report one rare case of a 31 year old female patient with
parry - romberg syndrome , accompanied by a brief review of literature.resultsclinical examination of the patient revealed evident facial asymmetry , malar
hypoplasia , atrophy of skin and other tissues on the left side ,
hyperpigmentation of skin on the left side of the face .
final diagnosis of a
parry - romberg syndrome ( progressive hemifacial atrophy ) was based on
thorough clinical and a radiological examination .
treatment using
alloplastic implants to improve facial disfigurement was suggested to the
patient.conclusionsin most cases , parry - romberg syndrome appears to occur randomly for unknown
reasons .
the pathophysiology of the syndrome remains unknown .
there is no
definitive treatment for this condition but an attempt to use restorative
plastic surgery which includes fat or silicone implants , flap / pedicle
grafts , or bone implants can be done to improve facial disfigurement . |
PubmedSumm118530 | ***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 liver , which is the key organ of metabolism and excretion , is constantly endowed with the task of detoxifying xenobiotics , environmental pollutants , and chemotherapeutic agents .
nonalcoholic fatty liver disease ( nafld ) and nonalcoholic steatohepatitis ( nash ) are the most common liver diseases in the world .
the mechanism involved in the pathogenesis of nafld / nash has not been thoroughly investigated .
the exact mechanisms that mediate the transition from steatosis to nash remain unknown , although oxidative stress and cytokine - mediated injuries may have a key role in nash pathogenesis.1 , 2 under oxidative stress conditions , reactive oxygen species ( ros ) lead to membrane lipid peroxidation , inflammatory responses , stimulation of stellate cells , and finally fibrosis .
hence , the current use of peroxisome proliferator - activated receptor gamma ( ppar- ) , corticosteroids , and immunosuppressive agents only produce symptomatic relief .
furthermore , their usage is associated with the risks of relapse and adverse effects.4 , 5 , 6 the indigenous system of medicine in india has a long tradition of treating liver disorders with plant drugs .
it is approved by the government of india 's drug regulatory authority , the department of ayurveda , yoga , naturopathy , unani , siddha and homoeopathy ( ayush ) of the ministry of health and family welfare ( new delhi , india ) .
the usefulness of liv.52 in liver disorders of various etiologies is confirmed by a substantial number of clinical trials conducted across the globe .
it is also beneficial in treating viral hepatitis , drug - induced hepatic damage , and alcoholic liver disorders.7 , 8 , 9 , 10 the present study aimed to evaluate the effect of liv.52 extract in an experimental model of high - fat diet ( hfd)-induced nonalcoholic steatohepatitis ( nash ) in rats . in the present study , pioglitazone , a standard reference drug that further validates the experimental model / procedure ,
the hfd model is a very appropriate model to induce nash , obesity , and insulin resistance .
overnutrition with carbohydrates or fats or both may lead to obesity - related nafld .
insulin resistance and obese diabetes do not solely initiate steatohepatitis , but they do contribute to the progression of the entire spectrum of pathology of steatohepatitis , at least partly , via the upregulation of genes involved in lipogenesis , inflammation , and fibrogenesis .
agonists of ppar- reportedly prevent the progression of nash in a dietary model of nash associated with obese diabetes .
the liv.52 extract constitutes a mixture of roots of capparis spinosa ( x su z ) , seeds of cichorium intybus ( j j ) , whole plant of solanum nigrum ( lng ku ) , terminalia arjuna ( bark ) , seed of cassia occidentalis ( wng jing nn ) , achillea millefolium ( yng sh co ; aerial plant ) , and tamarix gallica ( whole plant ) .
these crude herbal materials were subjected to pulverization to obtain their coarse powders , and then blended .
they were then soaked in pure water and boiled in a steam - jacketed stainless steel reactor until the extraction was complete .
the liquid extract thus obtained was filtered through a muslin cloth and concentrated in the reactors to attain 30% total solids .
the soft extract was then subjected to spray drying to obtain the dry extract powder .
it was tested for its quality and consistency at each manufacturing step per the accepted principles of good manufacturing practice ( gmp ) and good laboratory practice ( glp ) .
its botanical identification , quality parameters , and ayurvedic criteria complied with the international guidelines and pharmacopoeial standards.12 , 13
the concentration of the liv.52 extract ( dd-100 ) was 10 mg / ml in methanol .
liquid chromatography was performed by the shimadzu lc-20ad series pump ( shimadzu corporation , kyoto , japan ) and dug-20a3 series shimadzu degasser ( shimadzu corporation , kyoto , japan ) .
chromatographic separation was performed on the luna c18 column ( 250 mm 4.6 mm , 5 m ; phenomenex , torrance , ca , usa ) . for the separation , the mobile phase gradient consisted of water ( j.t . baker brand
; avantor performance materials , inc . , center valley , pa , usa ) with 10 mm ammonium acetate and 0.1% formic acid in pump a and acetonitrile ( j.t .
baker brand ; avantor performance materials , inc . ) in pump b. the linear gradient program was set as follows : 027 minutes of 20% of acetonitrile to 80% acetonitrile ( linear ) ; 2730 minutes of 80% acetonitrile to 20% acetonitrile ( linear ) ; followed by 30 minutes of 20% acetonitrile ( isocratic ) equilibration period for 2 minutes , delivered at a flow rate of 0.6 ml / min and a run time of approximately 32 minutes .
peak elution was monitored at 245 nm and 360 nm through the shimadzu spd-20a uv / vis detector ( shimadzu corporation ) .
the injection volume of 20 l was injected through the sil - htc shimadzu autosampler ( shimadzu corporation ) .
the ambient temperature was achieved through a cto-10 as vp column oven ( shimadzu corporation ) at 25 c .
the api 2000 mass spectrometer ( applied biosystems / mds sciex , ontario , canada ) was coupled with an electron spray ionization source and a chromatographic system .
optimization of the mass spectroscopy ( ms ) parameters was performed with 2 mg / ml of test solutions that were prepared separately and diluted in methanol ( j.t .
interface conditions such as the declustering potential ( 40 v ) , ion spray voltage ( 3500 v ) , nebulizing gas [ gs1 ( 55 psi ) and gs2 ( 65 psi ) ] , curtain gas ( 25 psi ) , focusing potential ( 400 v ) , entrance potential ( 10 v ) , and source temperature ( 420 c ) were optimized by multiple runs through liquid chromatography .
acquisition was performed by setting the mass of the analytes with the appropriate scan range .
liv.52 extract was procured from the phytochemistry department of the himalaya drug company ( bangalore , india ) and pioglitazone was procured from sun pharmaceuticals industries ltd .
all other chemicals used in the study were of reagent / analytical grade from reputed suppliers .
biochemical parameters such as glucose , cholesterol , triglycerides ( tgs ) , serum glutamic oxaloacetic transaminase ( sgot ) , serum glutamate pyruvate transaminase ( sgpt ) , and alkaline phosphatase ( alp ) were estimated in a biochemistry autoanalyzer ( em-360 ; erba diagnostics mannheim gmbh , mannheim , germany ) using ready - made assay kits ( erba kits ; erba diagnostics mannheim gmbh ) .
insulin was estimated using a radioimmunoassay kit ( riak-1 ) supplied by bhabha atomic research centre / board of radiation and isotope technology ( barc / brit ; mumbai , india ) . inbred male wistar rats ( 260280 g )
were housed under standard conditions of temperature ( 22 3 c ) at a relative humidity of 55 5% and 12-hour light / dark cycle prior to and during the study .
the normal group animals were fed a standard pellet diet ( provimi animal nutrition india pvt . ltd . ,
the experimental protocols were approved by the institutional animal ethics committee ( iaec ) of the himalaya drug company ( bangalore , india ) .
the animals received humane care as prescribed by the guidelines of the committee for the purpose of control and supervision on experiments on animals ( cpcsea ) , ministry of environment and forests , government of india ( new delhi , india ) .
the hfd consisted of 87.5% normal laboratory rodent feed , 10% animal fat , 0.5% cholic acid , and 2% cholesterol .
male wistar rats ( n = 36 ) that weighed 260280 g were randomly divided into four groups consisting of nine animals each .
group i rats received a normal diet and all other groups received hfd for 60 days .
after 60 days , blood was collected from the retro - orbital plexus under mild ether anesthesia to determine the lipid profile and to ensure that all rats in the hfd - fed groups were hyperlipidemic .
all rats received an equal amount of water ( 10 ml / kg b.wt . ) as a vehicle .
group i ( i.e. , animals fed a normal diet ) served as normal control , group ii ( i.e. , animals fed a hfd ) served as the positive control , and group iii rats received liv.52 extract ( 125 mg / kg b.wt . ) along with hfd .
the dose was selected based on dose range finding studies performed in the laboratory to evaluate its hepatoprotective activity in rats ; the dosing volume was determined by the weekly mean group body weight of the animals .
group iv rats ingested a hfd and received pioglitazone ( 4 mg / kg b.wt . ) .
daily clinical observations and the weekly body weights of the animals were recorded for all groups . at the end of the treatment period ,
their blood was collected from the retro - orbital plexus under mild ether anesthesia to estimate biochemical parameters such as glucose , insulin , cholesterol , tg , sgpt , sgot , and alp . after collecting their blood ,
a small portion of their liver was fixed in formalin , subjected to routine histological procedures , and stained with hematoxylin and eosin ( h&e ) and masson trichrome.15 , 16 , 17 the serum insulin was estimated by standard radioimmunoassay technique using a kit ( riak-1 ) supplied by baric / brit ( mumbai , india ) .
the degree of insulin resistance was estimated by using the homeostasis model assessment ( homa ) as the index of insulin resistance .
the formula for the homa index is : homaindex = insulin(uperliter)glucose(mmolperliter)22.5 all values are expressed as the mean standard error of the mean ( sem ) .
the results were statistically analyzed by one - way analysis of variance ( anova ) , followed by dunnett 's post test , using prism graphpad 4.03 software , windows version ( graphpad software inc .
the present study evaluated the effect of liv.52 extract in an experimental model of hfd - induced nash in rats .
feeding animals a hfd significantly impaired the lipid profile and elevated the level of serum insulin , glucose , and liver function marker enzymes sgpt , sgot , and alp .
the changes were statistically significant , compared to the normal controls ( i.e. , animals fed a normal diet ) .
treatment with the liv.52 extract was initiated at the end of 9 week of hfd supplementation .
group iv animals were treated with pioglitazone , which was used as the reference standard .
forty - two days of treatment orally with liv.52 extract ( 125 mg / kg ) reversed the elevated serum markers sgot , sgpt , alp , and reversed the cholesterol and tg levels to a statistically significant extent , compared to the untreated hfd control animals .
the oral administration of pioglitazone ( 4 mg / kg ) also decreased the aforementioned serum parameters to a statistically significant level , compared to the positive untreated control ( table 1 ) .
insulin resistance that developed because of the intake of a hfd was also decreased in animals treated with liv.52 extract or pioglitazone .
liv.52 extract and pioglitazone both decreased the fasting serum glucose , the insulin level , and the homa index , which are measures of insulin resistance ( table 1 ) .
the histopathological examination and scoring of the liver sections ( stained by h&e and masson trichome ) also revealed the beneficial effect of liv.52 extract and pioglitazone in reversing many of the pathological changes associated with a hfd in rats .
most notably , the drugs significantly reduced collagen deposition , necrosis , and steatosis in hepatic tissues , which are hallmarks of nash ( table 2 and fig . 2 , fig . 3 ) .
nonalcoholic steatohepatitis refers to a spectrum of hepatic pathology that resembles alcoholic liver disease , but appears in individuals who have low or negligible alcohol consumption .
increasing evidence suggests that nash is associated with progressive fibrosis , cirrhosis , and eventually hepatocellular cancer .
it has been suggested that the term nonalcoholic fatty liver disease should be used only for the more severe forms of nafld that correspond to types 3 and 4 with alcoholic - like histological findings .
the medical conditions most frequently associated with nafld and nash are obesity , diabetes mellitus , and dyslipidemia .
the hfd model is useful in reproducing the human condition because it contains predominantly saturated fat intake , which is positively correlated with the insulin sensitivity index , and alanine aminotransferase levels in patients with nash .
peripheral insulin resistance can induce hepatic steatosis , which then causes insulin resistance in the liver and is characterized by a reduced insulin - suppressing effect in hepatic glucose production ; this aggravates peripheral insulin resistance and contributes to hepatic lipogenesis .
insulin resistance is a complex metabolic abnormality that affects the ability of peripheral tissues to respond to insulin .
it is a prominent feature of metabolic syndrome and type 2 diabetes , and is a major risk factor for cardiovascular disease .
there may be a close interplay between increased tumor necrosis factor ( tnf)- expression , insulin resistance , and lipolysis in adipose tissue that results in the increased delivery of free fatty acids , tnf- , and cortisol to the liver , which initially lead to the development of steatosis . in patients with nafld ,
the insulin resistance increases fat oxidation , which in association with tnf- , generates oxidative stress and mitochondrial uncoupling .
the expression of tnf- and mitochondrial dysfunction leads to hepatocyte death , inflammation , and ultimately fibrosis.22 , 23 in the present study , the effect of liv.52 extract was compared with pioglitazone , which was used as the reference standard in a rat model of nash .
previous reports indicate the usefulness of pioglitazone in an experimental model of nash in rats .
pioglitazone is also a reasonable option for treating nash , particularly in patients with type 2 diabetes mellitus or impaired glucose tolerance .
however , the cardiovascular benefit risk ratio of this drug must at least be considered .
oxidative stress may contribute to the development of several age - related and chronic diseases such as cancer , diabetes , neurodegenerative diseases , and cardiovascular diseases.26 , 27 , 28 in particular , ros and reactive nitrogen species have a crucial role in disease induction and in the progression of liver diseases such as hepatocellular carcinoma , viral and alcoholic hepatitis , and nonalcoholic steatosis.29 , 30 in our previous studies , liv.52 extract exhibited a potent beneficial effect in regulating oxidative stress induced by various liver toxicants .
it abrogates copper ( ii)-induced cytotoxicity in hepg2 cells by inhibiting lipid peroxidation , increasing the glutathione content , and increasing endogenous antioxidant enzyme activities . by preventing intracellular glutathione depletion and lipid peroxidation
there are other reports that indicate the usefulness of plant - based antioxidants in the management of nash .
genistein is a strong antioxidant agent that is capable of decreasing the plasma tnf- level and attenuating the incidence of nash .
a chinese polyherbal blend comprising panax pseudoginseng ( sn q ) , eucommia ulmoides ( d zhng ) , polygonati rhizoma ( hung jng ) , and licorice root ( gn co gn ) reportedly markedly reduces macrosteatosis while significantly improving histological markers of inflammation in hfd - fed experimental animals .
these effects have also been associated with a marked reduction in serum aminotransferases and hepatic lipoperoxide and glutathione content , which implies that the herbal complex has noticeable antioxidant activity .
nonalcoholic steatohepatitis is histologically characterized by diffuse fatty infiltration , lobular inflammation , ballooning degeneration , and fibrosis in the liver.35 , 36 in the present study , many liver histopathological features of animals fed a hfd were similar to the findings of other published reports , and the treatment by liv.52 extract or pioglitazone significantly reversed these histopathological anomalies ( fig . 2 , fig . 3 ) .
the liv.52 extract treatment significantly reduced steatosis , collagen deposition , and necrosis of hepatic tissues , which indicate its antifibrotic and antinecrotic properties . increased mean body weight occurred in the animals treated a hfd , compared to the normal control group ; however , this difference was not statistically significant .
the treated groups showed a marginal decrease in mean body weight in comparison to the positive untreated controls ; however , this finding was similarly insignificant ( fig . 4 ) .
the results of the present study showed that the treatment with the liv.52 extract was comparable to pioglitazone at the selected dose , by the method employed , and by the mode of administration .
the mechanism behind the beneficial action of liv.52 extract in the present experimental model of nash could be because of its potent antioxidant and other hepatospecific actions , as reported previously .
from the biochemical and histopathological data obtained in the present study , the treatment by liv.52 extract administered orally at a daily dose of 125 mg / kg b.wt . exhibited a beneficial effect by reversing serum biochemical parameters in rats with nash induced by a hfd .
the liv.52 extract treatment also significantly reduced steatosis , collagen deposition , and necrosis in hepatic tissues , which indicate its antifibrotic and antinecrotic properties .
the effect of liv.52 extract was comparable to that of pioglitazone at the selected dose , by the method employed , and by the mode of administration .
the mechanism behind the beneficial action of liv.52 extract in the present experimental model of nash could be because of its potent antioxidant and other hepatospecific actions , as previously reported in the literature .
the authors declare no conflicts of interest and guarantee no ethical conflicts among the authors or the experimental methodology .
the test drug ( i.e. , liv.52 extract ) was received in a coded form from the phytochemistry department of the himalaya drug company ( bangalore , india ) and all experiments were performed in the department of pharmacology at the research & development center of the himalaya drug company ( bangalore , india ) .
Output:
| the objective of the present study is to evaluate the effect of the extract of a well - known hepatospecific polyherbal formulation , liv.52 , in an experimental model of high - fat diet ( hfd)-induced nonalcoholic steatohepatitis ( nash ) in rats . feeding a hfd for 15 weeks resulted in significant impairment of the lipid profile , elevation of hepatic enzyme markers , and insulin resistance in rats .
the histological examination of the liver furthermore indicated fibrotic changes and fat deposition in hepatic tissues .
the treatment with liv.52 extract [ 125 mg / kg body weight per os ( b.wt .
p.o . ) ] , which was administered from week 9 onward , reversed the hfd - induced changes to a statistically significant extent , compared to the untreated positive control animals .
the effect observed with liv.52 extract was comparable to that of pioglitazone ( 4 mg / kg b.wt . ) , a standard drug that is useful in the management of nash .
the treatment with liv.52 extract significantly reduced steatosis , collagen deposition , and necrosis in hepatic tissues , which indicates its antifibrotic and antinecrotic properties .
the results obtained in the present set of experiments indicate that liv.52 extract effectively reverses metabolic and histological changes associated with hfd - induced nash . |
PubmedSumm118531 | ***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: emphysematous pyelonephritis ( epn ) is a life - threatening , fulminant , necrotizing upper urinary tract infection associated with gas within the kidney and/or perinephric space .
we present the clinical profiles and outcome of eight patients with epn who were managed conservatively without any mortality .
during the period 20082011 , a total of eight diabetic patients with clinical features of epn and computerized tomography ( ct ) image showing gas in renal parenchyma , collecting system or perirenal space , and no fistulous connection between urinary tract and bowel were evaluated .
all of them presented with fever , loin pain , dysuria , and oliguria . at admission , renal dysfunction
was observed in all these patients with a mean serum creatinine of 5.47 2.3 ( 2.37.8 ) mg / dl .
most of them had poorly controlled blood sugar levels ( seven out of eight ) .
escherichia coli was found to be the causative organism in all the patients as per urine culture .
staging class iv ) and unilateral in 4 ( classes i , ii and iii ) .
hydronephrosis was seen in fifty percent of patients ( three unilateral and one bilateral ) .
there were air pockets in the perinephric collection , proximal ureter , and in the urinary bladder of two patients ( figures 1 , 2 , 3 , and 4 ) .
all patients were discharged in a stable condition with a mean serum creatinine of 2.40 0.76 ( 1.63.3 ) mg / dl .
epn is defined as a severe necrotizing renal parenchymal infection that is characterized by the bacterial production of gas within the renal parenchyma .
the commonest causative organism is escherichia coli , followed by proteus , klebsiella , anaerobic streptococci , and candida .
epn has been reported in renal transplant recipients [ 36 ] and in patients with polycystic kidney disease [ 7 , 8 ] .
the diagnosis of epn is often delayed because the appearances of symptoms are very hazy and nonspecific .
common presentation includes fever , abdominal pain , dysuria , vomiting , depressed level of consciousness , shock , renal angle tenderness , and acute kidney injury .
less common presentation includes dyspnea , crepitus over the flanks , and pneumaturia . in our study , all the patients were diabetics , and majority had uncontrolled blood sugars .
all of them presented with fever , loin pain , dysuria , pyuria , and oliguria .
dyspnea and pedal edema are seen in 5/8 , and one had altered sensorium . the causative organism was found to be escherichia coli in urine cultures in all the patients .
ct imaging not only reveals the presence and position of gas in the renal parenchyma but also is useful to assess the extent of renal parenchymal involvement and response to therapy .
abdominal ultrasonography ( usg ) and x - ray can also be used to diagnose epn . in our study , ultrasonography gave a clue for the presence of gas in renal parenchyma in five patients .
ct showed the presence of epn , even in those situations where usg could not pick up .
it is possible that urinary tract obstruction and decreased renal vascular supply due to diabetes might have contributed for the development of epn in our patients .
patients with emphysematous pyelonephritis ( epn ) should be treated with aggressive medical management and possibly prompt surgical intervention [ 1 , 13 , 14 ] .
active management with appropriate parenteral antibiotics , addressing the fluid - electrolyte and hemodynamic status , stringent control of diabetes with insulin , and relieving ureteric obstruction either by percutaneous drainage or internal stenting has improved the clinical outcome of our patients without any mortality .
none of them required any major surgical intervention , even though more than half of the patients were in class 3 and class 4 epn and having more than two risk factors such as elevated serum creatinine , altered sensorium , and shock .
recent case reports have also described successful outcome in patients with bilateral epn with medical therapy alone [ 15 , 16 ] . at discharge ,
all the patients had elevated serum creatinine ; time to normalization of renal parameters could not be assessed as most of these patients were lost for followup .
Output:
| emphysematous pyelonephritis ( epn ) is a severe , necrotizing renal parenchymal infection characterized by production of intraparenchymal gas .
epn predominantly affects female diabetics and immunocompromised patients . in a three - year period 20082011 ,
a total of 8 patients were admitted to our hospital .
all of them were diabetics , and both males and females were equally affected .
these patients showed vague symptoms at admission and frequently presented with fever , loin pain , dysuria , and pyuria necessitating urgent medical attention .
epn required radiological diagnosis .
ct scan revealed bilateral epn with urinary obstruction and hydronephrosis in 50% of patients .
escherichia coli was found to be the causative organism in all the patients .
treatment comprised of resuscitation , normalization of serum electrolytes and blood sugars , administration of parenteral antibiotics , and relieving ureteric obstruction if present .
all the patients improved with conservative management without any mortality . |
PubmedSumm118532 | ***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: diabetes and many other chronic diseases show a higher prevalence among groups of low socioeconomic status ( ses).1,2 in addition , patients with diabetes and a low ses have been shown to present with worse health outcomes such as poorer glycemic control , more diabetes - related complications , higher cardiovascular risk factors , and poorer self - rated health.37 a model has been proposed by brown et al8 to explain this association between ses and health outcomes in patients with diabetes .
it suggests that health outcomes ( which show the effects of care on the health status of patients9 ) are influenced by distal factors , such as individual ( eg , cultural background ) or community characteristics , as well as by more proximal factors such as health behaviors , access to health care , and processes of care ( ie , what is done to care for a patient ) .
most studies looking at the relationship between ses and processes of diabetes care reported worse processes of care among patients of lower ses.10,11 it is well accepted that processes of care influence diabetes outcomes , and many processes are considered indicators of quality of diabetes care .
thus , achieving optimal processes of care is postulated to be a key element in the care of patients with diabetes . in switzerland ,
health insurance is mandatory , and access to care is universal . despite that , health inequalities across ses groups have been reported , mostly for mortality and cardiovascular risk factors.12 moreover , recent studies have shown that individuals with low income were at high risk of foregoing healthcare for economic reasons,13 possibly because of the high out - of - pocket payments characterizing the swiss health care system .
however , it remains unknown whether once individuals have reached the health care system , social inequalities persist with regard to quality of care .
indeed , no study in switzerland has so far examined the relationship between education and quality of care in any disease .
the aim of this study was to determine the association between education and quality of care among patients with diabetes .
we used data from a cross - sectional paper survey , self - administered among a cohort of patients with any type of diabetes , living in the canton of vaud , a large french - speaking region in switzerland with more than 720,000 inhabitants .
adults ( aged 18 years ) presenting with a prescription for insulin , oral antidiabetics , glycemic strips , or a glucose meter were recruited by pharmacists in fall 2011 and summer 2012 .
although pharmacists checked the eligibility of the patients and presented the study , patients willing to participate were asked to fill in the questionnaire at home and send it back to the investigators .
patients with an obvious cognitive impairment , those who did not speak or understand french well enough , those who did not reside in the canton of vaud , and women with gestational diabetes were excluded . with patients approvals , treating physicians were contacted and asked to fill in a brief questionnaire to collect some laboratory and clinical data .
the final sample totaled 519 patients ( 406 from 1,013 eligible patients in 2011 and 113 from 328 eligible patients in 2012 , corresponding to participation rates of 40% and 34% , respectively ) .
the data collection process is described in more detail elsewhere.14 this study complies with the current laws of switzerland .
ethical approval was received from the cantonal ethics committee of research on the human being ( protocol 151/11 ) .
the variables considered in this study included one exposure variable , several dependent variables , and other independent variables considered as potential confounders .
the exposure variable was self - reported education , which is one of several dimensions of socioeconomic status .
it was grouped into three categories according to the international standard classification of education : primary education , corresponding to the completion of compulsory school or less ; secondary education , corresponding to vocational training or high school ; and tertiary education , corresponding to university or technical college .
patients were asked whether they had received the following processes of care during the last 12 months : hba1c level check ( yes , one time ; yes , more than one time ; no ; or i do not know ) , lipid blood test ( yes , no , or i do not know ) , microalbuminuria test ( yes , no , or i do not know ) , funduscopy ( yes , less than 1 year ago ; yes , 12 years ago ; yes , more than 2 years ago ; never ; or i do not know ) , feet examined by a physician ( yes , no , or i do not know ) , and influenza vaccination ( yes , no , or i do not know ) . we coded these variables into two categories : patients having received at least one check versus those not having received a check .
answers into the missing answer category . for the hba1c variable , we only considered the answers of patients reporting knowing the meaning of hba1c ( skip question ) .
most outcomes of care considered were reported by the treating physicians ( 162 physicians reported the values of 271 patients , for a physicians participation rate of 60% in 2011 and 63% in 2012 ) .
physicians reported values were the following : last measured value of hba1c ( % ) , systolic blood pressure ( mmhg ) , and low - density lipoprotein cholesterol ( mmol / l ) .
we also considered patient - reported health - related quality of life ( hrqol ) , as measured by two indicators : a disease - specific measure , the audit of diabetes - dependent quality of life,15 with values ranging between 9 ( maximum negative effect of diabetes ) and + 3 ( maximum positive effect of diabetes ) , and a generic instrument , the sf-12.16 the results of the sf-12 are expressed with two scores : the mental component summary and physical component summary scores , with each having been initially constructed so as to present a mean of 50 and a standard deviation of 50 in the us population , and with each presenting a clinically significant cut - off of 5.17 throughout the manuscript , hrqol refers to both audit of diabetes - dependent quality of life and sf-12 , unless otherwise stated .
further covariates considered were age , sex , and the presence ( yes / no ) of diabetes - related complications ( cardiovascular disease , stroke , vision problems not including cataracts or glaucoma , chronic kidney insufficiency , dialysis or kidney transplantation , foot neuropathy , foot ulcer , amputation of a lower limb , and severe hypo- or hyperglycemia ) .
bivariate analyses were first carried out between education and dependent variables ( processes and outcomes of care ) , using chi square test and analysis of variance for categorical and continuous variables , respectively .
we further built linear and logistic regression models to assess the association between education and processes and outcomes of care , respectively .
we adjusted all final models for age , sex , and the presence of diabetes - related complications , variables considered to be potential confounders of the association of interest . to take into account the intragroup correlation ( clusters of pharmacies ) , the clustered sandwich estimator was used to estimate the variance - covariance matrix .
we used data from a cross - sectional paper survey , self - administered among a cohort of patients with any type of diabetes , living in the canton of vaud , a large french - speaking region in switzerland with more than 720,000 inhabitants .
adults ( aged 18 years ) presenting with a prescription for insulin , oral antidiabetics , glycemic strips , or a glucose meter were recruited by pharmacists in fall 2011 and summer 2012 .
although pharmacists checked the eligibility of the patients and presented the study , patients willing to participate were asked to fill in the questionnaire at home and send it back to the investigators .
patients with an obvious cognitive impairment , those who did not speak or understand french well enough , those who did not reside in the canton of vaud , and women with gestational diabetes were excluded . with patients approvals , treating physicians were contacted and asked to fill in a brief questionnaire to collect some laboratory and clinical data .
the final sample totaled 519 patients ( 406 from 1,013 eligible patients in 2011 and 113 from 328 eligible patients in 2012 , corresponding to participation rates of 40% and 34% , respectively ) .
the data collection process is described in more detail elsewhere.14 this study complies with the current laws of switzerland .
ethical approval was received from the cantonal ethics committee of research on the human being ( protocol 151/11 ) .
the variables considered in this study included one exposure variable , several dependent variables , and other independent variables considered as potential confounders .
the exposure variable was self - reported education , which is one of several dimensions of socioeconomic status .
it was grouped into three categories according to the international standard classification of education : primary education , corresponding to the completion of compulsory school or less ; secondary education , corresponding to vocational training or high school ; and tertiary education , corresponding to university or technical college .
patients were asked whether they had received the following processes of care during the last 12 months : hba1c level check ( yes , one time ; yes , more than one time ; no ; or i do not know ) , lipid blood test ( yes , no , or i do not know ) , microalbuminuria test ( yes , no , or i do not know ) , funduscopy ( yes , less than 1 year ago ; yes , 12 years ago ; yes , more than 2 years ago ; never ; or i do not know ) , feet examined by a physician ( yes , no , or i do not know ) , and influenza vaccination ( yes , no , or i do not know ) .
we coded these variables into two categories : patients having received at least one check versus those not having received a check .
answers into the missing answer category . for the hba1c variable , we only considered the answers of patients reporting knowing the meaning of hba1c ( skip question ) .
most outcomes of care considered were reported by the treating physicians ( 162 physicians reported the values of 271 patients , for a physicians participation rate of 60% in 2011 and 63% in 2012 ) .
physicians reported values were the following : last measured value of hba1c ( % ) , systolic blood pressure ( mmhg ) , and low - density lipoprotein cholesterol ( mmol / l ) .
we also considered patient - reported health - related quality of life ( hrqol ) , as measured by two indicators : a disease - specific measure , the audit of diabetes - dependent quality of life,15 with values ranging between 9 ( maximum negative effect of diabetes ) and + 3 ( maximum positive effect of diabetes ) , and a generic instrument , the sf-12.16 the results of the sf-12 are expressed with two scores : the mental component summary and physical component summary scores , with each having been initially constructed so as to present a mean of 50 and a standard deviation of 50 in the us population , and with each presenting a clinically significant cut - off of 5.17 throughout the manuscript , hrqol refers to both audit of diabetes - dependent quality of life and sf-12 , unless otherwise stated .
further covariates considered were age , sex , and the presence ( yes / no ) of diabetes - related complications ( cardiovascular disease , stroke , vision problems not including cataracts or glaucoma , chronic kidney insufficiency , dialysis or kidney transplantation , foot neuropathy , foot ulcer , amputation of a lower limb , and severe hypo- or hyperglycemia ) .
the exposure variable was self - reported education , which is one of several dimensions of socioeconomic status .
it was grouped into three categories according to the international standard classification of education : primary education , corresponding to the completion of compulsory school or less ; secondary education , corresponding to vocational training or high school ; and tertiary education , corresponding to university or technical college .
patients were asked whether they had received the following processes of care during the last 12 months : hba1c level check ( yes , one time ; yes , more than one time ; no ; or i do not know ) , lipid blood test ( yes , no , or i do not know ) , microalbuminuria test ( yes , no , or i do not know ) , funduscopy ( yes , less than 1 year ago ; yes , 12 years ago ; yes , more than 2 years ago ; never ; or i do not know ) , feet examined by a physician ( yes , no , or i do not know ) , and influenza vaccination ( yes , no , or i do not know ) . we coded these variables into two categories : patients having received at least one check versus those not having received a check .
, we only considered the answers of patients reporting knowing the meaning of hba1c ( skip question ) .
most outcomes of care considered were reported by the treating physicians ( 162 physicians reported the values of 271 patients , for a physicians participation rate of 60% in 2011 and 63% in 2012 ) .
physicians reported values were the following : last measured value of hba1c ( % ) , systolic blood pressure ( mmhg ) , and low - density lipoprotein cholesterol ( mmol / l ) .
we also considered patient - reported health - related quality of life ( hrqol ) , as measured by two indicators : a disease - specific measure , the audit of diabetes - dependent quality of life,15 with values ranging between 9 ( maximum negative effect of diabetes ) and + 3 ( maximum positive effect of diabetes ) , and a generic instrument , the sf-12.16 the results of the sf-12 are expressed with two scores : the mental component summary and physical component summary scores , with each having been initially constructed so as to present a mean of 50 and a standard deviation of 50 in the us population , and with each presenting a clinically significant cut - off of 5.17 throughout the manuscript , hrqol refers to both audit of diabetes - dependent quality of life and sf-12 , unless otherwise stated .
further covariates considered were age , sex , and the presence ( yes / no ) of diabetes - related complications ( cardiovascular disease , stroke , vision problems not including cataracts or glaucoma , chronic kidney insufficiency , dialysis or kidney transplantation , foot neuropathy , foot ulcer , amputation of a lower limb , and severe hypo- or hyperglycemia ) .
bivariate analyses were first carried out between education and dependent variables ( processes and outcomes of care ) , using chi square test and analysis of variance for categorical and continuous variables , respectively .
we further built linear and logistic regression models to assess the association between education and processes and outcomes of care , respectively .
we adjusted all final models for age , sex , and the presence of diabetes - related complications , variables considered to be potential confounders of the association of interest . to take into account the intragroup correlation ( clusters of pharmacies ) , the clustered sandwich estimator was used to estimate the variance - covariance matrix .
the study participants had a mean age of 64.5 years , 40.3% were women , and 47.5% had at least one diabetes complication .
educational status distribution was as follows : 18.9% primary , 56.2% secondary , and 25.0% tertiary education ( table 1 ) .
in bivariate analyses ( tables 2 and 3 ) , the proportion of patients having received feet examination grew from primary to tertiary education , with a statistically significant trend .
bivariate analyses of outcomes of care showed that diabetes - specific and generic quality - of - life measures significantly increased with increasing educational level .
fully adjusted regressions showed a general pattern of higher quality of care among patients with higher educational levels ( table 4 ) .
funduscopy was the only process of care significantly associated with education : patients with tertiary education were more likely to receive a funduscopy than those with primary education ( odds ratio , 1.8 ; 95% confidence interval , 1.0043.3 ) .
in fact , patients with secondary and tertiary education had a higher quality of life , as measured by the audit of diabetes - dependent quality of life and the physical component summary score of the sf-12 compared with patients with primary education .
this study suggests the presence of social inequalities in the care of patients with diabetes , even in a wealthy country with universal health insurance coverage .
more specifically , we found educational disparities for one process of care ( funduscopy ) and hrqol .
our results are consistent with most studies assessing the relationship between ses and processes of diabetes care , which report , with few exceptions,18,19 an association between lower ses and worse processes of care .
indeed , low ses has been associated with worse diabetes education20 and poorer use of annual medical checks.2,7,11,21 a direct comparison to these findings is , however , rather difficult , as almost every study selected different sets of processes and outcomes of care .
our results nevertheless remain consistent with the literature , insofar as funduscopy is the process of care that has been most often related to lower ses.10,21 this may be explained by the fact that this exam has to be performed by a specialist , unlike the other considered processes of care .
in fact , a better - educated patient may be more likely to get an appointment directly with a specialist or to remind his general practitioner to refer him .
further , such a patient may also better understand what was done and better self - report the exam .
finally , our other processes of care share a feature that may explain their lack of association with education : they are all routinely performed and can all be performed in a general practitioner s practice . in line with other research , we also found that patients with lower education reported lower diabetes - specific and generic hrqol.22,23 our hypothesis is that a better education may contribute to increased hrqol through better understanding of the nature of the disease , better coping with the disease , and eventually better diabetes care overall .
the population - based design and the use of many processes and outcomes of care are the main strengths of this study .
yet our findings have limitations , with one issue being the selection bias resulting from a moderate participation rate and recruitment of patients in pharmacies .
however , this is more likely to have introduced an underestimation than an overestimation of the association between education and quality of care by excluding individuals of the lowest socioeconomic groups .
indeed , individuals not proficient in french were excluded at enrollment , and a prerequisite to study participation was a visit to the pharmacy .
these individuals ( of low ses ) are also more difficult to recruit for studies.24 in our study , people of lower ses may have visited a pharmacy less often than more wealthy individuals , and thus may have been less likely to be recruited .
however , we are confident that our population sample is representative , as some characteristics of our study patients were similar to those of a prior study conducted in the same region.25 another limitation was the sample size , which was not planned for the objective of the present analysis . as a possible consequence
, we may not have had enough power to always detect statistically significant differences , despite suggestive and consistent trends toward ses inequalities in quality of care .
finally , self - reported data are prone to recall bias , which may have affected our process and outcome measures .
our results are consistent with most studies assessing the relationship between ses and processes of diabetes care , which report , with few exceptions,18,19 an association between lower ses and worse processes of care .
indeed , low ses has been associated with worse diabetes education20 and poorer use of annual medical checks.2,7,11,21 a direct comparison to these findings is , however , rather difficult , as almost every study selected different sets of processes and outcomes of care .
our results nevertheless remain consistent with the literature , insofar as funduscopy is the process of care that has been most often related to lower ses.10,21 this may be explained by the fact that this exam has to be performed by a specialist , unlike the other considered processes of care .
in fact , a better - educated patient may be more likely to get an appointment directly with a specialist or to remind his general practitioner to refer him .
further , such a patient may also better understand what was done and better self - report the exam .
finally , our other processes of care share a feature that may explain their lack of association with education : they are all routinely performed and can all be performed in a general practitioner s practice .
in line with other research , we also found that patients with lower education reported lower diabetes - specific and generic hrqol.22,23 our hypothesis is that a better education may contribute to increased hrqol through better understanding of the nature of the disease , better coping with the disease , and eventually better diabetes care overall .
the population - based design and the use of many processes and outcomes of care are the main strengths of this study .
yet our findings have limitations , with one issue being the selection bias resulting from a moderate participation rate and recruitment of patients in pharmacies .
however , this is more likely to have introduced an underestimation than an overestimation of the association between education and quality of care by excluding individuals of the lowest socioeconomic groups .
indeed , individuals not proficient in french were excluded at enrollment , and a prerequisite to study participation was a visit to the pharmacy .
these individuals ( of low ses ) are also more difficult to recruit for studies.24 in our study , people of lower ses may have visited a pharmacy less often than more wealthy individuals , and thus may have been less likely to be recruited .
however , we are confident that our population sample is representative , as some characteristics of our study patients were similar to those of a prior study conducted in the same region.25 another limitation was the sample size , which was not planned for the objective of the present analysis . as a possible consequence , we may not have had enough power to always detect statistically significant differences , despite suggestive and consistent trends toward ses inequalities in quality of care .
finally , self - reported data are prone to recall bias , which may have affected our process and outcome measures .
achieving good quality of care is essential for individuals with diabetes , as it can decrease their mortality and morbidity risks .
recent studies have shown that tailored interventions for socially disadvantaged patients can have positive effects on diabetes care and that health inequalities may disappear after educational interventions.6 thus , interventions specifically targeting these groups of patients may have the potential to reduce social inequalities in health and should be among the priorities of diabetes management programs .
Output:
| purposelow socioeconomic status is associated with higher prevalence of diabetes , worse outcomes , and worse quality of care .
we explored the relationship between education , as a measure of socioeconomic status , and quality of care in the swiss context.patients and methodsdata were drawn from a population - based survey of 519 adults with diabetes during fall 2011 and summer 2012 in a canton of switzerland .
we assessed patients and diabetes characteristics .
eleven indicators of quality of care were considered ( six of process and five of outcomes of care ) .
after bivariate analyses , regression analyses adjusted for age , sex , and diabetic complications were performed to assess the relationship between education and quality of care.resultsof 11 quality - of - care indicators , three were significantly associated with education : funduscopy ( patients with tertiary versus primary education were more likely to get the exam : odds ratio , 1.8 ; 95% confidence interval [ ci ] , 1.0043.3 ) and two indicators of health - related quality of life ( patients with tertiary versus primary education reported better health - related quality of life : audit of diabetes - dependent quality of life : =0.6 [ 95% ci , 0.20.97 ] ; sf-12 mean physical component summary score : =3.6 [ 95% ci , 0.96.4]).conclusionour results suggest the presence of educational inequalities in quality of diabetes care .
these findings may help health professionals focus on individuals with increased needs to decrease health inequalities . |
PubmedSumm118533 | ***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: liver diseases , including viral hepatitis , toxic liver diseases , alcoholic liver diseases , and autoimmune hepatitis , represent a global health problem in humans .
so far , only some kinds of the liver diseases can be managed pharmacologically [ 1 , 2 ] .
therefore , new pharmaceuticals need to be developed and tested to provide more effective therapies in the clinic
. however , the study of new pharmaceuticals requires proper animal models that are relevant to human liver diseases .
the pathophysiology of liver disease is complex , and it depends upon humoral interorgan relationships , the integrity of metabolic pathways , and the highly sophisticated morphological organization of organs [ 35 ] .
the activation of t cells has been established to be the initial trigger of most cases of autoimmune and viral hepatitis [ 6 , 7 ] .
these conditions are characterized by increased levels of aspartate transaminase ( ast ) and alanine transaminase ( alt ) enzyme activities , and accompanied with lymphocyte activation and the inflammatory cytokines accumulation [ 8 , 9 ] . in mice injected with the t - cell mitogenic plant lectin concanavalin a ( cona ) , t lymphocytes become activated .
this process is consistent with a liver - specific inflammatory response that induces t - cell mediated hepatitis [ 9 , 10 ] .
pathological studies have shown that the destruction of liver tissue mainly depends upon the infiltration and accumulation of many lymphocytes in hepatitis , principally cd4 t cells , natural killer t ( nkt ) cells , and kupffer cells [ 1012 ] .
additionally , proinflammatory cytokines also play an important role in hepatitis , such as tumor necrosis factor- ( tnf- ) , interferon- ( ifn- ) , and interleukin- ( il- ) 6 .
nuclear factor - kappa b ( nf-b ) is a well - known transcription factor that can potently induce proinflammatory mediators ' secretion during the development of acute liver disease .
nf-b activity is mainly regulated by ib and can be affected by the pi3k / akt pathway . in summary ,
autophagy , known as type ii programmed cell death , is characterized as an intracellular protective mechanism by enveloping defective organelles by double - membrane vesicles formation termed autophagosomes which subsequently submitted to lysosomes to be degraded . paralleled with apoptosis , autophagy is another way of programmed cell death .
there are many regulators of autophagy , including mammalian target of rapamycin ( mtor ) , mtor kinase , 5-amp - activated protein kinase ( ampk ) , eukaryotic initiation factor 2 ( eif2 ) , inositol - trisphosphate ( ip3 ) , and c - jun - n - terminal kinase .
beclin 1 , uvrag , vps34 , vps15 , and bif-1 also play important roles in autophagosome nucleation .
one of the most important regulator pathway is the mtor pathway , which could be modulated by pi3k / akt pathway [ 16 , 17 ] .
light chain 3 is known to be an important marker of autophagy expressed on autophagic vesicles .
a certain extent of autophagy contributes to cellular homeostasis especially in stressed conditions such as nutrient restriction , hypoxia , and infection .
highly accelerated autophagy has been reported in ischemia - induced neuronal cell death in the mouse brain .
n - acetylcysteine ( nac ) is a thiol and a precursor of both l - cysteine and glutathione ( gsh ) .
it is known to be a source of sulfhydryl groups and a scavenger of free radicals .
the most established clinical application of nac is to prevent fulminant hepatic failure caused by acetaminophen poisoning in treatments .
the application of nac to research efforts for many diseases , such as cancer , human immunodeficiency virus ( hiv ) infection , and cardiovascular disease , has been reported [ 21 , 22 ] .
besides , nac has been shown to interact with many metabolic pathways , such as regulators of the cell cycle , apoptosis , gene expression , and signal transduction , as well as the cytoskeleton and immune system .
the mechanism of nac in hepatitis amelioration includes not only the conventional pathway of reactive oxygen species ( ros ) removal , but also other pathways such as nf-b and pi3k / akt pathways .
we have previously demonstrated that nac significantly alleviated ischemia - reperfusion induced acute liver injury , and a reduction of autophagy was observed in nac pretreatment group in that model . in the present study ,
we focus on the protective effects and probable mechanisms of nac in concanavalin a - induced hepatitis in mice .
enzyme - linked immunosorbent assay ( elisa ) kits for detecting il-2 , il-6 , and tnf- and ifn- were purchased from r&d systems ( minneapolis , mn , usa ) .
the antibodies used in this study include akt , p - akt , il-2 , il-6 , tnf- , ifn- , nf-b , lc3ii , beclin 1 , ib- , and ib- ( cell signaling technology , beverly , ma , usa ) .
male balb / c mice ( 68 weeks old , 22 2 g ) and male c57 mice ( 68 weeks old , 21 2 g ) were obtained from shanghai laboratory animal co. ( slac , shanghai , china ) .
mice were fasted in an environment at a temperature of 25 2c and 55% humidity with an alternating 12 h light dark cycle .
all experiments were performed according to the national institutes of health guidelines and were also approved by the animal care and use committee of shanghai tongji university .
cona was dissolved in normal saline solution at a concentration of 20 mg / kg .
male balb / c mice were randomly divided into one of four groups : group i ( saline only ) included 18 mice that were injected with saline via the tail vein , group ii ( cona - treated ) included 18 mice that were injected with cona ( 20 mg / kg ) via the tail vein , group iii ( 2 h after nac - treatment ) included 18 mice that were injected with nac ( dissolved in saline , 150 mg / kg ) which was administrated via the tail vein 2 h before injection with cona via the tail vein , and group iv ( before nac - treatment ) included 18 mice that were injected with nac ( dissolved in saline , 150 mg / kg ) via the tail vein 30 min after they were injected with cona via the tail vein .
male c57 mice were randomly divided into two groups : group a ( cona - treated ) included 18 mice that were injected with cona ( 20 mg / kg ) via the tail vein and group b ( nac - treatment ) included 18 mice administrated with nac ( dissolved in saline , 150 mg / kg ) via the tail vein 2 h before cona injection .
we selected and sacrificed 6 mice from each group at 6 , 12 , and 24 h time points after cona administration . at the end of the experiment
, serum and liver tissue samples were obtained from each mouse and stored for further analysis .
serum was separated by centrifugation at 2000 rpm at room temperature for 10 min . to assess the level of hepatocellular injury after cona - treatment
, serum alt and ast levels were measured using an automated chemistry analyzer ( olympus au1000 , tokyo , japan ) . to measure the serum levels of il-2 , il-6 , tnf- , and ifn- ,
mouse liver tissues were collected and stored in 4% paraformaldehyde for at least 24 h , and paraffin blocks were then prepared .
paraffin sections were stained with hematoxylin and eosin ( h&e ) to observe the level of inflammation and tissue damage by light microscopy .
antigen was recovered in citrate buffer by incubation in a 95c water bath for 20 min and then endogenous peroxidase activity was blocked by incubating in 3% hydrogen peroxide for 20 min at 37c .
membranes were ruptured with 0.2% triton at room temperature for 30 min and nonspecific binding sites were blocked with 5% bsa at 37c for 20 min followed by room temperature incubation for 10 min .
liver slices were incubated overnight with rabbit anti - mouse p - akt ( 1 : 500 ) , rabbit anti - mouse lc3ii ( 1 : 500 ) , rabbit anti - mouse beclin 1 ( 1 : 500 ) , or rabbit anti - mouse nf-b ( 1 : 50 ) . the next day , slices were incubated with secondary antibody ( goat anti - rabbit ; epitomics , burlingame , ca , usa ) for 30 min at room temperature .
next , slides were counterstained with hematoxylin , dehydrated using a graded ethanol and xylene series , and mounted with entellan .
the assay was carried out using image - pro plus software 6.0 ( media cybernetics , silver spring ,
the frequency of nf-b - positive nuclei was also calculated using image - pro plus 6.0 .
the same method was used with an additional two series for mice that were randomly selected from the same group .
the portal vein of male balb / c mice was cannulated after anesthesia and laparotomy by 20 ml prewarmed 37c d - hanks buffer , followed by 20 ml of 0.02% collagenase at a flow rate of 2 ml / min .
after perfusion , liver tissues were removed and washed with 20 ml d - hanks buffer .
the capsule of the liver was removed , and hepatic tissues were dispersed and incubated in 20 ml of 0.01% collagenase in a shaking water bath at 37c for approximately 30 min . after filtering through 60-mesh sterile nylon gauze , centrifuging at 500 rpm , and resuspending three times with rpmi-1640 culture medium , the hepatocytes were finally extracted and cultured in rpmi-1640 culture medium in a humidified incubator at 37c and 5% co2 .
liver tissues were washed with saline through portal vein 12 hours after con a or pbs injection , then dissociated by 0.05% type iv collagenase for 30 min , centrifuged and then resuspended in rpmi-1640 culture medium , pipetted 10 ml into 50 ml tubes above 25 ml 25% percoll , over 15 ml 50% percoll , and then centrifuged at 2100 rpm / min for 15 min at 4c .
kupffer cells at and above the third interface ( between 25% and 50% percoll solutions ) were collected and centrifuged at 2100 rpm / min for 15 min at 4c , washed twice by pbs , then resuspended in rpmi-1640 culture medium containing 10% fbs , and cultured in a 37c incubator with 5% co2 for 12 hours , removed spent medium , and was washed once by pbs and added in fresh medium ; the remained adherent cells were kupffer cells .
the isolated macrophages were first washed three times with pbs solution for 5 min and then fixed with 4% paraformaldehyde for 10 min .
the cells were then permeabilized in 0.3% triton x-100 ( sigma , usa ) for 10 min and washed with pbs solution .
the macrophages were blocked with 5% bovine serum albumin ( bsa ) in pbs for 1 h at room temperature and incubated with rabbit anti - mouse il-2 antibody ( diluted 1 : 100 ) , rabbit anti - mouse il-6 antibody ( diluted 1 : 100 ) , rabbit anti - mouse tnf- antibody ( diluted 1 : 100 ) , and rabbit anti - mouse ifn- antibody ( diluted 1 : 100 ) overnight at 4c .
next day , the slides were washed with pbs solution again and incubated with appropriate fluorescein isothiocyanate - conjugated secondary antibody for 1 h. the secondary antibody was subsequently washed and the slides were incubated with 2-(4-amidinophenyl)-6-indolecarbamidine dihydrochloride ( dapi ) ( life technologies , usa ) 3 min for nuclear staining and finally visualized with lsm710 carl zeiss confocal microscope ( carl zeiss ag , germany ) .
liver tissues were recovered from 80c storage and rapidly ground in liquid nitrogen before lysis in ripa lysis buffer with protease inhibitors .
equivalent amounts of total protein ( 120 g ) were boiled and subjected to sodium dodecyl sulfate
polyacrylamide gel electrophoresis ( sds page ) and then transferred onto a polyvinylidene fluoride ( pvdf ) membrane .
nonspecific binding was blocked with 5% nonfat milk ( dissolved in pbs ) for 1 h and then blots were incubated overnight at 4c with rabbit anti - mouse il-2 ( 1 : 500 ) , rabbit anti - mouse il-6 ( 1 : 500 ) , rabbit anti - mouse tnf- ( 1 : 500 ) , mouse anti - mouse -actin ( 1 : 1000 ) , rabbit anti - mouse lc3ii ( 1 : 500 ) , rabbit anti - mouse beclin 1 ( 1 : 500 ) , or rabbit anti - mouse ifn- ( 1 : 500 ) antibodies diluted in 5% milk .
all pvdf membranes were washed with pbst ( pbs containing 0.1% tween 20 ) , then were incubated with a secondary goat anti - mouse or anti - rabbit antibody ( 1 : 1000 ) , and dissolved in pbst for 45 min at 37c .
finally , membranes were washed with pbst three times for 5 min and proteins were detected using an odyssey two - color infrared laser imaging system ( detected based on fluorescence ) . in this study ,
mrna transcription of liver tissue was detected and analyzed via quantitative rt - pcr ( qrt - pcr ) .
total rna was extracted from frozen liver tissue using trizol reagent ( takara , shiga , japan ) following the manufacturer 's instructions . to measure the expression of target genes in the liver , qrt - pcr
was performed using a 7900ht fast real - time pcr system ( abi , foster city , ca , usa ) according to the manufacturer 's instructions and using sybr premix ex taq ( takara biotechnology , china ) .
following the harvesting of liver tissues , a portion of mouse liver tissue was placed in 4% glutaraldehyde and then fixed in 1% oso4 .
date of elisa , real - time pcr , levels of alt , ast , necrotic area , and western blot and immunohistochemistry were analyzed using one - way analysis of variance ( anova ) and student 's t - test .
anova was used in groups and student 's t - test on the statistical analyses applied in two groups separately . in all comparisons ,
all statistical analyses were performed using spss 17.0 for windows ( chicago , il , usa ) .
u / l ) in cona model group when compared to the both nac - treated groups ( ast , 130 12 u / l ; alt , 300 24 u / l in nac - pretreatment ; ast , 130 12 u / l ; alt , 300 24 u / l in post - nac - treatment ) ( figure 1(a ) ) at 3 time points as designed .
the control groups showed much lower levels of aminotransferase ( ast , 53 17
we observed massive areas of necrosis in the cona - alone group ( figure 1(b ) ) .
by contrast , the nac - treated groups showed minor liver damage , indicating that nac - treatment significantly reduced liver necrosis .
based on a statistical analysis using image - pro plus 6.0 software , we detected a robust statistically significant difference between the different groups .
considering the balb / c mice are relatively resistant to cona hepatitis , we used c57 mice , a strain relatively susceptible to cona hepatitis strain , to test the effectiveness of nac .
indeed , the cona - treated groups showed a more serious injury compared with balb / c mice , and nac still exhibited effective therapy effect ( figures 1(c ) and 1(d ) ) .
these results indicated that nac - treatment ameliorated cona - induced immune hepatitis in mice .
a number of proinflammatory cytokines play key roles in the progression of hepatitis , such as il-2 , ifn- , and tnf-. therefore , serum levels of il-2 , ifn- , and tnf- were measured by elisa in the control , cona - treated , nac - pretreated , and post - nac - treated groups ( figure 2(a ) ) .
our result shows that the levels of these cytokines increased in the cona - treated group after cona induction and peaked at 12 h. additionally , as expected , the production of il-2 , ifn- , and tnf- was reduced after nac - treatment , as seen at 6 and 12 h , especially in the nac - pretreated group .
furthermore , to confirm our observations , mrna and protein expression levels of il-2 , il-6 , ifn- , and tnf- were detected by real - time pcr and western blotting , respectively , at the designed time points ( figures 2(b ) and 2(c ) ) .
we found that il-2 , il-6 , ifn- , and tnf- were significantly increased in the cona - treated group and were diminished in the nac - treated groups for both mrna and protein expression levels at all three time points .
additionally , il-2 , il-6 , ifn- , and tnf- expression peaked at 12 h , indicating that these cytokines were most robustly expressed during the early phase of cona - induced hepatitis .
additionally , the western blot results were analyzed using quantity one , indicating that these changes in levels were statistically significant ( figure 2(d ) ) .
in addition , we performed immunofluorescence test of macrophages to observe the changes of inflammatory cytokines .
the immunohistochemistry graphs show that il-2 , il-6 , ifn- , and tnf- were increased in the cona - treated group and were diminished in the nac - treated groups .
thus , treatment with nac attenuated the release of cona - induced hepatitis - associated cytokines , such as il-2 , il-6 , ifn- , and tnf-. we further characterized the possible mechanism whereby nac ameliorates cona - induced hepatitis . it has been reported that activation of the akt pathway can reduce the severity of cona - induced hepatitis .
therefore , we asked whether nac acts by activating the akt pathway in cona - induced hepatitis .
the mrna expression levels of akt and pi3k were measured by qrt - pcr , and we found that the expression of total akt showed no obvious change in all groups and time points , while the expression of pi3k increased in the nac - treated groups compared to the cona - treated group .
this result was supported by measurements of protein expression of total akt , p - akt , and pi3k , as determined by western blotting .
the total protein levels of akt showed no obvious change in the cona - treated , nac - treated , or control groups , and also there was no significant change for all time points ( figure 3(b ) ) .
the expression of p - akt and pi3k was significantly increased in the nac - treated groups compared to the cona - treated group .
these data were analyzed using quantity one , indicating that there was a statistically significant difference among these changes ( figure 3(c ) ) .
this finding indicated that nac clearly upregulated the akt pathway by phosphorylation the akt protein .
we extracted the macrophages and hepatocytes to observe the protein expression of pi3k / akt pathway in 12 hours after cona injection ( figures 3(c ) and 3(d ) ) .
to further confirm these observations , we measured the expression levels of proteins in the akt pathway in liver tissues using immunohistochemistry .
as expected , our findings supported the conclusions mentioned above ( figure 3(d ) ) .
the statistical analysis was carried out using image - pro plus 6.0 software , and we clearly detected a statistically significant difference among the different groups . based on these results , we conclude that nac - treatment can ameliorate cona - induced hepatitis at least in part through regulation of the akt pathway .
nf-b plays a key role in the activation of several proinflammatory cytokines . to determine whether nac inhibited the nf-b pathway in cona - induced hepatitis , we measured the mrna expression levels of nf-b , ib- , and ib- by real - time pcr ( figure 4(a ) ) .
we measured the protein expression levels of nf-b , ib- , and ib- by western blotting .
we found that nac - treatment reduced the degradation of ib- and ib- in protein level , especially at 12 h , and nac - treatment also reduced the expression levels of nf-b ( figure 4(b ) ) .
furthermore , we explored the expression of proteins in the nf-b pathway in the liver tissue using immunohistochemistry .
we found that nf-b was mostly expressed and located in nuclei in the cona - induced compared to the control group .
additionally , we found that the expression of nf-b in nuclei was obviously reduced in the nac - treated groups , especially at 12 h ( figure 4(c ) ) .
we analyzed these data with image - pro plus 6.0 software , and statistically significant differences between the treatment groups had been detected ( figure 4(d ) ) .
to evaluate the effects of nac on autophagy in cona - induced hepatitis , we measured the levels of lc3ii and beclin 1 by real - time pcr and western blotting . lc3ii is a marker of autophagy activation that plays a significant role in regulating autophagy .
we detected changes in lc3ii and beclin 1 cdna levels by real - time pcr ( figure 5(a ) ) .
we detected a statistically significant increase in the cona - treated group compared to the control and nac - treated groups ( p < 0.05 ) .
the protein expression levels , which were detected by western blotting , were in accordance with the above results ( figure 5(b ) ) .
the protein expressions of both two autophagy makers were also learned in macrophages and hepatocytes in 12 hours after cona injection ( figure 5(b ) ) .
the results showed a consistency with the tissue experimental results . to further confirm this observation , we assessed the protein expression levels of lc3 and beclin 1 in liver tissues using immunohistochemistry ( figure 5(c ) ) .
we observed high expression levels of lc3 and beclin 1 in the cona - treated group compared to the control group .
nac downregulate the expression of lc3 and beclin 1 , which could be observed in the nac - treated groups .
these data were analyzed using image - pro plus 6.0 software , and we detected a statistically significant difference among the groups .
it is also important to note the morphology of the autophagosome during autophagy , which we assessed using tem to determine the ultrastructure of hepatocyte .
additionally , lysosomes and autophagosome were obviously increased ( figure 5(d ) ) . in the nac - treated group ,
destruction of the cells was obviously reduced , as was the number of agglutinations , and the mitochondrial structural integrity was improved .
hepatitis remains a global health problem , which consist of viral hepatitis , toxic liver disease , alcoholic liver disease , and autoimmune hepatitis , of which only a portion can be treated pharmacologically .
additionally , a large amount of evidence supports a relationship between hepatitis and hepatocellular carcinoma .
therefore , novel pharmaceuticals need to be developed and tested to provide more effective therapies in the clinic .
nac is a thiol and a precursor of l - cysteine and gsh that has potential health benefits . in this study
, we demonstrated that cona - induced hepatitis was ameliorated in nac - treated mice .
hepatitis , especially immune hepatitis , is mainly caused by the activation of immune cells .
mice injected with the t - cell mitogen plant lectin cona exhibit t lymphocyte activation [ 10 , 13 ] .
previous studies have demonstrated that the pathogenesis of cona - induced hepatitis mainly occurs as a consequence of inflammatory cytokine release .
proinflammatory cytokines play important roles in hepatitis , including tnf- , ifn- , il-2 , and il-6 . in this study , pcr and elisa
analysis revealed that the mrna expression levels of tnf- , ifn- , il-2 , and il-6 in the liver of cona - treated mice were significantly upregulated at three time points . in the nac - treated groups
one of the major consequences of reduction of these proinflammatory cytokines was the difference of serum alt and ast levels , which were considered to be one metric to assess the severity of liver injury , in cona - treated group and nac - treated groups .
besides , the histology change of liver , observed by h&e staining , corroborated the serological changes , shown in figure 1 .
nf-b is a key regulator of the expression of a variety of genes involved in immune and inflammatory responses .
it can potently induce proinflammatory mediators and plays an important role in the development of cona - induced hepatitis [ 29 , 30 ] . in this study
, we found that nac can inhibit the degradation of ib- and impede the nuclear translocation of nf-b .
increased protein of expression of ib- and ib- and reduced expression of nf-b were observed in nac pretreatment groups , shown in figure 4 .
the combination of ib- , with nf-b will inhibit the translocation of nf-b into nucleus . as a result , proinflammation cytokines expression was reduced .
therefore , we speculated that nac attenuating cona induced inflammation by reduction of ib- and ib- degradation .
we also explored autophagic cell death , one important form of cona - induced hepatitis .
we observed that cona - induced hepatitis was associated with obvious autophagic cell death , and in the nac - treated groups we observed that autophagic cell death was significantly inhibited .
autophagy is regulated by many regulators ; one of the most important ones is the mtor pathway , which can be controlled by the pi3k / akt pathway .
we measured the expression of beclin 1 and lc3 to explore the effects of nac in cona - induced autophagy .
the levels of beclin 1 and lc3ii in the nac - treated group were significantly reduced .
compared to the nac - treated and control groups , the levels of beclin 1 and lc3ii in the cona - treated group were significantly increased .
this finding indicates that nac can mitigate cona - induced autophagy and liver injury and suggest that the inhibition of autophagy may represent a new therapy for autoimmune hepatitis .
it has been well established that the pi3k / akt pathway can regulate cell proliferation , apoptosis , differentiation , and senescence .
it has been also reported that cona treatment can reduce akt phosphorylation and pi3k activity , indicating the downregulation of the pi3k / akt pathway . in the nac - treated group ,
this investigation may further support that the supplementation of nac enhances hepatocyte pi3k / akt pathway activation and leads to further suppression of autophagic cell death .
our results are as follows : ( 1 ) nac can attenuate cona - induced immune hepatitis in balb / c mice ; ( 2 ) nac reduces tnf- , il-2 , il-6 , and ifn- expression and inhibits nf-b activation in cona - induced hepatitis ; ( 3 ) nac inhibits autophagy in cona - induced immune hepatitis by activating pi3k / akt signaling pathway .
Output:
| this study was designed to study the protective effects and mechanisms of n - acetylcysteine ( nac ) in concanavalin a - induced hepatitis in mice . in this study , pretreatment with nac ameliorated the histopathological changes and suppressed inflammatory cytokines in cona - induced hepatitis .
the expression of il-2 , il-6 , tnf- , and ifn- was significantly reduced in the nac - treated groups .
nac activated pi3k / akt pathway and inhibited the activation of nf-b .
additionally , nac reduced autophagosome formation , as assessed by detecting the expression of lc3 and beclin 1 .
our results demonstrate that nac can alleviate cona - induced hepatitis by regulating the pi3k / akt pathway and reducing the late stages of autophagy .
our results described a new pharmaceutical to provide more effective therapies for immune hepatitis . |
PubmedSumm118534 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
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the output is the summary of an input biomedical literature in six sentences
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Input: the past decade has seen major shifts in how we view the biology and consequences of regimen - related toxicities associated with cancer therapy .
tissue - specific damage such as mucositis , dermatitis , or fibrosis is no longer thought to be the sole consequence of direct clonogenic cell death . a relationship between toxicities that results in their presentation as symptom clusters has been documented and attributed to common underlying pathobiology [ 1 , 2 ] .
active roles for the local microbiota and tumour as biologically active contributors and modifiers of toxicity development are being assessed .
genomic differences among patients have been identified which are major determinants of toxicity risk [ 35 ] . and the finding that patients commonly develop toxicities representing tissue injury ( i.e. , diarrhoea ) outside radiation fields and side effects such as fatigue or cognitive dysfunction suggests the generation of systemic and local mediators .
cumulatively , this information has formed the basis for a robust pipeline of investigative agents that offer the hope of effective toxicity interventions . among cancer patients ,
those being treated for cancers of the head and neck ( hncps ) represent one of the most robust populations to evaluate and analyse focal tissue injury such as mucositis or dermatitis or systemic side effects such as fatigue , cachexia , or cognitive dysfunctions [ 69 ] .
rather , treatment - related complications appear to occur as nonrandom clusters [ 1 , 2 ] , which share a common underlying pathobiological basis .
in fact , it might be most appropriate to consider the study of toxicity syndromes , rather than the traditional approach in which each side effect was considered as an autonomous entity .
the historical reductionist view that attributed iatrogenic damage solely to the clonogenic cell death of tissue stem cells , mostly in the epithelium of the entire gastrointestinal tract , has been experimentally reevaluated to reveal that iatrogenic toxicities including mucositis [ 10 , 11 ] , dermatitis , and pneumonitis [ 13 , 14 ] represent the culmination of a series of biologically complex events that occur in all directly and indirectly injured tissues .
in addition , the observation of toxicities , which are systemically manifested , have provided a rationale for the application of the abscopal effect to normal tissues in addition to tumours .
this hypothesis suggests that focal radiation , even in the absence of concomitant chemotherapy ( ct ) , can result in biologically active mediators that have diffuse targets at remote sites .
the clustering of ct- and radiotherapy ( rt)-induced toxicities sharing common pathobiology reported by aprile et al . provided a biological basis for clinical observations .
understanding the nature of the genesis of these toxicities is critical to establishing an effective interventional strategy . based on the pathobiology of diseases which result in similar phenotypes ( i.e. , chronic fatigue syndrome , crohn 's disease , and sjogren 's syndrome as examples )
it is becoming increasingly clear that the wide variety of proteins elicited by ct or rt to cause local toxicities may have significant abscopal effects that put the patient at risk for a systemic inflammatory reaction that , in many ways , resembles what is seen clinically in sepsis .
while the true definition of sepsis is not satisfied in cases with no identifiable microbial invasion , the scope of a systemic inflammatory response can result in marked clinical morbidity or even death [ 1721 ] .
moreover , bacteraemia , due to the loss of integrity of a physical barrier ( mucosa , skin ) , are not always associated with sepsis [ 22 , 23 ] but may lead to sepsis when they are associated with a panoply of nonspecific inflammatory responses .
in addition , it has been postulated that an inflammatory response induced by the tumour itself may play a role and , together with inflammation induced by iatrogenic cytolysis , may contribute to the main adverse events in ct - rt - treated hncps . in this manuscript
, we attempt to develop a biologically based explanation which forms the basis for the diverse constellation of toxicities seen in response to current regimens used to treat cancers of the head and neck .
until the late 1990 's , the historical paradigm of cancer regimen - related epithelial injury held that damage was essentially the consequence of nonspecific clonogenic cell death in which rapidly dividing epithelial basal cells were indiscriminately destroyed by chemotherapy or radiation .
this hypothesis was subsequently overturned in favour of a concept which identified that radiation and chemotherapy induce a plethora of biological events , largely in the submucosa , which activate a collection pathways which in turn mediate basal cell injury and death [ 27 , 28 ] . a role for the local mucosal environment , including microorganisms ,
has also been suggested but is still in need of study as interventional strategies aimed at eliminating or modifying the microbial flora have failed [ 3033 ] .
furthermore , it is possible that rather than being inert to the effects of radiation , the functional characteristics of the gastrointestinal tract microflora might be inadvertent targets of radiation and , when radiated , undergo changes that modify their potential effects on tissue [ 3436 ] .
the evolution of ct - rt - induced mucosal injury was schematically classified in a five - phase model by sonis : initiation , upregulation / activation , signal amplification , ulceration , and healing .
interestingly , the activation of at least 14 canonical pathways has been identified as a consequence of chemoradiation ( crt ) .
thus , the engine which drives tissue and systemic symptom development is diverse .
the initiation of rt or ct - induced tissue injury is associated with biological events , clonogenic cell death as a consequence of dna damage and strand breaks , oxidative stress , and activation of the innate immune response .
oxidative stress results in the creation of reactive oxygen species ( ros ) inside injured cells [ 15 , 29 ] at a rate that overcomes cell repairing capability [ 35 ] .
ros created by the ionization of intracellular water cause a spectrum of lesions in cellular macromolecules ( e.g. , lipid peroxidation ) .
these macromolecular lesions can damage intracellular organelles such as mitochondria [ 40 , 41 ] , which in turn release additional ros .
ros further damage cell membranes and connective tissue , stimulate macrophages , and trigger a cascade of critical biological molecules that activate the immune inflammatory response [ 39 , 4247 ] .
nuclear factor erythroid 2-related factor-2 ( nrf2 ) has been implicated as an important element in mediating oxidative stress and preclinical data suggest that it may be a relevant target for toxicity intervention [ 48 , 49 ] .
data supporting a role for the innate immune response in the genesis of radiation injury continues to accumulate .
it also seems highly probable that normal cells , made apoptotic or necrotic by ct or rt , release endogenous damage - associated molecular patterns ( damps ) or chemoradiation associated molecular patterns ( cramps ) , which play an integral role in initiating inflammation toxicity .
an example of cramps is the high - mobility group box 1 ( hmgb1 ) . in healthy cells ,
this molecule is released by necrotic cell death and pulsatile - released by cells made apoptotic by rt and ct .
once outside the cell , hmgb1 has the potential to activate the host 's immune system [ 15 , 53 ] via the activation of the multiple surface receptors including toll like receptor ( tlr)2 , tlr4 , and receptor for advanced glycation end products ( rage ) .
the true biological and clinical consequences of hmgb1 [ 55 , 56 ] are unresolved .
the observation that high hmgb1 serum levels were associated with increased risk of sepsis - mediated death might be associated with the effectiveness of the molecule as a potent mediator of a systemic inflammatory response .
somewhat perplexing is the observation that hmgb1 activation is more strongly associated with low radiation exposure . in experimental settings ,
hmgb1 was found to be involved in the loss of endothelial barrier function , the increase of both ileal mucosal and alveolar permeability [ 5961 ] , and the fostering of bacterial translocation to mesenteric lymph nodes [ 58 , 60 ] .
table 1 summarises the factors hypothesized to be involved in the initiation of the pathobiology of mucositis and other rt - ct associated toxicities sharing the involvement of inflammation mediators .
these factors can cause injury to cells , but not of sufficient magnitude from a toxicity standpoint to explain the extensive injury that characterizes the clinical presentation of mucositis .
activation of the biological cascade within minutes of rt and , long before any tissue changes are noted , changes in gene expression are manifest by a diverse group of cells within the targeted tissue including macrophages , endothelial cells , and fibroblasts .
whether this is a consequence of damage to cells or , rather , a consequence of the immune system itself needs to be confirmed [ 15 , 99 ] .
however , the involvement of pattern recognition receptors ( prrs ) such as tlr and rage receptors of the host 's innate immune system has been hypothesized .
demonstrated the activation of transcription factors such as nf-b , p53 , and sp1 related retinoblastoma , ceramide pathway , and nrf2 transcription factors [ 48 , 49 ] and their role in the development of radiation - induced mucosal injury has been confirmed by others . at least , 14 canonical pathways associated with the development of ct - rt mucositis are triggered .
nf-b seems to have a central - hub role in activating inflammation [ 28 , 53 , 86 , 104 ] ; its activation precedes peaks in proinflammatory cytokines in mucosa after ct and upregulates cyclooxygenase-2 ( cox-2 ) [ 105 , 106 ] in submucosal fibroblasts and endothelial cells after radiation .
disruption of connective tissue fibronectin leads to the deregulation of matrix metalloproteinases ( mmp ) [ 81 , 107 ] which impact tissue injury and inflammation . in animal model studies , a significant alteration in both gene expression - tissue levels of mmps and tissue inhibitor of metalloproteinase ( timps ) following ct
the presence of receptors ( e.g. , tlr4 and cd14 ) for inflammatory products on nociceptive fibres has been shown [ 73 , 109 ] .
the activation of peripheral nerve endings via these receptors ultimately results in the local release of several neurotransmitters and neuropeptides ( substance p and calcitonin gene - related peptide 1 ( cgrp1 ) ) , which have strong vasodilatory and chemotactic properties .
this may explain the reversible pruritus and faint erythema that develop during the first hours after irradiation [ 75 , 76 , 111 ] .
many of the proteins produced during the primary damage response ( upregulation phase ) also amplify proinflammatory pathways which intensifies primary damage .
accordingly , a broad range of biologically active proteins accumulates and targets the mucosal tissues ( endothelial , epithelial , mesenchymal , and neuronal endings ) triggering intracellular and intercellular feedback mechanisms .
these feedback mechanisms may induce vicious circles , which can also involve distant organs via neuronal and bloodstream networks .
below , we present examples of interrelated feedback mechanisms that may act alone or in concert and are thought to play a role in the pathobiology of tissue - centric toxicities such as mucositis and dermatitis .
activation of transcription factors ( nf-b)-cytokines ( e.g. , tnf- ) transcription factors ( nf-b ) loop .
nf-b , upregulated in the previous phase , acts as a gatekeeper for various inflammatory pathways one of which is the proinflammatory pathway characterized by cytokines such as tnf , il-6 [ 112 , 113 ] , and il-1 [ 12 , 87 ] . in turn , these cytokines ( particularly tnf- ) are potent activators of nf-b , sphingomyelinase [ 114116 ] , and members of the tnf receptor family .
these loops drive the nf-b and ceramide pathways to produce and accelerate tissue injury and initiate mitogen - activated protein kinase ( mapk ) signalling .
mapk signalling then activates c - jun aminoterminal kinase , which plays a role in regulating the ap1 transcription factor , which , in turn , is thought to affect mmp secretion [ 82 , 107 , 108 ] .
in addition , nf-b upregulates cyclooxygenase-2 ( cox-2 ) , an inducible enzyme involved in inflammation , through its role in prostaglandin production [ 106 , 118 ] .
coupled with proinflammatory cytokines , it is now apparent that anti - inflammatory cytokines such as il-10 , il-11 [ 120 , 121 ] and the anti - inflammatory amino acid decapeptide ( rdp58 ) play a key inflammatory role in both oral and gi rt / ct toxicities [ 112 , 121 , 123126 ] .
the activation of this cytokine storm favours the chemoattraction of immune cells ( mononuclear cells and macrophages ) causing local infiltration and oedema .
the importance of inflammatory pathways in regimen - related mucosal injury has potential therapeutic leverage .
interventions aimed at attenuating proinflammatory cytokines or stimulating anti - inflammatory cytokines may offer a way to prevent toxicities [ 120 , 121 , 127131 ] .
peripheral neuronal amplification loop . while a role of neurotransmitters and neuropeptides in mucosal injury has not been well studied , it is quite possible that the activation of peripheral nerve endings and the release of several neurotransmitters and neuropeptides ( substance p and calcitonin gene - related peptide ( cgrp1 ) ) lead to the recruitment of innate immune cells .
studies of genetic predilection for regimen - related toxicities demonstrate the presence of single nucleotide polymorphisms associated with genes for both substance p and cgrp1 .
these mechanisms could potentiate the local immune response and thereby lead to the activation of additional nociceptive sensory nerves in a positive feedback manner .
endothelial damage and iatrogenic - induced cytokine synthesis upregulate procoagulation [ 79 , 80 , 133 ] .
indeed , laboratory and in vivo studies showed the potential of upregulating coagulation tissue factor ( tf ) by means of inflammatory mediators such as tnf- , c - reactive protein ( c - rp ) , and long pentraxin-3 ( ptx3 ) . in turn
, tf generates coagulant mediators ( fviia , fxa , fiia , and fibrin ) that upregulate inflammatory mediators by means of protease - activated receptors ( pars ) and tlr-4 [ 137139 ] .
this triggers an inflammation - coagulation circuit that increases local and/or systemic proinflammatory and procoagulative activity [ 137 , 139 ] .
the potential therapeutic implications of this loop is illustrated by the finding that hirudin , a direct thrombin inhibitor , was observed to ameliorate radiation induced intestinal toxicity in a rat model .
ros - extracellular matrix ( ecm)-immune cell loop . the extracellular matrix ( ecm ) is a complex structural network of fibrous proteins , proteoglycans , and glycoproteins . aside from its role during the healing phase of mucositis , during which ecm signalling plays a critical role in establishing the fate of wound resolution
, it also may have an active role during the more proximal aspects of radiation or chemotherapy - induced damage . a relationship between changes in ecm component expression and chemotherapy - induced intestinal injury
furthermore , ecm mediates mesenchymal - epithelial communication and is also a reservoir of latent cytokines ( such as tgf- and il1- ) , which can be activated in consequence of the action of proteases ( plasmin and thrombin ) and ros [ 142 , 143 ] .
activation of mmps through oxidants , which are generated by leukocytes or other cells , follows . in turn , mmps control chemokine activity .
activated cytokines and chemokines , in turn , attract and activate other immune cells ( such as neutrophils ) , which in turn , release ros , thus restarting the loop .
endothelial - epithelial loop .
morphologic evidence from histological studies using light and electron microscopy shows damage to the microvascular endothelial cells occurring earlier than that to the epithelium [ 83 , 121 ] .
endothelial - cell apoptosis interrupts the protective effect on the epithelia due to the endothelial - produced keratinocyte growth factor ( kgf ) , which activates the protective nrf2-antioxidant pathway in the epithelia .
this results in epithelial thinning due to a loss of epithelial stem cells , which in turn generates further endothelial damage , ultimately leading to ulceration .
the abscopal effect was the term that mole proposed sixty years ago to describe the observation that patients demonstrate a range of responses distant from the radiated tumour .
initially , abscopal effects were focused on distant tumour response , but it is now clear that the same phenomenon is relevant to normal tissue response and the aetiology of systemic side effects of treatment . in an excellent review of the topic , siva et al .
they propose that the basis of the response stems from the development of a chronic inflammatory environment and overall genomic instability .
the finding that focal radiation produces changes in gene expression detectable in peripheral blood monocytes consistent with pathways known to play a role in radiation toxicity supports this hypothesis .
( fatigue , cognitive dysfunction , cachexia , etc . ) and tissue centric ( diarrhoea , nausea and vomiting , etc . ) toxicities ( figure 1 ) .
the two major mediators of the abscopal effect are cytokines and the immune system . in healthy humans ,
cytokines are usually produced at low constitutive levels ( picograms / ml ) in plasma , and they function in an endo- , para- , or autocrine manner . in inflamed ( injured and/or infected ) tissues , there is an excessive cytokine production that can become detectable in peripheral blood [ 11 , 86 , 147 ] .
the production of proinflammatory cytokines , particularly il-1 , il-6 , and tnf- , occurs not only in tissue , but in peripheral blood and increased levels of systemic proinflammatory cytokines which correlate with nonhaematological toxicities [ 121 , 148151 ] after rt , suggesting that the mediators of toxicities are not simply compartmentalised into the radiation field .
indeed , peripheral activated cells ( such as b - lymphocytes , myeloid lineage cells , and monocytes ) have an increased transcription of inflammation - related genes , particularly those responsive to the proinflammatory nf-b transcription control pathway .
in addition , it is conceivable that the use of concomitant ct offered an additional opportunity for the systemic effects to occur [ 11 , 62 , 153 ] . cytokine production from activated cells is likely enhanced by activation of an innate immune response ( see above ) triggered by rt or crt and tissue - borne pathogens . as a result
peripheral blood levels of cytokines increase and remain elevated as has been reported in patients being treated for cancers of the head and neck .
a similar inflammatory response has been noted subsequent to ct - induced injury to the oral or gastrointestinal mucosal barrier where a systemic inflammatory response is elicited when various prrs expressed by nonepithelial cells within the mucosa ( e.g. , macrophages , neutrophils , and dendritic cells ) are exposed to severe endogenous ( damp ) and exogenous ( pamp ) stress [ 32 , 155158 ] .
for example , blijlevens and colleagues reported that mucositis induced a systemic inflammatory response characterized by fever in neutropenic stem cell recipients , even in the absence of bacteraemia .
the impact of systemic cytokines as mediators of clusters of toxicities was suggested by aprile et al . , who used a bayesian analytical approach in a cohort of patients receiving ct to treat colorectal cancer .
they noted that some toxicities were more frequently interconnected than would be expected by chance .
the most frequently associated toxicities were those that probably share a common pathobiology ( fever , fatigue , anorexia , and weight loss ) .
furthermore , some authors [ 2 , 159 ] showed the plausibility of these associations , whereas others showed that it is possible to predict both the risk of oral mucositis and severe sepsis [ 161 , 162 ] by the dosage of plasma levels of inflammatory mediators in patients receiving mucotoxic treatments .
thus , it is conceivable that the ct - rt - induced inflammation can act both locally , as a consequence of a paracrine signalling amplification , and systemically , as a consequence of a sort of endocrinal - like signalling amplification .
while behavioural toxicities such as fatigue and cognitive dysfunction are commonly recognised to occur among patients receiving crt , it is only recently that the physiological basis for these changes has been assessed in the context of focal rt regimens .
we know that the nervous system can be activated systemically by circulating cytokines , such as il-6 .
the finding that the microvasculature in the mediobasal hypothalamus has a specialised fenestrated endothelium might explain the transfer of cytokines from the circulation to the central nervous system ( cns ) , where they in turn could stimulate the local production of cytokines or initiate behavioural changes .
thus , while the sensory nervous system activates the sympathetic nervous system both segmentally , at the level of the spinal cord , and centrally , the circulating cytokines ( such as il-6 ) provide a sensor for the extent of inflammation and the consequent energy needed at a systemic level [ 161 , 162 ] .
specifically , the hypothalamic - pituitary - adrenal ( hpa ) axis has been identified as a possible conduit for the mediation of behavioural toxicities .
concomitantly , parasympathetic activity , which has anti - inflammatory effects [ 163 , 164 ] , is inhibited during initial inflammation [ 165 , 166 ] in order to modulate adequate inflammation intensity . at any rate , parasympathetic activity plays a role in systemic inflammation such as sepsis .
indeed the experimental stimulation of the peripheral vagus nerve strongly inhibits lipopolysaccharide - induced acute inflammation and leukocyte recruitment . to further support the link between
ct - rt induced inflammation and the clinical symptoms frequently associated to mucositis , recent literature has shown that fatigue [ 90 , 169 ] , cachexia , and systemic inflammatory response syndrome ( sirs ) [ 71 , 169 , 170 ] have been associated to a deregulated systemic inflammatory response to ct - rt of the organism ( figure 1 ) .
fatigue is defined as the physical and/or mental weariness resulting from exertion : an inability to continue exercise at the same intensity with a resultant deterioration in performance [ 97 , 171 ] .
the underlying mechanism of cancer - related fatigue ( crf ) remains unclear ; it is probably due to multifactorial causes .
prue 's systematic review found that there were significant increases in fatigue during anticancer therapy ( fatigue prevalence 39%90% ) .
fatigue has been demonstrated to increase during rt [ 174 , 175 ] and does not depend on concomitant increases in emotional distress [ 176 , 177 ] . yet
two randomised controlled trials have reported that while paroxetine improves the mood of patients undergoing outpatient ct , it has no effect on fatigue relief [ 178 , 179 ] .
taken together , these studies suggest that fatigue and depression / psychological distress are related but distinct phenomena .
a number of authors have suggested that crf may be related to an elevated or prolonged inflammatory response in cancer patients .
two recent reviews showed a positive association between crf and inflammatory / immunity circulating marker levels during rt and ct [ 90 , 181 ] .
however , the majority of studies was cross - sectional in nature and did not use well - validated fatigue assessment instruments .
, 98 ] of cancer cachexia has only recently been made ( table 1 ) . since no standard definition had been available , cachexia was previously underdiagnosed .
even today , physicians usually treat the symptoms of anorexia , weight loss , and insulin resistance without diagnosing cachexia . in the retrospective study by fox et al . ,
physicians diagnosed cachexia only in 6.1% of 246 patients , even though 19.9% of them had lost > 5% of their body weight and 37% of them had at least one of the cachexia definitions .
cancer cachexia has a multifactor pathogenesis due to tumour - releasing factors [ 183 , 184 ] or to treatment /sepsis immune responses , or both .
indeed , the circulating inflammatory cytokines such as tnf- [ 186 , 187 ] , il-6 , tgf family members ( e.g. , myostatin and activin ) seem to have a role in inducing cachexia acting both peripherally on the muscle and centrally on the cns .
peripherally , cytokines activate nf-b in muscles and promote muscle degeneration by accelerating protein breakdown and by dysregulating protein - turnover leading to catabolism .
indeed , the rise in circulating cytokines has been implicated in the physiologic and behavioural responses to inflammation in rodents , including anorexia , hpa axis activation , and fever . in humans ,
recent trials on a monoclonal anti - il-6 antibody used in order to contrast lung cancer patients ' weight loss have shown that it is able to reverse anorexia , fatigue , and anaemia , but it had no significant effect on the lean body mass loss .
the study by silver et al . , who treated seventeen hncps with induction ct followed by concomitant ct - rt , is interesting because it related wasting syndrome to ct - rt .
these patients showed a wasting syndrome with a statistically lean body mass loss ( p = .005 ) , declined total physical activity , increased resting energy expenditure ( p = .019 ) , and increased inflammatory cytokines and inflammatory mediators ( c - reactive protein ( c - rp ) , p = .09 and il-6 , p = .08 ) ) during concomitant ct - rt even though there were no significant differences in energy intake or calorie / nitrogen ratio from pretreatment to posttreatment .
other authors have found that c - rp was an independent predictor of weight loss ( p < .001 ) in hncps treated with crt .
we hypothesise that in hncps , the cachexia syndrome is particularly reinforced by systemic inflammation induced by oral mucositis and reduced energy intake due to reduced swallowing capacity [ 195 , 196 ] .
the complexity of the molecular and cellular response to chemotherapy and radiation , the observation of distant or systemic toxicities following focal radiation therapy , and the discovery of genomic features that are associated with toxicity risk have only found their way to mainstream thinking in the past decade .
it is now clear that the molecular events that occur within tissues following radiation begin within seconds of the challenge . and the consequences of the resulting biological cascade not only result in local tissue injury , but in the release of active proteins in the circulation .
it is this systemic cytokine storm and its companion molecules that lead to abscopal effects in normal tissue .
clinically , these are manifest by both distant distal injury and by behavioural toxicities such as fatigue , cognitive dysfunction , and cachexia .
furthermore , it is now clear that the clustering of toxicity symptoms that is most commonly not random .
rather , these changes , which distinct clinically represent the consequences of shared biology . it is the target tissue responding to common drivers that results in the distinct phenotypes .
thus , the concept of toxicity syndromes defined , not clinically , but by common bioetiological features is becoming increasingly important in the determination of patient status and in establishing pharmacological targets . ultimately , it is the discovery and definition of the pathways that lead to toxicities that will define and optimise a comprehensive approach to their amelioration .
Output:
| treatment - related toxicities are common among patients with head and neck cancer , leading to poor clinical outcomes , reduced quality of life , and increased use of healthcare resources . over the last decade , much has been learned about the pathogenesis of cancer regimen - related toxicities .
historically , toxicities were separated into those associated with tissue injury and those with behavioural or systemic changes .
however , it is now clear that tissue - specific damage such as mucositis , dermatitis , or fibrosis is no longer the sole consequence of direct clonogenic cell death , and a relationship between toxicities that results in their presentation as symptom clusters has been documented and attributed to a common underlying pathobiology .
in addition , the finding that patients commonly develop toxicities representing tissue injury outside radiation fields and side effects such as fatigue or cognitive dysfunction suggests the generation of systemic as well as local mediators . as a consequence , it might be appropriate to consider toxicity syndromes , rather than the traditional approach , in which each side effect was considered as an autonomous entity . in this paper , we propose a biologically based explanation which forms the basis for the diverse constellation of toxicities seen in response to current regimens used to treat cancers of the head and neck . |
PubmedSumm118535 | ***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 discussed elsewhere , the congenital adrenal hyperplasias ( cahs ) are genetic defects in cortisol biosynthesis
. low cortisol removes feedback inhibition of adrenocorticotropin ( acth ) secretion , which causes adrenal hyperplasia .
the clinical consequences of cah derive from both the shunting of cortisol precursors along other pathways and the biological activities of these precursors and their unusual metabolites , which accumulate above the block .
treatments will ideally replace the glucocorticoid deficiency and normalize both mineralocorticoid and androgen biosynthesis without inducing untoward effects from the drugs themselves .
the most common cause of cah is 21-hydroxylase deficiency ( 21-ohd ) , which afflicts about 1 : 15,000 live births . since the introduction of cortisone therapy by wilkins et al . in the early 1950s ,
these children have been able to survive into adulthood . now that over a half century has passed
, one would think that abundant information would have accumulated on the care of adults with cah , as is now the case for children .
regrettably , very little is known about the physiology and management of adults with cah , and what is known is essentially limited to 21-ohd .
genetic disorders , which manifest with congenital disease , are largely the providence of pediatrics . with the completion of the human genome project , internists have become more aware of genetic disorders , but largely the focus has been on susceptibility genes for cancer , diabetes , and cardiovascular diseases .
training in the care of patients with congenital biosynthetic defects , such as glycogen storage diseases and cah , is generally not considered an important component of internal medicine residencies and endocrinology fellowships .
consequently , few doctors who care for adults , even those at academic medical centers , are adequately trained or interested in rare genetic diseases .
most internal medicine endocrinology trainees will see only a few patients with cah , mainly if they rotate in the pediatric endocrinology clinic , and many will never see a single adult with cah during their training .
a search of the nih crisp database revealed only a few grants awarded to the study of cah in the last 5 years , none of which were awarded to investigators in departments of internal medicine . without interest and research in academic centers , there is little chance that internal medicine endocrinology fellows will receive adequate training in cah .
adults do neither , but they do age , and many have children or at least wish to become parents . with age , they are prone to all the maladies of adult life , including heart disease , osteoporosis , and cancer . consequently , the focus and goals of treatment are quite different in adults and children .
treatment of cah in infancy and early childhood strives first to prevent salt - wasting and hypotensive crises due to adrenal insufficiency .
treatment of adults with cah should be tailored to meet the needs of the patient at the present time , but with a long - term view of mitigating consequences of therapy . as a rule
, the medications used and intensity of monitoring will vary as the objectives change with time .
this feeling is particularly true if the doctor knows very little about their condition and shows little interest or concern for their specific needs .
many patients with cah have stopped seeing physicians altogether and have discontinued corticosteroid replacement for long periods of time .
women may become comfortable living in a state of androgen excess and may even experience fatigue from testosterone withdrawal if therapy is resumed .
men with cah of experience few symptoms from reducing or stopping therapy , until they become seriously ill or their testicular rests become uncomfortably large .
these considerations are important in understanding the approach to the adult with cah , both medically and psychologically .
many of the general principles are the same as for children with cah , but the importance of the various factors is considerably different .
cytochrome p450c21 ( cyp21a2 ) deficiency precludes aldosterone and cortisol synthesis , limiting steroidogenesis to the reactions catalyzed by 3-hydroxysteroid dehydrogenase type 2 ( 3-hsd2 ) , cytochrome p450c17 ( cyp17a1 ) , and a bit to cytochrome p450c11 ( cyp11b1 ) ( figure 1(a ) ) .
low cortisol increases acth production , flooding the adrenal steroidogenic machinery with upstream precursors ( figure 1(b ) ) . over time , the adrenals enlarge due to the chronic trophic stimulus of acth .
consequently , the adult adrenal of a patient with 21-ohd makes large amounts of a few steroids , mainly progesterone ( p4 ) , 17-hydroxyprogesterone ( 17-ohp ) , dehydroepiandrosterone and its sulfate ( dhea[s ] ) , plus lesser amounts of androstenedione ( ad ) , testosterone ( t ) , and 21-deoxycortisol which has little glucocorticoid or mineralocorticoid activity .
due to zonation , two critical enzyme activities required for t synthesis are physically separated in the adrenal gland .
the zona fasciculata cells , which contain 3-hsd2 activity , also contain cyp17a1 ; however , these cells have low 17,20-lyase activity because expression of the important cofactor protein cytochrome b5 ( b5 ) is low [ 8 , 9 ] .
in contrast , the zona reticularis in which acth also stimulates steroid production has abundant cyp17a1 , b5 , and thus high 17,20-lyase activity , but these cells are deficient in 3-hsd2 and have robust dhea - sulfotransferase activity ( sult2a1 ) .
furthermore , the adrenal gland lacks 17-hsd3 , the enzyme responsible for reduction of ad to t in the testis , but contains akr1c3 ( 17-hsd5 ) , which has weak activity in catalyzing this reaction .
consequently , the adrenal gland of a patient with 21-ohd has high capacity to synthesize dheas , but little of this 19-carbon precursor escapes the adrenal as t. alternative routes to 5-reduced , 19-carbon steroids have been described in other species [ 11 , 12 ] .
these routes involve the 5-reduction of 21-carbon pregnanes p4 and 17-ohp , followed by 3-reduction , to yield 5-pregnan-3-ol-20-one ( allopregnanolone ) and its 17-hydroxy derivative , 5-pregnane-3 , 17-diol-20-one ( pdiol ) .
pdiol is then cleaved to androsterone by the 17,20-lyase activity of cyp17a1 . androsterone reduction by 17-hsd enzymes yields 5-androstane-3 , 17-diol ( adiol ) , which is metabolized by oxidative 3-hsd enzymes such as 17-hsd6 ( rodh ) to dht ( figure 2(b ) ) . via this pathway
considerable genetic and biochemical evidence suggests that this route contributes to dht formation and genital virilization in female fetuses with cytochrome p450-oxidoreductase deficiency , presumably due to the accumulation of 17-ohp [ 1518 ] . in 21-ohd
, intra - adrenal 17-ohp accumulates as well ; consequently , this pathway is likely to be important in the fetus with 21-ohd . in adults with 21-ohd , however , the pathway may not be very active , due to lower expression of 5-reductase activity in the adult adrenal .
based on the above discussion , the adrenal glands of adults with 21-ohd produce little t and huge amounts of other steroids , yet none are active hormones except for p4 .
nevertheless , without proper treatment , ad , t , and dht concentrations are high in women and men with 21-ohd , and a high proportion of t in men with 21-ohd derives from the adrenal .
this t is produced by peripheral metabolism of the adrenal secretions , primarily in the liver but also in skin and even target tissues .
the peripheral metabolism of steroids is more difficult to define than the intra - adrenal steroidogenic pathways , due to redundancy of enzymes , competing routes of metabolism , and variability amongst individuals .
nevertheless , steroid sulfatase ( sts ) is present in liver , skin , and many other tissues , and these tissues also contain 3-hsd type 1 .
conversion of ad to t is efficiently catalyzed by 17-hsd3 , but its cognate gene is only expressed in the leydig cell of the testis .
as mentioned above , 17-hsd5 also has weak activity for conversion of ad to t , but other routes from dhea to t also exist .
dhea can be reduced by 17-hsd1 , which is an efficient enzyme , to androst-5-ene-3 , 17-diol , a substrate for 3-hsds , yielding t ( figure 2(a ) ) .
even 17-hsd2 , which is thought of as an inactivating enzyme by efficiently converting t to ad , achieves a pseudo - equilibrium in intact cells with 1 - 2% t generated from ad and increases the apparent potency of ad as an androgen in model systems . in liver and skin ,
5-reductase type 1 further activates t to dht , but t and dht are also substrates for udp - glucuronyl transferases ( ugts ) , which conjugate active androgens and their metabolites for excretion in the urine .
consequently , the route(s ) from dhea to t even in normal women are not obvious , and the biochemistry is even more complex in 21-ohd , as androgen precursor production is very high .
in addition to peripheral conversion of dhea[s ] to active androgens , p4 , which accumulates 2 steps prior to the block , can be 21-hydroxylated by hepatic cytochromes p450 [ 27 , 28 ] to yield 11-deoxycorticosterone ( doc ) , a potent mineralocorticoid .
the extent and routes of peripheral metabolism vary considerably amongst individuals and might explain to some degree the differences in disease control for adults with 21-ohd .
conversely , greater accumulation of p4 can contribute to anovulation and infertility in women with 21-ohd .
for these reasons , not only the control of steroids exiting the adrenal , but also the extra - adrenal metabolism of these steroids is an important consideration in understanding the physiology of cah in the adult .
as with physiology , the principles governing the treatment of adults with cah share many similarities with those for children with cah ; however , the differences relate to growth , pubertal development , and fertility .
in addition , the care of adults is often more individualized based on patient choices than in children . as previously mentioned , the treatment goals of patients with 21-ohd evolve with the transition to adulthood .
salt - wasting crises occur much less frequently , typically only during a severe concurrent illness . during childhood ,
tight control prevents premature somatic growth and development of secondary sexual characteristics , but both concerns are no longer germane in adulthood .
the three major concerns for the adult with 21-ohd are : ( 1 ) the prevention of adrenal and gonadal hyperplasia and neoplasia ; ( 2 ) the prevention of long - term consequences of adrenal replacement therapies , and ( 3 ) the restoration of fertility in those who desire to have children .
consequently , the intensity and complexity of treatment regimen is individualized and changed over time to meet the needs of the patient and to optimize the risk / benefit ratio .
mineralocorticoid replacement with 9-fludrocortisone acetate , 0.050.2 mg / d , is usually continued , with the goal of a suppressed or low - normal plasma renin activity , which blunts the hypovolemic drive to acth production . in most developed nations ,
the sodium content of the adult diet is high , and salt craving in adults with 21-ohd is uncommon .
in fact , children and adults with 21-ohd are prone to develop hypertension , prompting reduction or rarely discontinuation of mineralocorticoid dosing , or the paradoxical need for antihypertensive drugs plus fludrocortisone acetate . to titrate mineralocorticoid replacement , the serum potassium concentrations , plasma renin activity , and blood pressure in the sitting and standing positions are monitored , with the goals of renin as low as possible , normokalemia , and lack of orthostasis .
glucocorticoid replacement therapy remains of central importance in the adult with 21-ohd , despite the disturbing fact that many patients will discontinue or neglect their treatment for months at a time .
hydrocortisone remains the safest drug for long - term replacement , as is the case for other forms of adrenal insufficiency .
regimens that require 3 doses a day , as is often used in children to suppress adrenal 19-carbon steroid production , pose compliance difficulties for some adults with busy schedules .
most patients manage to take 2 doses a day consistently , patterned after doses used for adrenal insufficiency , such as 1520 mg on arising and 510 mg after the midday meal .
the disadvantage of such a two - dose regimen is the tendency for acth to rise robustly in the early morning hours prior to the first dose , which worsens control , at least for a few hours until the first dose . in children ,
several groups have found empirically that administration of the largest dose at bedtime is associated with tightest control of adrenal steroidogenesis .
other groups have argued that the half - life of hydrocortisone is so short that an evening dose is only effective in suppressing the morning acth rise if a highly supraphysiologic dose is administered , such that hydrocortisone should be given during the day only .
addition of an evening dose can cause poor sleep and worsen weight gain and other glucocorticoid - related side effects , but not in all patients .
unfortunately , well - designed and controlled studies comparing various regimens are lacking , so the clinician is advised to generally try the safest and most physiologic replacement regimen , and then to intensify therapy gradually if symptoms and signs of undertreatment become evident .
sustained - release hydrocortisone preparations administered once daily with promising pharmacokinetics have been developed , but these products currently are not widely available . to simplify dosing and to increase suppression of acth , synthetic glucocorticoids such as prednisone , prednisolone , methylprednisolone , and dexamethasone may be employed .
the problem with these drugs is that long - term usage almost invariably results in iatrogenic cushing syndrome , due to their potency and long half - life .
dexamethasone needs only to be given once daily , with bedtime administration being the most effective means to suppress acth and adrenal 19-carbon steroid production .
in fact , the suppressive effect of single dose of dexamethasone on dheas production often lasts longer than 24 hours .
prednisolone or prednisone may also be used once daily as in adrenal insufficiency , but divided doses may be better in certain situations discussed below . combined regimens , using more potent steroids only a few days per week , are more complicated , but this approach features the advantage of mitigating many of the side effects of taking these drugs chronically while utilizing their capacity to suppress dheas production longer and more completely than hydrocortisone .
chronic acth excess juxtaposed with chronic glucocorticoid therapy , often at supraphysiologic doses , might place patients with 21-ohd at high risk for long - term complications .
the adrenal glands become progressively hyperplastic in most patients with 21-ohd , and adrenal tumors , including massive myelolipomas , have been described .
in addition to these tumors , a paradoxically increased prevalence of hypertension has been found in adolescents and adults with 21-ohd
. reduced bone mineral density has been found in 21-ohd in most studies [ 35 , 36 ] , but the degree is moderate , and frank osteoporosis is uncommon .
other reports note a higher prevalence of glucose intolerance , obesity , and dyslipidemia in adults with 21-ohd compared to controls , raising their risk for cardiovascular disease .
these health problems are similar to those maladies associated with poor quality of life in patients with adrenal insufficiency or cured cushing 's disease after long - term followup .
curiously , concomitant androgen excess might mitigate some of the catabolic consequences of chronic glucocorticoid exposure , and some benefit is suggested by the observation that the increased risks appear not large , and major health problems are not consistently seen .
above all , the management of the patient with 21-ohd should recognize that these patients are vulnerable to all the other diseases that people without this condition suffer , and they require the same general healthcare as any adult .
women should receive cervical smears , breast exams , and/or mammograms at the standard ages , and men require screening for prostate disease
. men and women should have blood pressure and cholesterol screening , colon cancer screening , education to avoid smoking and to follow a healthy lifestyle , and care for acute illnesses .
glucocorticoid doses should be increased for surgery and for acute illness when volume depletion from high fever , vomiting , diarrhea , or poor oral intake occurs but not for any minor illness or injury . in women with 21-ohd , two additional key issues
are : ( 1 ) whether androgen excess symptoms are currently a problem , and ( 2 ) if the patient trying to conceive a child now . at a minimum
, all women with 21-ohd must receive replacement doses of hydrocortisone and fludrocortisone acetate , as would any other patient with adrenal insufficiency .
higher doses and more potent steroids are used to the extent demanded by the two issues above . a normal serum testosterone and absence of androgen excess symptoms
if not , measurement of 17-hydroxyprogesterone and androstenedione , preferably in the follicular phase , will help to assess the degree of control . chronic normalization of 17-hydroxyprogesterone indicates overtreatment and should be avoided , as values well above normal are acceptable if androgen concentrations are controlled and the patient is clinically well .
androgen excess is always a problem for these women , but the degree and its clinical consequences vary tremendously , and there is no reason to expose the woman to higher doses of corticosteroids if no benefit will be derived . if control has been poor in childhood , the patient seems to be more vulnerable to androgen excess , possibly due to greater adrenal hyperplasia .
in addition , women with 21-ohd often develop a secondary polycystic ovary syndrome ( pcos ) , such that androgens and 17-ohp also derive from the ovaries and persists even after adrenal suppression .
consequently , menses may remain irregular even with good control of the adrenal axis .
if pregnancy is not desired , oral contraceptive pills provide several benefits , including lowering ovarian androgen production , maintaining monthly menses , and raising sex hormone binding globulin ( shbg ) , which lowers free testosterone and mitigates some of the hyperandrogenism with lower doses of glucocorticoid therapy .
antiandrogen therapy is a logical approach for treatment of 21-ohd , but with the exception of multidrug regimens , has received little attention .
spironolactone , an effective and inexpensive agent used to treat other forms of hirsutism and pcos , is difficult to use in 21-ohd because it is both androgen and mineralocorticoid receptor antagonist , which causes salt loss . with the exception of flutamide , androgen antagonists and 5-reductase inhibitors ( finasteride and dutasteride )
have not been formally studied in women with 21-ohd , although some patients have experimented with regimens containing these drugs .
topical agents , such as eflornithine cream , and mechanical methods ( laser , electrolysis , shaving , and plucking ) should not be neglected . for women who are trying to become pregnant , 21-ohd introduces multiple barriers to conception . in the first place , a minority of women with 21-ohd even attempt to become pregnant , especially those with the most severe or salt - wasting
the reasons for their not attempting pregnancy include vaginal abnormalities , such as inadequate caliber for coitus or strictures following repair and dyspareunia .
finally , even in those who wish to become mothers , chronic oligoanovulation is common due to high androgens and secondary pcos , whereas high circulating progesterone , which accumulates 2 steps behind the block , prevents favorable endometrial maturation and cervical mucus formation .
unlike the multiple options available for women not attempting pregnancy , the only approach that will improve the hormonal milieu for ovulation and implantation is to intensify the glucocorticoid therapy , and the clinician should not be reluctant to use supraphysiologic dosing for several months to accomplish this purpose .
in addition to controlling androgen excess , follicular phase progesterone should be suppressed below 2 nmol / l ( 0.6 ng / ml ) to favor fertilization and implantation .
this goal can be achieved with prednisolone or hydrocortisone divided into 2 or more commonly 3 daily doses , as an evening dose is often necessary to lower morning serum progesterone adequately .
a recent report demonstrated that 21/23 women with 21-ohd who desired pregnancy became pregnant and had live births using these regimens . in these women ,
prenatal therapy is another issue if their spouse is a carrier ; this topic is reviewed elsewhere . despite years of work and innovative surgical approaches ,
often staged procedures are employed with the goal of urinary hygiene and appropriate clitoral reduction in the neonate .
the trend now is to minimize surgery in the newborn and child and to leave complete establishment of an adequate vaginal orifice for when the woman becomes sexually active . consequently , many adult women with 21-ohd face the need for definitive reconstruction surgery . the choice of procedure is important , but the woman must be motivated to use lubricants and dilatators regularly to obtain the best results and satisfaction .
traditional skin or bowel grafts often give suboptimal results , particularly in severely virilized girls .
buccal mucosa grafts have shown good results in series with limited followup and may become a procedure of choice in the future [ 48 , 49 ] . men with 21-ohd are spared the disturbing and disfiguring effect of contrasexual hormone excess , which probably renders men with 21-ohd more prone to neglect their treatment than women .
unfortunately , men are not spared some of the long - term health consequences of both 21-ohd and glucocorticoid therapy , and male physiology and anatomy predispose these men to other problems .
adrenal androgen excess , when severe , can suppress gonadotropins and lead to testicular atrophy and infertility .
reduced fertility has been observed in small cohorts of men with 21-ohd [ 5153 ] , but aberrant androgen metabolism is only one reason .
the second major cause of infertility and testicular dysfunction in men with 21-ohd is the presence and hyperplasia of adrenal rest tumors in the testes ( tarts ) .
the prevalence of tart in men with 21-ohd is as high as 50% , if ascertained by sensitive ultrasonography or magnetic resonance imaging [ 51 , 54 ] .
these tarts can become large and cause pain in addition to impaired testicular function .
treatment of the tarts with intensified glucocorticoid replacement may cause regression and restoration of normal sperm counts . at a minimum , men with 21-ohd should have an annual testicular exam , and screening ultrasonography is recommend by some authorities . if a mass is found , glucocorticoid treatment is intensified , such as dexamethasone 0.752 mg / d .
if the mass regresses , the treatment is continued for several weeks to months until a satisfactory result is obtained .
if the mass does not shrink with dexamethasone , testicular cancer should be excluded by referral to an urologist .
surgical resection of the tarts effectively controls testicular size and leydig cell function but fails to restore fertility .
it is likely that , when a large tart is present , the testis is already damaged from increased pressure in the testicular capsule , which reduces testicular blood flow and obstructs the seminiferous tubules [ 52 , 53 ] .
consequently , if preservation of fertility is a priority , the tarts should be managed early and aggressively with medical therapy .
replacement doses of hydrocortisone suffice for most men with 21-ohd , but which laboratory parameters should be monitored to guide glucocorticoid dosing is not known .
if the 17-ohp is normal , the patient is overtreated , but values up to about 100 nmol /
the goal is to have a normal testosterone and normal gonadal function in the absence of tarts , and men with a 17-ohp < 3,000 are unlikely to have large tarts .
measurement of adrostenedione and gonadotropins is appropriate if gonadal dysfunction becomes evident to determine if the adrenals or testes are the dominant source of androgens .
the presence of tarts prompts intensification of therapy to induce regression regardless of apparent hormonal control .
the curative potential of bilateral adrenalectomy for children with 21-ohd has been recognized , and its utility has been debated aggressively . in adults with 21-ohd ,
first , massive adrenal myelolipomas may develop and can be bilateral and require surgical removal .
second , although infertility in both men and women is often managed with intensified glucocorticoid therapy , adequate control can not be achieved medically in some cases , and surgical management is required .
restoration of fertility in women [ 46 , 60 ] and men with 21-ohd after bilateral or unilateral adrenalectomy , respectively , has been observed and should be considered as an alternative approach .
the management of the adult with 21-ohd is a humbling and perilous process , given the lack of long - term data and comparative studies . emerging evidence from centers with growing experience around the world is beginning to crystallize a set of guiding principles and concerns . the mere fact that we are now attentive to the long - term health consequences of this disease and its treatment attests to the success in the management of children with 21-ohd , which has been achieved over the last several decades .
the challenges that remain are now to refne our approach to the adolescent and adult with 21-ohd , to develop better adjunctive treatments , and to optimize the quality of life for these patients .
therapy is expected to change over time as the norm rather than the exception . with each experience
, we learn a little more about the physiology of adults with 21-ohd . above all
, the needs of the patient , their unique physiology , and their past experiences should be borne in mind when developing treatment regimens .
Output:
| congenital adrenal hyperplasia ( cah ) , most commonly due to 21-hydroxylase deficiency ( 21ohd ) , has been studied by pediatric endocrinologists for decades .
advances in the care of these patients have enabled many of these children to reach adulthood .
in contrast to the course and management of the disease in childhood , little is known about cah in adults . in many patients , the proclivity to salt - wasting crises decreases .
linear growth ceases , and reproductive function becomes an issue .
most importantly , management must minimize the potential for long - term consequences of conventional therapies . here
we review the existing literature regarding comorbidities of adults with 21ohd , goals of treatment , and approaches to therapy , with an emphasis on need for improved management strategies . |
PubmedSumm118536 | ***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
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Input: text real time sonoelastography ( rte ) is a new sonographic/ imaging method used for the appreciation of the physical characteristics of the tissues .
the method differentiates between the hardness of the diseased tissue and of the surrounding one .
malignant tumors are harder compared to benign ones and about 100 times harder than the surrounding tissue . because of their reduced elasticity , malignant tumors can change their shape less than the benign ones and the latter less than the surrounding tissue . by means of the ability to appreciate the elasticity of the tissues , the real time sonoelastography can make the difference between benign and malignant tumors . it has already been proved that measuring elasticity is useful in the differential diagnosis of some tumoral lesions , especially breast , prostate , lymph [ 1 , 2 ] , and pancreatic lesions .
however , the role of rte in differentiating liver lesions is approached in few studies only [ 4 - 6 ] the purpose of this paper is to appreciate if the dynamic computer analysis of the sonoelastography is able to characterize and differentiate between the benign and malignant liver lesions .
the study was a retrospective one and included patients with focal liver lesions examined by means of the rte between 2007 and 2010 .
the sonoelastography was performed by a hitachi 6500 with an rte module : hitachi medical systems europe holding ag , zug , switzerland .
it was a transabdominal approach with a linear probe of 6,5 mhz or an endoscopic ultrasound one .
the final diagnosis was made by considering both the sonographic / imaging and histopathological data and/or recheck after 6 months .
each sonoelastography film was subjected to computer analysis by using a java instrument to process the image - imagej - developed at the national institute of health , bethesda , maryland , for which a special dynamic analysis plug - in was created . to minimize the subjectivity given by the examining doctor
, all the digital postprocessing analyses were performed by the it center of the university of medicine and pharmacy in craiova , the it team unaware of the clinical and laboratory data of the patients . for each sonoelastography film , 10 seconds long ( about 125 frames ) , only the color frames were automatically selected , which contain elastography information , for which the histograms were calculated . the final numeric value attributed to each examination was calculated as the average of individual histograms of each elastography frame . the roc analysis of the average color obtained from the direct analysis of the histograms of the concerned region ( the liver tumor ) , after averaging the individual pixels from the 10-second - long elastography film , was used to evaluate the color information about the concerned region for the purpose of differentiating between the benign and the malignant liver lesions .
in all , 39 focal liver lesions have been studied : 30 malignant and 9 benign tumors . out of the 30 malignant tumors , 6 were hepatocellular carcinoma , 2 cholangiocarcinoma , and 22 liver metastases .
the sonoelastographic examination was performed during the endoscopic ultrasound ( 2 cholangiocarcinoma , 8 liver metastases , and 2 haemangioma ) or transabdominal ultrasound ( 6 hepatocellular carcinoma , 7 haemangioma , 14 liver metastases ) . out of the studied tumors ,
the cholangiocarcinoma were the hardest [ fig.1 ] , followed by the liver metastases [ fig.2 ] , the hepatocellular carcinoma and the liver haemangioma [ fig.3 ] .
the aspects in rt - e examination is predominant blue ( average histogram= 221.81 ) suggest a hardness of the lesion .
figure take a elastography image during fine needle aspiration guided by endoscopic ultrasound appearance of liver metastases in rt - e by transabdominal approach ( 2a ) and endoscopic ultrasound ( 2b ) .
the images illustrate the hard aspect of lesions predominantly blue . in fig 2a rt - e demarcates very well a liver metastasis which was very difficult visible in standard ultrasound haemangioma to a young patient .
average histogram was in this case 147.73 the average histogram obtained by analyzing the sonoelastographic films , on types of tumors , was : haemangioma 161.4226.72 ; hepatocellular carcinoma 187,7124,72 ; cholangiocarcinoma 208.9318.22 and liver metastasis 204.2916,99 [ figure 4 ] .
moreover , the difference was statistically significant between the value of the average histogram for the benign and malignant tumors [ figure 5 ] .
graph shows box plots of average histogram to type of tumors . from examined tumors cholangiocarcinoma and liver metastases
had the highest hardness graph shows box plots of average histogram for benign versus malignant tumors for a cutoff value of 170 of the average histogram obtained from the concerned region , the sensitivity , specificity and accuracy of the differentiation between the benign and malignant liver lesions , was 92.5% , 88.8% and respectively 88.6% [ figure 6 ] .
roc analysis used for the differentiation between benign and malignant focal liver lesions based on pattern analysis of elastography images
taking into account the risks of the liver biopsy , lately there have been attempts to find other noninvasive methods to help the doctor differentiate between the benign and the malignant liver lesions .
the sonoelastography , by its ability to appreciate the elasticity of tissues , can be one of the noninvasive sonographic / imaging methods of diagnosis .
it is , in fact , a soft attached to a highly professional ultrasound system .
that is why , the rte is performed immediately after the discovery of a focal lesion by means of the standard ultrasound , using the same machine and saving time for both the doctor and the patient .
studies have shown that the rte is really accurate in differentiating breast , thyroid , prostate , pancreas tumors or adenopathies [ 1 - 3 , 7 - 12 ] .
the study conducted by l. gheorghe has proven that the rte is accurate enough in differentiating the regenerating hepatocarcinoma nodules .
the study has been conducted on patients with cirrhosis with small , under 3 centimetres , subcapsular nodules .
the article published by kato k. and his collaborators has also shown good results of the rte in differentiating hepatocarcinoma metastases .
the authors have divided the tumors according to a new system called elasticity type of liver tumour ( etlt ) . according to this , most hepatocarcinoma
were included into the type b , while most metastases were included into type c and d. another role of the rte was demonstrated by the team led by inoue y. , namely the discovery of small lesions which are hardly visible at the standard ultrasound . unlike the previous articles which analysed images of static rte , our study had as a protocol , the recording and analysis of an elastography film which comprised at least 125 frames .
the film was analysed by the it department of the university represented by an independent researcher .
thus , we eliminated the subjectivity of the first examiner who has information about the patient , which might influence the diagnosis .
the rte had 88.6% accuracy in differentiating between the benign and malignant lesions . moreover ,
the results match those of previous studies that is the significant hardness of cholangiocarcinoma , followed by hepatocarcinoma , while the liver haemangioma have proved the least hard .
the present study included a smaller number of patients with cholangiocarcinoma and included no patients with adenoma or hepatic nodular hyperplasia . in the future all types of liver tumor are intended to be studied and an increasing number of patients included .
the rte might be used as a noninvasive method to diagnose liver tumor , as well as the ultrasound with contrast ( ceus ) .
it would be interesting to find out if the ceus combined with rte would have higher accuracy as compared to ceus as the only method of diagnosis . in conclusion ,
the rte is a sonographic / imaging method with promising results in the characterization and differentiation of focal liver lesions visualized transabdominally or endoscopically ultrasound .
Output:
| introduction : real time - sonoelastography ( rte ) is a new developed technique that reveals the physical properties of the tissue by characterizing the difference in hardness between diseased tissue and surrounding tissue .
elasticity measurements have been already reported to be useful for the diagnosis and differentiation of many tumors : breast lesions , prostate cancer , lymph nodes and pancreatic masses but there are only few studies for the focal liver lesions .
the aim of the study was to analyze whether computer enhanced dynamic analysis of elastography images is able to better characterize and differentiate benign and malignant liver lesions .
material and methods : the study group included , in total thirty nine liver tumors .
rte was performed by eus or transabdominal ultrasound .
roc analysis for the mean hue obtained through histogram analysis of the region of interest ( liver lesion ) after averaging individual pixels over a 10-second elastography movies was used to assess the color information inside the region of interest and to consequently differentiate benign and malignant liver lesions . based on a cutoff of 170 for the mean hue histogram values recorded on the region of interest , the sensitivity , specificity , and accuracy of differentiation of benign and malignant masses were 92.5% , 88.8% , and 88.6% , respectively .
the positive and negative predictive values were 86.7% and 92.3% , respectively . in conclusion ,
real time sonoelastography is a promising technique that might improve the characterization and differentiation between benign and malignant focal liver lesions visualized during transabdominal or endoscopic ultrasound . |
PubmedSumm118537 | ***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 35-year - old previously healthy woman was admitted to the emergency unit of ramn y cajal university hospital , madrid , spain , on march 25 , 2011 , because of a 4-day fever and arthralgias .
she had just returned from an 11-month leisure travel trip through africa , during which she visited madagascar and 14 countries in west africa . at admission , she had fever ( 39c ) and inflammatory signs on the left ankle .
the patient was treated with intravenous ceftriaxone ( 2 g / d ) ; oral doxycycline ( 100 mg 2/d ) was added the next day . on the third day , acute progressive dyspnea , cough , hypoxemia , and hypotension developed .
cultures of blood samples taken in the emergency unit were negative , but a gram - negative bacillus was cultured from blood taken on the third day of hospitalization .
gram stain of respiratory specimens taken at bronchoscopy showed a substantial number of polymorphonuclear leukocytes with predominant gram - positive flora .
after 48-h incubation at 35 2c in sheep blood ( ambient air ) and chocolate agar ( 5% co2 ) , mostly -hemolytic colonies of streptococci with a few colonies of saprophytic neisseria spp . were cultured .
treatment was changed to intravenous ceftazidime ( 2 g 4/d ) and oral doxycycline ( 100 mg 2/d ) , and the patient showed rapid clinical improvement .
after 3 weeks of treatment , the patient was discharged with maintenance treatment of oral amoxicillin / clavulanic acid ( 1 g 3/d ) and doxycycline ( 100 mg 2/d ) , later changed to oral cotrimoxazole ( 1,920 mg / d ) for 3 months course .
after a year , the patient had no sequelae or relapsing symptoms attributable to melioidosis .
the aerobic bottles of the 2 sets of blood specimens collected from the patient after hospitalization were positive for gram - negative rods with clear , bipolar staining .
subcultures on sheep blood agar plates ( 35 2c ) yielded a bacillus forming greyish colonies with an intense , earthy odor .
the organism was identified as b. pseudomallei with a 79.0% probability score by the wider system ( fco .
soria - melguizo , madrid , spain ) ; the api 20ne system ( biomrieux , marcy ltoile , france ) identified the isolate as b. pseudomallei with the numeric profile 1156577 ( 99.9% certainty ) .
mass spectrometry ( maldi - tof ms ; bruker daltonics , gmbh , leipzig , germany ) initially identified the isolate as burkholderia thailandensis , likely because of the paucity of entries in the database at that time ( 10 ) .
the full 16s rrna gene ( 1,500 bp ) of the isolate was amplified and sequenced .
nucleotide sequence alignment results were identical to results of a b. pseudomallei isolate from genbank ( accession no .
susceptibility testing was performed ( wider system ) , and results were interpreted according to clinical and laboratory standards institute burkholderia cepacia guidelines ( 11 ) . the isolate was susceptible ( mic , g / ml ) to ceftazidime ( < 1 ) , meropenem ( < 2 ) , minocycline ( < 2 ) , levofloxacin ( < 2 ) , and cotrimoxazole ( < 2/38 ) .
the isolate was sent to the national reference center for microbiology ( majadahonda , spain ) , where it was labeled bpsp2 and analyzed by a reverse line blot pcr that enables the specific identification of b. mallei , b. pseudomallei , and b. thailandensis ( 7 ) .
the isolate was further characterized by multilocus sequence typing ( mlst ) ( 12 ) ; the allele sequence and profile identified were submitted to the public database ( http://bpseudomallei.mlst.net ) for number assignation , and the obtained sequence type ( st ) was compared with other published sts .
in addition , the concatenated sequences of the 7-mlst genes ( 3,399-bp ) of the bpsp2 strain and the sts available in the public database were aligned by using clustalx ( www.clustal.org ) , and neighbor - joining phylogenetic trees were constructed by using mega4 software ( 13 ) .
two serum samples from melioidosis patients in thailand were used as positive controls , and a serum sample from a patient in spain who had bacteremia caused by b. cepacia was used as a negative control . a convalescent - phase serum sample from the patient , a sample from her husband , and serial serum samples from 7 hospital workers suspected of potential exposure were analyzed .
the bpsp2 isolate was confirmed as b. pseudomallei by pcr by using the specific probe for this pathogen ( data not shown ) .
mlst showed a new allelic profile for this strain , including a new allele for ndh that was numbered 39 .
this st was identified as 879 ( 1 , 1 , 10 , 2 , 6 , 1 , 39 ) in the database and is close to the human st349 ( martinique and spain ) ( 7 ) , st7 ( vietnam ) , and st662 ( france ) . these sts , however , showed 2 different loci compared with st879 , which grouped in the same clade with st662 and st7 but also with st26 ( niger ) and st707 ( nigeria ) ( figure ) .
other than st29 , st20 , and st319 ( burkina faso , niger , and mauritius , respectively ) , the isolates from africa grouped in the same clade with the sts from south america and the caribbean ( figure ) .
phylogenetic position of burkholderia pseudomallei isolate bpsp2 , sequence type ( st ) 879 ( boldface ) , from a patient in spain who had traveled to africa .
the dendrogram was built by using 852 isolates from the public b. pseudomallei database ( http://bpseudomallei.mlst.net ) .
the clade in which most sts from africa , south america , and the caribbean are located has been enlarged ; location , source type , and year collected are indicated for each isolate .
black circle indicates isolates from africa ; black squares indicate isolates from south america or the caribbean ; black triangles indicate st349 from martinique and the first patient described in spain ( 7 ) .
location of other sts from africa , b. mallei , and b. thailandensis are also indicated .
the patient s husband and the laboratory workers were negative for igg and igm , except that in 1 of the workers , a titer of 40 for igm was detected , but no seroconversion occurred .
although africa is not considered a melioidosis - endemic zone , melioidosis in humans has been reported ; melioidosis was confirmed in a traveler returning from africa to spain in 2009 ( 7 ) . for the patient we report , common predisposing factors for melioidosis were not observed , and an inoculation event or definite exposure to contaminated soil or water were not identified .
the patient had consumed raw , nonpasteurized goat milk , and b. pseudomallei has been isolated from this food ( 14 ) , but this possible link was not conclusive . confirmatory diagnosis of b. pseudomallei infection is isolation of the pathogen from clinical samples of patients , but the identification of b. pseudomallei can be elusive because automated systems used in clinical microbiology laboratories may misidentify it as b. cepacia ( 15 ) .
however , api 20ne has proven to give accurate identification , as has mass spectrometry with an extensive database support . despite high variability among the b. pseudomallei
isolates , most of the sts from africa grouped in the same clade and seemed to be phylogenetically related , particularly with strains from south america and the caribbean .
the phylogenetic analysis strongly suggests that bpsp2 has an african origin . in conclusion , because of difficulties in diagnosis , cases of melioidosis outside areas to which it is endemic may be more common than realized .
an increase in nongovernment organization and medical cooperation programs in africa , as well as leisure travelers moving to and from africa , may have resulted in increased frequency of some infections , such as imported melioidosis .
these findings require clinicians to recognize the disease and microbiologists to identify the causative agent .
Output:
| the worldwide epidemiology of melioidosis is changing .
we describe a case of acute melioidosis in spain in a patient who had traveled to africa .
a novel sequence type of burkholderia pseudomallei was identified in this patient .
clinicians should be aware of the possibility of melioidosis in travelers returning from melioidosis - nonendemic regions . |
PubmedSumm118538 | ***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 microfluidic cell is made by fusing a patterned , 2 mm thick , polydimethylsiloxane ( pdms ) disk to a freshly cleaned quartz cover slip .
the pdms disk contains four 30 l rectangular chambers that are accessed by inlet and outlet flexible capillaries connected to a buffer reservoir and a syringe pump , respectively , for the controlled flow of buffer .
the ow cell is supported on its back side by a glass window and placed on a custom - made cell holder containing a water cooled thermoelectric element to regulate temperature . to make the patterned pdms disk , mix 10 parts silicone elastomer base with 1 part curing agent , mix well and leave degassing for 1 hour in vacuum .
gently pour the elastomer mix onto the microfluidic cell mold . in our case , this is a 1 " silicon wafer with four strips ( 1x10 x 1x10 x 300 m ) made from negative photoresist .
leave this to cure on a hot plate at 70 c for two hours . carefully peel the cured pdms disk from the mold using a razor blade .
fuse the disk onto a 1 '' glass window ( containing 8 x 2 mm - diameter pre - drilled holes at both ends of the channels ) by plasma oxidizing both surfaces for 30 seconds .
fuse the glass windows onto the flat side of the pdms disk ( the side not containing the channels ) . insert a 2-inch long flexible fused silica capillary tubing through each glass window 's hole until it reaches the channel . inserting a needle first and then following with the capillary
seal the glass window holes using a fast curing silicone casting compound such as kwik - cast .
rinse the channels with ethanol and water , and plasma - activate the cell together with a freshly cleaned , 1-inch circular quartz cover slip for 30 seconds .
we suggest cleaning this cover slip using piranha*. fuse the cover slip to the side of the cell containing the channels , sealing the chambers . leave the assembled cell to cure overnight at room temperature .
* piranha is a solution of h2o2 and h2so4 in 1:2.5 proportions . to clean the cover slips , immerse them in piranha at 90 c for 20 min . for nucleic acid studies ,
the simplest surface immobilization scheme consists of first coating a glass or quartz cover slip with biotinylated bovine serum albumin ( bsa ) and then with streptavidin .
this allows the biotinylated sample to be immobilized with high specificity for days at room temperature .
connect flexible tubing to the capillaries for easy buffer injection using a syringe and needle .
inject a solution of 0.1 mg / ml of biotinylated bsa in buffer a ( 10 mm tris - hcl , ph 8.0 , 50 mm nacl , filtered using 0.02 m filters ) into the channel and incubate for at least 30 min .
flow 300 - 500 l of buffer a to remove any free biotinylated bsa from the channel , being careful not to trap any air bubbles inside the chamber .
inject a solution of 0.1 mg / ml of streptavidin in buffer a and incubate for 15 min .
. the microfluidic cell is mounted on a motorized x - y stage allowing coarse ( up to 25 mm ) motion using optically encoded dc motors , and ne ( 1 nm ) motion using two closed - loop piezo actuators ( physik instrumente model m-014 or similar ) .
the ib consists of an enzymatic oxygen scavenging system and a triplet quencher , such as trolox .
since the ib is flushed through constantly overnight , at least 10 ml should be prepared in advance .
d - glucose , at least 35 mm tris - hcl ph 8.0 and 50 mm nacl in deionized water . the higher concentration of buffer is important for two reasons : dissolving trolox will acidify the solution , and the enzymatic reaction will also lower the ph of the solution over time . since this solution has a long shelf life it can be stored as a stock solution . dissolve 5 mg of trolox in the buffer prepared in step 1 by vortexing for a couple of minutes and then shaking for > 10 min .
trolox is not very soluble in water at ph > 7 , so do not rush this step .
filter the solution using a 0.2 m filter and leave degassing in vacuum for 10 minutes .
prepare the " gloxy " enzymatic solution by mixing 60 l water , 20 l of 5x buffer a , 20 l of catalase , 1 mg glucose oxidase and 100 l of 10 mg / ml bsa .
filter the solution using a 0.22 m centrifuge filter . gently mix the buffer from step 2 with the " gloxy " solution from step 3 avoiding the formation of air bubbles .
flow the ib through the channel at a constant rate of 5 l / min using a mechanical syringe pump to control the flow rate .
bubble argon gas into the ib reservoir to prevent atmospheric oxygen from re - dissolving into the buffer .
the surface scanning , molecule localization and acquisition of single molecule intensity traces is controlled by a labview program that permits automated data collection .
the program scans 20x20 m areas at 0.2 m resolution , with a rate of 0.1 m / ms .
data is immediately processed to yield intensity - weighted locations of all pixels above the background counts .
once the immobilized molecules are found , they are moved one by one into the confocal volume and the intensities of the donor and acceptor fluorophore are recorded as a function of time until both fluorophores photobleach .
the stage is then programmed to move to a new origin 100 m away , and the scanning process is repeated .
below are some images showing the assembled microfluidic cell before surface activation and after being mounted on the microscope ready for molecule immobilization .
if the channel is activated successfully , surface scans should be similar to the scans depicted below showing emission of the donor dye ( green ) and acceptor ( red ) after direct donor excitation .
these molecules are moved one by one into the probing volume and the fluorescence is recorded over time until both dyes photobleach , as shown in the single molecule traces . from traces like these one can obtain the fret efficiency which informs on the instantaneous donor - acceptor separation , which in turn is used to explore the structure and dynamics of molecules of biological interest .
figure 1 : microfluidic cell with four channels , each with inlet / outlet capillaries .
figures 4 and 5 : red and green channel of a surface scan of immobilized fret molecules excited with green laser
. please click to see a larger version of figure 4 , or figure 5 .
figures 6 , 7 , 8 , and 9 : intensity trajectories of donor ( green ) and acceptor ( red ) fluorophores labeled to a dna molecule 8 , 10 , 16 and 18 basepairs apart
. please click to see a larger version of figure 6 , figure 7,figure 8 , or figure 9 .
the microfluidic cell is made by fusing a patterned , 2 mm thick , polydimethylsiloxane ( pdms ) disk to a freshly cleaned quartz cover slip .
the pdms disk contains four 30 l rectangular chambers that are accessed by inlet and outlet flexible capillaries connected to a buffer reservoir and a syringe pump , respectively , for the controlled flow of buffer .
the ow cell is supported on its back side by a glass window and placed on a custom - made cell holder containing a water cooled thermoelectric element to regulate temperature . to make the patterned pdms disk , mix 10 parts silicone elastomer base with 1 part curing agent , mix well and leave degassing for 1 hour in vacuum .
gently pour the elastomer mix onto the microfluidic cell mold . in our case , this is a 1 " silicon wafer with four strips ( 1x10 x 1x10 x 300 m ) made from negative photoresist .
leave this to cure on a hot plate at 70 c for two hours . carefully peel the cured pdms disk from the mold using a razor blade .
fuse the disk onto a 1 '' glass window ( containing 8 x 2 mm - diameter pre - drilled holes at both ends of the channels ) by plasma oxidizing both surfaces for 30 seconds .
fuse the glass windows onto the flat side of the pdms disk ( the side not containing the channels ) . insert a 2-inch long flexible fused silica capillary tubing through each glass window 's hole until it reaches the channel . inserting a needle first and then following with the capillary
seal the glass window holes using a fast curing silicone casting compound such as kwik - cast .
rinse the channels with ethanol and water , and plasma - activate the cell together with a freshly cleaned , 1-inch circular quartz cover slip for 30 seconds .
we suggest cleaning this cover slip using piranha*. fuse the cover slip to the side of the cell containing the channels , sealing the chambers . leave the assembled cell to cure overnight at room temperature .
* piranha is a solution of h2o2 and h2so4 in 1:2.5 proportions . to clean the cover slips , immerse them in piranha at 90 c for 20 min .
for nucleic acid studies , the simplest surface immobilization scheme consists of first coating a glass or quartz cover slip with biotinylated bovine serum albumin ( bsa ) and then with streptavidin .
this allows the biotinylated sample to be immobilized with high specificity for days at room temperature .
connect flexible tubing to the capillaries for easy buffer injection using a syringe and needle .
inject a solution of 0.1 mg / ml of biotinylated bsa in buffer a ( 10 mm tris - hcl , ph 8.0 , 50 mm nacl , filtered using 0.02 m filters ) into the channel and incubate for at least 30 min .
flow 300 - 500 l of buffer a to remove any free biotinylated bsa from the channel , being careful not to trap any air bubbles inside the chamber .
inject a solution of 0.1 mg / ml of streptavidin in buffer a and incubate for 15 min .
perform a surface scan to check the coverage of fluorescent molecules . if necessary , increase the sample concentration to obtain better coverage .
the microfluidic cell is mounted on a motorized x - y stage allowing coarse ( up to 25 mm ) motion using optically encoded dc motors , and ne ( 1 nm ) motion using two closed - loop piezo actuators ( physik instrumente model m-014 or similar ) .
the ib consists of an enzymatic oxygen scavenging system and a triplet quencher , such as trolox .
since the ib is flushed through constantly overnight , at least 10 ml should be prepared in advance .
prepare 10 ml of 0.8% w / v d - glucose , at least 35 mm tris - hcl ph 8.0 and 50 mm nacl in deionized water .
the higher concentration of buffer is important for two reasons : dissolving trolox will acidify the solution , and the enzymatic reaction will also lower the ph of the solution over time . since this solution has a long shelf life it can be stored as a stock solution . dissolve 5 mg of trolox in the buffer prepared in step 1 by vortexing for a couple of minutes and then shaking for > 10 min .
trolox is not very soluble in water at ph > 7 , so do not rush this step .
filter the solution using a 0.2 m filter and leave degassing in vacuum for 10 minutes .
prepare the " gloxy " enzymatic solution by mixing 60 l water , 20 l of 5x buffer a , 20 l of catalase , 1 mg glucose oxidase and 100 l of 10 mg / ml bsa .
filter the solution using a 0.22 m centrifuge filter . gently mix the buffer from step 2 with the " gloxy " solution from step 3 avoiding the formation of air bubbles .
flow the ib through the channel at a constant rate of 5 l / min using a mechanical syringe pump to control the flow rate .
bubble argon gas into the ib reservoir to prevent atmospheric oxygen from re - dissolving into the buffer .
the surface scanning , molecule localization and acquisition of single molecule intensity traces is controlled by a labview program that permits automated data collection .
the program scans 20x20 m areas at 0.2 m resolution , with a rate of 0.1 m / ms .
data is immediately processed to yield intensity - weighted locations of all pixels above the background counts .
once the immobilized molecules are found , they are moved one by one into the confocal volume and the intensities of the donor and acceptor fluorophore are recorded as a function of time until both fluorophores photobleach .
the stage is then programmed to move to a new origin 100 m away , and the scanning process is repeated .
below are some images showing the assembled microfluidic cell before surface activation and after being mounted on the microscope ready for molecule immobilization . if the channel is activated successfully , surface scans should be similar to the scans depicted below showing emission of the donor dye ( green ) and acceptor ( red ) after direct donor excitation .
these molecules are moved one by one into the probing volume and the fluorescence is recorded over time until both dyes photobleach , as shown in the single molecule traces . from traces like these one can obtain the fret efficiency which informs on the instantaneous donor - acceptor separation , which in turn is used to explore the structure and dynamics of molecules of biological interest .
figure 1 : microfluidic cell with four channels , each with inlet / outlet capillaries .
figures 4 and 5 : red and green channel of a surface scan of immobilized fret molecules excited with green laser
. please click to see a larger version of figure 4 , or figure 5 .
figures 6 , 7 , 8 , and 9 : intensity trajectories of donor ( green ) and acceptor ( red ) fluorophores labeled to a dna molecule 8 , 10 , 16 and 18 basepairs apart .
please click to see a larger version of figure 6 , figure 7,figure 8 , or figure 9 .
although the above protocol has been optimized for our particular system and for a specific choice of dyes ( tmr and atto647n ) , it is by no means the only proved method .
recently , an alternative oxygen scavenging system consisting of protocatechuic acid ( pca)/protocatechuate-3,4-dioxygenase ( pcd ) was shown to increase the photostability of certain dyes .
likewise , other triplet - state quenchers such as -mercaptoethanol ( bme ) can be used instead of trolox , although these might not suppress long - lasting blinking of some dyes , in particular cy5 .
although immobilization via biotin - streptavidin - biotinylated bovine serum albumin ( bsa ) is the preferred choice for nucleic acids studies , a polyethylene glycol ( peg)-coated surface is better suited for studies of proteins since it prevents non - specific adhesion .
additionally , sub - diffraction - limited size vesicles can be used to encapsulate the biomolecule of interest in cases where it can be affected by surface interactions . in this article
we have used a confocal setup equipped with silicone avalanche photodiodes to acquire the fluorescence intensity traces .
this protocol works equally well with total internal reflection fluorescence microscopes ( tirf ) equipped with ccd cameras .
regardless of the microscopy used , sm - fret can inform on spatial resolutions approaching the angstrom when the donor and acceptor signal are properly corrected .
Output:
| fluorescence resonance energy transfer ( fret ) microscopy has been widely used to study the structure and dynamics of molecules of biological interest , such as nucleic acids and proteins .
single molecule fret ( sm - fret ) measurements on immobilized molecules permit long observations of the system -effectively until both dyes photobleach- resulting in time - traces that report on biomolecular dynamics with a broad range of timescales from milliseconds to minutes . to facilitate the acquisition of large number of traces for statistical analyses , the process must be automated and the sample environment
should be tightly controlled over the entire measurement time ( ~12 hours ) .
this is accomplished using an automated scanning confocal microscope that allows the interrogation of thousands of single molecules overnight , and a microfluidic cell that permits the controlled exchange of buffer , with restricted oxygen content and maintains a constant temperature throughout the entire measuring period .
here we show how to assemble the microfluidic device and how to activate its surface for dna immobilization .
then we explain how to prepare a buffer to maximize the photostability and lifetime of the fluorophores .
finally , we show the steps involved in preparing the setup for the automated acquisition of time - resolved single molecule fret traces of dna molecules . |
PubmedSumm118539 | ***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: at the core of personalized medicine is the identification of factors influencing disease processes and therapy [ 1 , 2 ] .
consequently , characterizing the pharmacokinetics and pharmacodynamics of a drug in diverse populations is essential in improving therapeutic effectiveness while minimizing adverse events . for a drug to work ,
it is necessary to reach and maintain a minimum drug concentration at the site(s ) of action .
many factors influence circulating drug concentrations , as well as the concentrations at the sites of action , and determine the resulting outcome .
sex , in particular , can influence how the body handles a drug as well as what the drug does to the body .
this paper , which examines sex differences in pharmacokinetics and pharmacodynamics , is an update of current knowledge on this topic and includes peer - reviewed literature published until october 2010 .
the keywords used were : sex / gender differences , pharmacokinetics , pharmacodynamics , adverse drug events , and sex differences in drug metabolism / elimination . all reviewed manuscripts pertain to publications concerning humans only , written and published in the english language .
gender , a social construct , is expressed in terms of masculinity and femininity .
it is defined by the way people perceive themselves and how they expect others to behave .
sex differences result from the classification of organisms based on genetic composition as well as reproductive organs and function .
men and women differ in response to drug treatment and occupational exposures , a consequence of differences in body weight , height , body surface area , total body water , and the amount of extracellular and intracellular water .
pharmacokinetics and pharmacodynamics are also attributable to the differences seen between males and females [ 5 , 79 ] . since pharmacokinetics , pharmacodynamics , and responses during clinical trials differ between men and women , u.s .
fda regulations and guidance are in place to ensure that both sexes are represented in all phases of clinical trials and that medical products are labeled to alert physicians and patients to sex differences in drug responses . in 1999 , the national institutes of health published the agenda for research on women 's health for the 21st century , concluding that sex - related differences in pharmacokinetics and pharmacodynamics must be further assessed . in an effort to overcome gaps in knowledge regarding the actions of drugs in women , more women
the nih biennial report of the director of 2006 - 2007 reported that in 2006 , of 624 extramural and intramural phase iii clinical research protocols ( 499,430 participants ) , 63% were women [ 10 , 11 ] . more attention
is currently being drawn towards the ways in which clinical therapeutics can be tailored according to sex , age , body weight , and genotype to yield the best possible outcomes .
the fda adverse events reporting system ( aers ) is a voluntary database of adverse events .
based on an analysis of aers data and other data resources , women experience more adverse events than men , and in general , these adverse events are of a more serious nature [ 1317 ] . the u.s .
general accounting office ( gao ) reviewed the ten drugs withdrawn from the market during the period january 1 , 1997 through december 2000 ; eight of the ten were withdrawn due to greater risks of adverse effects in women .
sex - related differences in the frequencies of adverse events reporting may be due to pharmacokinetic or pharmacodynamic factors , polypharmacy , or differences in reporting patterns ( table 1 ) .
women are generally smaller and have a different body composition than men , the recommended dose may result in higher drug concentrations or area under the concentration time curve ( auc ) in women because the drug has lower clearance and/or smaller volume of distribution ( vd ) . alternatively
, pharmacodynamic factors ( alterations in drug - target numbers or responses ) may increase female sensitivity to specific drugs . in this instance
, free drug concentrations and drug persistence would be similar in men and women , but women would respond to a greater or lesser extent .
it is also possible that sex differences between men and women result in similar rates of adverse events but that women experience more severe events .
another plausible explanation might be attributed to prescribing patterns ; women ingest more medications than men , increasing the risk of adverse events from drug - drug interactions .
drug absorption and bioavailability are influenced by drug- and route - specific factors ( oral , dermal , rectal , vaginal , intramuscular , intravenous , intra - arterial , intrathecal , and intraperitoneal ) .
routes of absorption occur across body surfaces , such as the gastrointestinal tract , respiratory tract , or skin , which differ in males and females .
for example , drug absorption occurs at different sites throughout the gastrointestinal tract , and rate of absorption is influenced by gut transit times , lipid solubility of the agent , ph at the site of absorption , and the ionization and molecular weight of the agent .
transit times differ significantly in men and women , with mean transit times being shorter in men ( 44.8 hours ) than in women ( 91.7 hours ) . while fiber ingestion decreases transit time , female gut transit times are consistently longer .
sex differences have also been noted in bile acid composition , which may impact the solubility of various drugs .
men have higher concentrations of cholic acid , while women have higher concentrations of chenodeoxycholic acid .
the fda evaluated sex differences in bioequivalence among 26 studies submitted to the agency between 1977 and 1995 [ 20 , 24 ] .
it is a major concern that over a 20-year period , only 26 studies submitted to the fda had data addressing sex differences in drug absorption . among the 26 studies ,
there were 47 datasets addressing sex differences in maximum concentration ( cmax ) and auc .
most had no more than 10 men or women , so the sample size available to assess sex differences in bioavailability was limited . however , among these studies , the cmax was greater in women 87% of the time and auc was greater in women 71% of the time .
other investigators have utilized multidrug cocktails to assess bioavailability and metabolism across age and sex .
the advantage of this approach is the ability to phenotype multiple cytochrome p450 ( cyp ) enzymes including cyp1a2 , 2c19 , 2d6 , 2e1 , and 3a4 ( although differences in intestinal and hepatic metabolism and transport may complicate the interpretation of the data ) . using this approach
, the investigators suggested that the activities of cyps 2c19 , 2d6 , and 3a4 were equivalent and that the activities of cyps 1a2 and 2e1 were decreased in women than in men .
however , using well - characterized human liver samples , another group of investigators observed 2-fold greater hepatic cyp3a4 activity in women , suggesting sex differences in first pass metabolism and bioavailability .
analysis of 24 studies of cyp3a4 substrates observed that clearance was greater in women than men for 15 substrates ( 60% ) .
in addition to sex differences in bioavailability , it is important to consider that food interactions ( e.g. , grapefruit juice ) , gut motility and transit time , gut ph , biliary secretion and gut flora , enterohepatic circulation and oral contraceptives can differentially influence the bioavailability of a drug in men and women [ 28 , 29 ] .
for example , it was recently observed that polyethylene glycol enhances the bioavailability of ranitidine in men and decreases it in women .
sex differences in bioavailability of cyclosporine a have also been observed after a fat - rich meal : decreased bioavailability in females and increased bioavailability in males .
it has been hypothesized that , because of differences in subcutaneous lipid content , the bioavailability of transdermally administered drugs is different in women . additionally , women have greater respiratory minute ventilation and lower tidal volume , which may result in decreased ingestion of inhaled aerosol drugs , such as ribavirin and cyclosporine , although only limited data are available so far [ 23 , 33 ] .
an important part of bioavailability includes the gastric and hepatic enzymes and transport proteins that oral drugs interact with prior to reaching the systemic circulation [ 34 , 35 ] .
gastric and hepatic enzymes and transporters change across the course of development , forming the basis for sex differences .
these metabolic and transport processes are critical for the success or failure of drugs developed for oral use .
successful oral drugs are soluble , permeable , and poorly metabolized by intestinal and hepatic enzymes . for example , the bioavailability of alcohol is greater in women than in men , with cmax and auc being greater .
these can be partly ascribed to differences in vd and gastric alcohol dehydrogenase activity .
transport proteins play a critical role in transporting drugs into and out of all cells and are consequently involved in hepatobiliary and urinary excretion .
tissue distribution and elimination pathways , as well as efficacy and toxicity of drugs , are explained in many cases by transport proteins .
one interesting example is paclitaxel neurotoxicity , which appears to be dependent on phenotypic and genotypic variation in cyp3a4/5 , as well as transport proteins ( oatp 1b1/3 and pgp ) , which vary with sex .
variability in the intestinal expression of transport proteins may result in sex differences in plasma drug concentrations .
for example , p - glycoprotein ( pgp ) , a membrane adenosine triphosphatase transporter protein found in high concentrations in the enterocytes of the small intestine , is encoded by the multidrug resistance transporter-1 gene ( mdr1 ) expressed in the human intestine , liver and other tissues .
pgp , expressed in higher numbers in men , has been shown to decrease intracellular concentrations of certain drugs at the intestine by transporting them out of the enterocytes and back into the intestinal lumen .
this mechanism results in the drug being repeatedly exposed to intestinal drug - metabolizing enzymes [ 23 , 40 ] .
synthetic and endogenous sex hormones have been shown to regulate pgp expression and inhibit pgp function at the gut wall , enhancing drug absorption .
absorptive transporters such as h+/ditripeptide transporter and organic anion transporting polypeptide ( oatp ) facilitate drug absorption , while efflux transporters such as pgp sometimes work as drug absorption barriers .
sex differences are also exhibited by the serotonin 5-ht1a receptor and serotonin transporter ( 5-htt ) , which is a target for selective serotonin reuptake inhibitors ( ssris ) , psychotropic drugs used in the treatment of depression , anxiety , and personality disorders .
women have significantly higher 5-ht1a receptor and lower 5-htt binding potentials throughout the cortical and subcortical brain regions and exhibit a positive correlation between 5-ht1a receptor and 5-htt binding potentials for the hippocampus .
thus , sex differences in 5-ht1a receptor and 5-htt binding potentials may result in biological distinctions in the serotonin system , thereby contributing to sex differences in the prevalence of psychiatric disorders such as depression and anxiety .
gastric fluids are generally more acidic in males than females ( ph 1.92 versus ph 2.59 ) , and basal and maximal flow of gastric fluid and acid secretion are both higher in men
. reduced ph results in decreased absorption of weak acids and increased absorption of weak bases .
the absorption of antidepressants , the majority of which are weak bases , is greatly increased in women , further enhanced by slower rates of gastric emptying and prolonged gut transit times .
the kidneys are responsible for the maintenance of water / electrolyte balance , the synthesis , metabolism , and secretion of hormones , and excretion of waste products from metabolism as well as most drugs and xenobiotics .
the human kidney demonstrates sex - related differences in the subunits of glutathione - s - transferase isoenzyme .
iron also has significant differences between males and females in gastrointestinal absorption . in preadolescent males and females
, it has been shown that 45% of ingested iron is incorporated into erythrocytes by females compared to 35% in males ( iron - regulated surface determinant 0.78 ) [ 47 , 48 ] . once absorbed and in the circulation , most drugs bind to plasma proteins .
sex differences in these parameters may account for differences in the concentration of a drug at the target site and result in varying responses .
however , differences in protein binding between men and women are generally rare , and there is still no convincing link between protein - binding differences and sex - specific adrs , with the exception of lignocaine and diazepam . on average ,
total body water , extracellular water , intracellular water , total blood volume , plasma volume , and red blood cell volume are greater for men . therefore , if an average man and an average woman are exposed to the same dose of a water - soluble drug , vd will be increased in the man , thus decreasing drug concentration . for lipid - soluble drugs
alcohol , a water - soluble drug , has a smaller vd in women than in men , producing higher cmax in women .
the vd values of salbutamol ( albuterol ) and ofloxacin have been shown to be significantly greater in men , most likely due to sex differences in lean body mass .
the liver accounts for a greater percentage of lean body mass in women compared to men .
it is currently believed that the larger liver mass and smaller vd observed in women accounts for the more rapid rate of elimination of alcohol from the blood .
in general , the reference values for resting blood flow to organs and tissues for 35-year - old males and females show significant differences as a percentage of cardiac output .
for example , blood flow to skeletal muscle is greater for men and to adipose tissue is greater for women .
these differences may reflect sexbased differences in the percentage of total body mass represented by each tissue .
females exhibit decreased liver blood flow rates which , despite higher cyp3a4 amounts and activity , may result in lower drug clearance .
the main binding proteins for various drugs in plasma are albumin , 1-acid glycoprotein ( aag ) , and globulins .
aag levels and aag glycosylations vary in association with endogenous and exogenous estrogen , inducing hepatic glycosylation of these proteins and thus decreasing plasma aag levels .
albumin concentrations do not consistently vary by sex . estrogens also increase the levels of the serum - binding globulins ( sex - hormone - binding globulin , corticosteroid - binding globulin , and thyroxin - binding globulin ) .
sex - related differences in plasma binding of selected compounds are listed in table 2 .
variations in levels of plasma binding can alter the free ( active ) fraction of drugs .
therapeutic drug monitoring is the measurement of specific drugs in order to maintain a relatively constant circulating drug concentration .
drugs that are monitored tend to have a narrow therapeutic rangethe drug quantity required to be effective is not far removed from the quantity that causes significant side effects and/or signs of toxicity . maintaining drug concentrations within the therapeutic range is not as simple as giving a standard dose of medication .
often , if the free fraction increases , there is a shift of the drug to the tissues / target or resultant higher clearance , with the total concentration not changing , for example , phenytoin .
body fat as a percentage of total body weight is higher in women than in men and increases by age in both sexes .
the total body fat values are 13.5 kg in an adult reference male and 16.5 kg for an adult reference female
. the larger proportions of body fat in women may increase the body burden of lipidsoluble , slowly metabolized toxicants .
differences in body fat and in organ blood flow in women have been implicated in the faster onset of action and prolonged duration of neuromuscular blockade in women ( e.g. , vecuronium and rocuronium ) [ 57 , 58 ] .
differences in body fat content and in protein binding are responsible for sex - related pharmacokinetic differences in the distribution of diazepam ( free fraction : in females 1.67% versus 1.46% in males ) .
females have been shown to have larger vd than males ( vd = 1.87 versus 1.34 l / kg ) .
several studies have observed that when dose is corrected by body weight , some of the sex differences seen in pharmacokinetics disappear .
this suggests body weight ( and by inference , composition ) may be responsible for some differences seen in drug disposition .
a recent study examined the plasma concentrations of the antibiotic clindamycin in twenty - four male and female subjects .
higher plasma concentrations were seen in women . however , when the 600 mg dose was normalized to individual body weight , plasma concentrations between men and women were comparable .
aliskirin , an antihypertensive rennin inhibitor , as well as fluconazole , an antifungal drug , both appear to require dosage adjustments by body weight [ 61 , 62 ] .
furthermore , the pharmacokinetics of citalopram does not display differences between males and females when adjusted by dose and body weight . cardiac output and regional distribution of flow
cardiac output is commonly standardized and reported as the cardiac index , which is similar for both sexes between 18 and 44 years of age .
the distribution of cardiac output , or regional blood flow , is similar for men and women for some organs ( adrenal 0.3% , bone 5% , brain 12% , lung 2.5% , skin 5% , and thyroid 1.5% , reported as percent of cardiac output ) and different for others ( adipose : male = 5% , female = 8.5% ; heart : male = 4% , female = 5% ; kidney : male = 19% , female = 17% ; liver : male = 25% , female = 27% ; muscle : male = 17% , female = 12% ) , reflecting sex - based differences in body composition .
drug metabolism ( biotransformation ) occurs predominantly in the liver , as well as in extrahepatic sites such as the intestinal tract , lung , kidney , and skin .
hepatocytes and intestinal cells express significant levels of cyp3a and phase ii enzymes such as uridine diphosphate glucoronosyltransferase ( ugt ) , which may significantly contribute to the first pass metabolism of many orally administered drugs ( see discussion above on bioavailability ) .
lipid solubility , protein binding , the dose , and the route of exposure all affect the rate of biotransformation . despite the large variations in drug metabolism among individuals , correction for height , weight , surface area , and body composition eliminates some but not all of the sex - dependent differences .
however , sex - dependent differences in biotransformation have been observed for drugs such as nicotine , chlordiazepoxide , flurazepam , aspirin ( acetylsalicylic acid ) , and heparin [ 6569 ] .
these are a large family of related enzymes housed in the smooth endoplasmic reticulum of the cell .
while the cyp enzymes discussed in this paper are all coded for by autosomal chromosomes , it is possible that sex - related disparities in pharmacokinetics arise from variations in the regulation of the expression and activity of cyp enzymes through endogenous hormonal influences . for reviews that deal specifically with cyp enzymes
ingested compounds may remain unchanged ( and possibly accumulate in a storage compartment ) or , based on their degree of lipophilicity and polarity , they may be subject to metabolism .
hepatic drug metabolism is divided into two usually sequential enzymatic reactions : phase i and phase ii reactions .
some of the cyp enzymes show clear sex - related differences ( table 3 ) . in general ,
lipophilic compounds have a tendency to pass through biological membranes and/or be stored and are often susceptible to phase i types of metabolism .
sex - related differences have been shown for some cyps , with a higher activity in females for cyp3a4 ( table 3 ) .
an analysis of previously published studies of 14 different drugs demonstrated that females displayed an average of 2030% increased clearance for drugs that were cyp3a substrates compared to those of males . in 2009 ,
lutz and colleagues demonstrated for the first time in a caucasian population that the endogenous marker for cyp3a activity the metabolic ratio of 6 -hydroxycortisol to cortisol found in urine was significantly increased in females compared to males . by studying the activity of sex hormones , as a consequence of physiological , pathological , or pharmacological manipulations
, researchers now believe that many of the changes seen in cyp enzymes may be gender specific .
the sex - dependent expression of cyp3a4 is thought to be regulated by sex - specific temporal patterns of plasma growth hormone release by the pituitary gland .
males display a pulsatile pattern while females exhibit a more continuous pattern of release .
growth hormone regulation of cyp3a4 has been discerned in primary human hepatocyte cultures ; cyp3a4 protein and mrna are induced by continuous treatment with growth hormone and suppressed with pulsatile treatment .
cyp3a4 activity , however , has not been seen to vary throughout the menstrual cycle , suggesting that sex hormones may not be responsible for the gender - specific expression observed .
antihistamines , in particular , have been shown to exhibit sex - specific differences in pharmacokinetics .
they act as cyp2d6 substrates , which have been shown to exhibit slower metabolic elimination in women .
this may explain why women are more vulnerable to sedation and drowsiness effects of antihistamines than men .
gender differences in pgp expression in the brain may also underlie the sedative side effects often experienced by women .
however , even if there are true sex differences in drug pharmacokinetics , only few drugs exhibit significantly different plasma concentrations in women . a comprehensive review of second - generation ( atypical )
antipsychotics concludes that even though sex differences in cases of adverse events have not been well studied , some adverse effects such as weight gain , hyperprolactinemia , and cardiac effects , are particularly problematic for women .
most studies that were reviewed indicate that clozapine and olanzapine are associated with greater body weight gain than other atypical antipsychotics and that serious adverse effects such as metabolic syndrome ( which includes increased visceral adiposity , hyperglycemia , hypertension and dyslipidemia induced by atypical antipsychotics ) are more frequent in females .
although women are at a lower risk of sudden cardiac death , they have a higher risk of induced long - qt syndrome from antiarrhythmic and , probably , antipsychotic drugs [ 82 , 83 ] .
this adverse effect has been seen with drugs that block cardiac voltage - gated potassium channels , prolonging repolarization and the qt interval .
metabolism of chemicals may be estimated by basal metabolic rates . for all ages , on average ,
since the metabolism of adipose tissue differs from that of muscle tissue , some of the differences between men and women are attributable to body composition metabolism of adipose tissue . a lower basal metabolic rate per unit body surface area reflects the lower lean body mass in women due to a smaller skeletal muscle component .
hepatic clearance of drugs is a function of liver blood flow and hepatic enzyme activity .
although cardiac output and hepatic blood flow are lower in women than in men normalized per m / kg , sex differences in hepatic enzymes also play a major role in determining sex - related pharmacokinetic activity . at the canalicular surface of hepatocytes ,
pgp will direct the biliary excretion of certain drugs , and its expression has been found to be twofold lower in women than in men . consequently , women display increased and sustained intracellular concentrations of pgp substrates , increased activity of hepatic drug - metabolizing enzymes , and thus increased clearance of the drug .
much is unknown regarding pgp expression although it is currently thought to be controlled and regulated by sex hormones .
two processes , metabolism and elimination , are responsible either separately or together for drug inactivation . without these means
, drugs would continuously circulate throughout our bodies , bind to various receptors , and interrupt important physiological processes .
drugs are generally eliminated from the body by renal , hepatic , or pulmonary routes .
consequently , drugs may be eliminated from the body in sweat , tears , breast milk , and expired air .
the kidney is the major organ of drug excretion of either the parent drug compounds or drug metabolites .
there are known sex differences in all three major renal functions - glomerular filtration , tubular secretion and tubular reabsorption .
a recent study on the transdermal absorption of fentanyl , a pain management drug for cancer patients , found that particularly at high doses , urinary excretion of fentanyl was markedly decreased in women .
gender also has a significant impact on the elimination of the loop diuretic torasemide , contributing to higher rates of adverse drug reactions in women . hospitalizations due to adrs from diuretics are more prevalent in women , irrespective of differences in prescription rates between the sexes .
adjusting for age , body mass index ( bmi ) , and modification of diet in renal disease ( mdrd ) , oral clearance of torasemide was on average one - third lower in women , associated with 30%40% higher mean auc24 and cmax values in females than in males .
chemicals can be excreted into the urine through glomerular filtration , passive diffusion , and active secretion .
increases in renal blood flow and glomerular filtration increase the elimination rate of drugs cleared by the kidneys . when standardized for body surface area , renal blood flow , glomerular filtration , tubular secretion , and tubular reabsorption are all greater in men than in women [ 89 , 90 ] .
sex - dependent differences among the three primary opioid receptor subtypes mu , delta , and kappa have been extensively studied .
the kappa opioid receptor subtype may be sex - dependently modulated by mc1r , a gene that encodes for melanocortin-1 receptors .
women with two or more variant alleles of this gene were more responsive to pentazocine than women with one or no variants of the gene .
morphine , a mu - opioid receptor agonist , has been shown to be more potent and also exhibits a slower onset and offset in women . additionally , women perceived more pain and required greater dosages of morphine to achieve the same antinociceptive effect as men .
this may be explained by the higher mu - opioid receptor binding in various cortical and subcortical brain regions exhibited in women than in men . according to a 2009 comprehensive review on sex - specific influences on pain
, women appear to be not only more sensitive to pain but also more vulnerable to chronic , widespread , and postprocedural pain conditions . designing and tailoring treatment plans for pain may certainly need to take sex into account .
sex differences in pharmacokinetics of self administered drugs and in drug dependence have also been explored .
biologically , it is believed that sex and gonadal hormones underlie many of the differences seen in drug sensitivity , addictive behavior , and susceptibility to drug abuse . in general , women appear to be more vulnerable to the rewarding and dependent properties of cannabinoids , alcohol , opioids , and cocaine .
many animal models of gender influences on substance abuse have confirmed clinical findings . with an ever - growing population using self - administered drugs and
the pressing need to effectively address and treat substance abuse , larger clinical studies focusing on this topic must be carried out .
for cortisol and first - generation antihistamines , there appears to be significant sex differences in pharmacodynamics . because women are more sensitive to cortisol suppression , they may also be more sensitive to the effects on basophils and helper t lymphocytes [ 9698 ] .
this is interesting because of the balance in sex differences in both pharmacokinetics and pharmacodynamics , suggesting that men and women should receive the same dose and treatment schedule .
a recent epidemiological study showed that women being treated for allergic diseases display lowered levels of eosinophils and ige than men .
additionally , there appear to be a lower expression of erk / mapk signaling genes , leukocyte extravasation , antigen presentation , and chemokine signaling in women than in men .
digoxin therapy has been shown to differ by sex and was associated with an increase in all - cause death among women .
there are numerous examples supporting the contention that female sex hormones impact drug - metabolizing pathways . for example
, drug - induced long qt syndrome has a higher rate of incidence in females , particularly during the ovulatory phase of the menstrual cycle compared to the luteal phase .
it has been established that there exists a basal sex hormonal regulatory impact on cardiac potassium channels and that in drug - induced qt prolongation , drug - hormone interactions seen at particular doses cause a blockade in these channels [ 101103 ] .
we now know that opioid receptor density and dopaminergic function is influenced by female hormones , leading to a higher rate of adrs in women under anesthesia , such as difficulties in respiration and increased chronic pain .
moreover , sex hormones have also been implicated in functional altering of gaba receptors , the target of anesthetic drugs .
estrogen has been shown to bind and modulate membrane ion channels and receptors , such as cardiac atp - k+ cardiac channels and opioid receptors .
the estrogen receptor is a cytosolic target which serves to trigger downstream kinase activation .
nuclear targets include hormone receptors such as er , which directly modulates cyp1b1 expression .
a recent review on sex differences in pharmacokinetics of antidepressants highlights possible hormone - drug competition for hepatic metabolic enzymes .
since estrogen is a substrate for cyp3a4 and cyp1a2 , antidepressant metabolism may be significantly impacted during the late luteal phase of the menstrual cycle or with estrogen replacement therapy . increased levels of estrogen and progesterone alter hepatic enzyme activity , which can increase drug accumulation or decrease elimination of some drugs .
regulation of immunity and interactions between the hypothalamic - pituitary - adrenal and hypothalamic - pituitary - gonadal axes contribute to the 2- to 10-fold incidence and severity of autoimmune / inflammatory diseases in females compared to males .
metabolic changes can also depend on hormone levels that change during the menstrual cycle , with use of oral contraceptives , throughout pregnancy , or during menopause .
an increase in oxidative stress in females has been described during intensive physical exercise , particularly in postmenopausal women .
moreover , sex hormone levels throughout the menstrual cycle are associated with the activation of specific hepatic enzymes and the rate of clearance of certain drugs .
caffeine and theophylline clearance , for example , is higher during the early follicular phase and prolonged during the mid - luteal phase .
although sex hormones are thought to play a dominant role in modulating sex - based differences in pharmacokinetics , studies examining this have yielded conflicting results .
midazolam clearance ( reflecting cyp3a4 metabolic activity ) failed to show fluctuations during the menstrual cycle .
similarly , studies of eletriptan ( to treat migraines ) demonstrated no sex - related or menstrual cycle - related differences .
there are conflicting data that exist on pharmacokinetic changes in women relating to menopausal status . to examine menopause - related alterations in intestinal or hepatic cyp3a4 activity , several studies compared the pharmacokinetics of midazolam , erythromycin , and prednisolone clearance in pre- and postmenopausal women and found no significant differences in drug metabolism according to menopausal status .
data acquired on sex differences in absorption , distribution , metabolism and elimination allow exploration of sex differences in disposition and response to chemicals and drugs .
results from clinical trials focusing on hiv - infected female subjects have suggested that there are clinically relevant sex - related differences in the efficacy and safety of drug treatment ( table 4 ) .
it is , therefore , essential to understand those sex differences in drug disposition and response , as they may affect drug safety and effectiveness . to minimize therapeutic adverse events , clinicians and
the pharmaceutical industry must establish clear therapeutic goals for the drugs of choice prior to treatment of women .
it must be determined if the treatment should be assessed by clinical signs and symptoms or by laboratory test results whether drug toxicity will be evaluated by clinical or laboratory assessment , and what determines the appropriate duration of treatment .
furthermore , clinicians should be aware of and understand the principles of clinical pharmacology and absorption , disposition , metabolism , and elimination as they apply to the drug of choice .
in particular , the prescribing physician should understand the relationship between drug dose , drug concentration and desired biological effect at the action site , the mechanism of action of the drug , the impact of the chosen drug on the patient 's signs , symptoms of adverse effects , and laboratory testing .
in general , data on sex differences are mostly obtained by post hoc analysis ; therefore , the conclusions that can be drawn are limited . for a better understanding of the basic mechanisms of sex differences ,
future large - scale prospective studies should be designed with a primary focus on this topic .
although we have been able to articulate many of the sex differences in drug absorption , metabolism , and elimination , it is still necessary to identify the specific adrs these differences can lead to as well as the mechanisms behind differences seen in pharmacokinetics and pharmacodynamics between the sexes .
in particular , the potential for competitive hormone - drug interactions could provide us with more detailed mechanisms behind the pharmacokinetic differences seen between sexes .
further genetic studies in the context of drug toxicity and adrs would contribute to our understanding of gender - specific pharmacokinetics .
more specific data will help to determine the extent to which these differences will have implications for clinical management .
Output:
| physiological , hormonal , and genetic differences between males and females affect the prevalence , incidence , and severity of diseases and responses to therapy .
understanding these differences is important for designing safe and effective treatments .
this paper summarizes sex differences that impact drug disposition and includes a general comparison of clinical pharmacology as it applies to men and women . |
PubmedSumm118540 | ***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 total of 15 children in the age group of 7 - 9 years participated in the study .
all the children and their parents were informed before sealing and they gave their consent . at the baseline , status of occlusal surface
was evaluated under standardized conditions by a trained examiner using a flat mirror and a blunt explorer probe .
first permanent molars with deep pit and fissures and which were fully erupted into the oral cavity were included .
previously sealed first permanent molars or those with detectable caries or restorations were excluded from the study . only mandibular molars were used in the study . on each patient ,
one side molar was sealed using est and other side molar was sealed using cst .
then the surface was thoroughly rinsed with water and dried with air . using a specially designed bur [ figure 1 ] , ( fissurotomy nf bur , s.s.white corp . ) , the deep pit and fissures on the occlusal surface of the first molars were enlarged slightly with care to keep the preparation in enamel [ figure 2 ] .
dry surface is paramount to successful retention of sealant . to avoid salivary contamination and to provide a dry surface ,
the tooth was isolated with cotton rolls and saliva was ejected with a high volume suction device .
the enamel surface was acid etched with 37% phosphoric acid gel [ figure 3 ] ( ss white corp . ) for 20 s. the tooth surface was then washed with water for 40 s and dried for 15 s using oil free compressed air .
helioseal sealant ( ivoclar vivadent ) was applied to the prepared tooth surface with a fine haired brush . to avoid incorporation of air bubbles ,
it was light cured for 40 s. occlusion was checked for high points and adjusted [ figure 4 ] .
enameloplasty sealant technique on 36 the same procedure ( without enlarging the pit and fissure with bur ) was done on the other side first permanent molar [ figures 5 ] and . conventional sealant technique on 46 all standard preventive measures
all children were recalled and examined after 6 months , 12 months and 18 months .
then the surface was thoroughly rinsed with water and dried with air . using a specially designed bur [ figure 1 ] , ( fissurotomy nf bur , s.s.white corp . ) , the deep pit and fissures on the occlusal surface of the first molars were enlarged slightly with care to keep the preparation in enamel [ figure 2 ] .
dry surface is paramount to successful retention of sealant . to avoid salivary contamination and to provide a dry surface ,
the tooth was isolated with cotton rolls and saliva was ejected with a high volume suction device .
the enamel surface was acid etched with 37% phosphoric acid gel [ figure 3 ] ( ss white corp . ) for 20 s. the tooth surface was then washed with water for 40 s and dried for 15 s using oil free compressed air .
helioseal sealant ( ivoclar vivadent ) was applied to the prepared tooth surface with a fine haired brush . to avoid incorporation of air bubbles , the sealant was gently teased through the fissure .
it was light cured for 40 s. occlusion was checked for high points and adjusted [ figure 4 ] .
the same procedure ( without enlarging the pit and fissure with bur ) was done on the other side first permanent molar [ figures 5 ] and . conventional sealant technique on 46 all standard preventive measures
all children were recalled and examined after 6 months , 12 months and 18 months .
evaluation was carried out as follows : a tooth was decided to be registered as sound without caries or carious ( including cavitated , non - cavitated , restored . )
sealants were decided to be recorded as present or lost ( including partial or totally ) . at the end of 18 months , no teeth were found carious in est and cst group . at the end of 6 , 12 , 18 months there was no loss of sealants in both est and cst group .
occlusal surface decay is seen commonly because of inaccessibility of the area to routine hygiene measures .
so american dental association ( ada ) in 1983 recommended that pit and fissure sealant should be used as a part of total caries preventive program that also includes among others optimum fluoride treatment and restricted frequency of refined carbohydrate intake . in case of a deep pit and fissures
if we follow est , if carious lesion is detected on enlarging the fissure , we can modify our treatment plan accordingly .
the tapered shape and small size of fissurotomy bur are designed specifically to enlarge deep pit and fissures .
this has the advantage of decreased patient discomfort and there is no need of local anesthetic .
traditional cutting burs remove far more enamel at any depth of cut and are more invasive . following enameloplasty ,
tooth surface should be acid etched to create microporosities for the sealant to enter and form resin tags .
helioseal f ( ivoclar vivadent ) is a light curing , white shaded , fissure sealant featuring fluoride release .
its monomer matrix consists of bisphenol a glycidyl methacrylate ( bisgma ) , urethane di methacrylate , tetra ethylene glycol di methacrylate ( tegdma ) .
so we can do est in deep i - type and k - type pit and fissures .
however , we should conduct more studies on a larger sample size with longer recall period before reaching a definitive conclusion .
Output:
| aim : the aim of the study is to compare two different methods : enameloplasty sealant technique ( est ) and conventional sealant technique ( cst ) in terms of the presence or loss of sealant and the presence or absence of caries after 6 , 12 , and 18 months.materials and methods : a total of 15 children in the age group of 7 - 9 years participated in the study . after taking consent , status of occlusal surface was evaluated under standardized conditions .
only mandibular molars were used in the study . on each patient ,
one side molar was sealed using est and other side molar was sealed using cst .
all children were recalled and examined after 6 months , 12 months and 18 months.results:at the end of 18 months , no teeth were found carious in est and cst group . at the end of 6 , 12 , 18 months there was no loss of sealants in both est and cst group .
there was no difference between est and cst success rates.conclusion:in our study both est sand cst showed good results .
so we can do est in deep i - type and k - type pit and fissures . |
PubmedSumm118541 | ***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: spectrum disorders include localized scleroderma ( ls ) variants and systemic sclerosis ( ssc ) the latter of which is further divided into diffuse cutaneous ( dc)ssc , limited cutaneous ( lc ) ssc , and ssc sine scleroderma .
the forms of ssc are differentiated primarily on the basis of the pattern of skin involvement , autoantibody association , and characteristics of internal organ involvement .
the main clinical differences between ls and ssc are the absence in the former of sclerodactyly , raynaud 's phenomenon , absence of widespread vasculopathy , nail fold capillary changes , and internal organ fibrosis .
five subtypes of ls or morphea are recognized by peterson et al . and include plaque , generalized , bullous , linear , and deep .
mixed variant morphea which includes a combination of two or more subtypes in the same patient .
immunologic tests show that although autoantibodies are highly prevalent in both ls and ssc , they differ in prevalence and antigen specificity in these major divisions of scleroderma spectrum disease .
for example , antinuclear antibodies are present in only 20% to 80% of patients with ls and in > 90% of patients with ssc [ 4 , 5 ] .
moreover , anti - topoisomerase ii alpha antibody is present in up to 85% of patients with ls and in 14% of patients with ssc . in this present study
, we show profound differences in the immune responses of patients with dcssc compared to patients with ls .
peripheral blood mononuclear cells ( pbmc ) from patients with dcssc , but not patients with ls , cultured in vitro with soluble ci or 1(i ) generate cytokine / growth factor - rich supernatants .
these supernatants induce a reduction in matrix metalloproteinase ( mmp)-1 production , when added to cultures of ssc dermal fibroblasts , but not to normal donor dermal fibroblast lines .
we hypothesize that t cells from patients with dcssc are activated by ci to produce cytokines that act on fibroblasts to reduce synthesis of mmp-1 .
a decrease in the skin fibroblast 's ability to synthesize mmp-1 could shift the balance of collagen metabolism toward collagen excess resulting in fibrotic lesions . in these studies ,
pbmc from patients with dcssc or ls were cultured with or without ci , and the harvested supernatants were added to cultures of ssc fibroblasts to evaluate the effects on mmp-1 production .
we found that long - term exposure to supernatants that had been generated by culturing ci - stimulated pbmc from adult or pediatric patients with dcssc caused a significant decrease in the production of mmp-1 by ssc fibroblasts .
in contrast , long - term exposure of ssc fibroblasts to supernatants from ci - stimulated pbmc from patients with ls did not induce suppression of mmp-1 production by tumor necrosis factor alpha ( tnf-)-stimulated dcssc fibroblasts .
these data suggest that therapies aimed at reducing the suppression of mmp may decrease collagen accumulation in skin and vital organs of patients with ssc , preventing the development of chronic fibrosis .
moreover , the results of this study may help elucidate the pathogenesis of impaired mmp-1 production by fibroblasts in ssc .
to determine whether cytokine / growth factors present in supernatants from culture of ci - stimulated ssc pbmc would effect a change in mmp-1 production by dermal fibroblasts , we obtained pbmc from ten adult patients with dcssc and stimulated them in vitro with ci or medium alone for 6 days .
the harvested supernatants were pooled and added at 30% v / v to a culture of dermal fibroblasts from normal donors and from involved skin of patients with dcssc for 14 days as described in the patients and methods section , and mmp-1 production in response to tnf- stimulation was assessed . as shown in table 1 ,
culture of dcssc fibroblasts for 14 days with supernatants from ci - stimulated adult dcssc pbmc resulted in significant reduction in mmp-1 protein produced in response to tnf- stimulation .
compared to normal fibroblasts , production of mmp-1 was also reduced in the dcssc fibroblast cultures not stimulated with tnf- but cultured for 14 days with ci - stimulated pbmc from patients with dcssc . in contrast , fibroblasts from normal donors cultured for 2 weeks with the same pooled supernatants from ci - stimulated dcssc pbmc and stimulated with tnf- showed an actual enhancement of mmp-1 ( table 1).table 1effect of supernatant from type i collagen - stimulated pbmc ( from patients with dcssc ) on mmp-1 production by dcssc and normal fibroblastsadditions for 48 hdcssc fibroblast linesmean senormal donor fibroblast linesmean sep valuefibroblasts cultured with medium004008168518221326036858pbs418693832 14515602927 12nstnf- ( 5 ng / ml)100100100100100100100100100100fibroblasts cultured with 30% v / v ci - stimulated dcssc pbmc supernatantpbs215272317 512569922277 220.036tnf- ( 5 ng / ml)5460643453 7578413210106327 1050.041mmp1 was measured by western blot using pooled supernatants of ci - stimulated pbmc from ten dcssc patients . the pooled pbmc supernatants were added at 30% v / v to cultures of normal and dsssc fibroblasts for 14 days as described in the patients and methods section .
normal and dcssc fibroblasts cultured with pooled ( n = 10 ) ci - stimulated dcssc pbmc supernatants ( bottom panel ) were compared to the same cells cultured with the medium alone ( top panel ) . the mmp-1 response to tnf- in the medium alone was arbitrarily set at 100%mmp-1 calculated as a percent of that seen with tnf- stimulation in fibroblasts cultured with the medium alonemmp-1 produced by ssc fibroblasts compared to normal dermal fibroblast cell lines following treatment with pbsmmp-1 produced by ssc fibroblasts compared to normal dermal fibroblast cell lines following treatment with tnf- effect of supernatant from type i collagen - stimulated pbmc ( from patients with dcssc ) on mmp-1 production by dcssc and normal fibroblasts mmp1 was measured by western blot using pooled supernatants of ci - stimulated pbmc from ten dcssc patients .
the pooled pbmc supernatants were added at 30% v / v to cultures of normal and dsssc fibroblasts for 14 days as described in the patients and methods section .
normal and dcssc fibroblasts cultured with pooled ( n = 10 ) ci - stimulated dcssc pbmc supernatants ( bottom panel ) were compared to the same cells cultured with the medium alone ( top panel ) . the mmp-1 response to tnf- in the medium alone was arbitrarily set at 100% mmp-1 calculated as a percent of that seen with tnf- stimulation in fibroblasts cultured with the medium alone mmp-1 produced by ssc fibroblasts compared to normal dermal fibroblast cell lines following treatment with pbs mmp-1 produced by ssc fibroblasts compared to normal dermal fibroblast cell lines following treatment with tnf- since the spectrum of scleroderma can range from very minimal involvement ( ls ) to extensive fibrosis ( dcssc ) , it was of interest to compare the effect of supernatants from the culture of pbmc from patients with ls to supernatants from the culture of pbmc from patients with dcssc on mmp-1 production by ssc fibroblasts . in order to determine the variability among individual patients , we cultured pbmc with and without ci for 6 days and studied the effect of each individual donor pbmc supernatant on a single dcssc dermal fibroblast line ( ssc008 ) that became responsive ( after subpassage 4 ) to mmp-1 upregulation by tnf-. pbmc from four dcssc patients ( one juvenile and three adults ) and five juvenile patients with ls were cultured with or without native ci for 6 days .
the harvested supernatants from the culture of pbmc from each of these patients were added at 30% v / v to cultures of dermal fibroblasts ( ssc008 ) for 21 days with fresh media and pbmc supernatant added every 3 days .
after 21 days , tnf- was added to the cultures of ssc008 fibroblasts , to stimulate production of mmp-1 . as illustrated in fig . 1 , the ssc 008 fibroblast line produced significantly less mmp-1 after being cultured for 21 days with ci - stimulated supernatants from dcssc patients compared to fibroblasts cultured with ci - stimulated supernatants from ls patients.fig . 1the effect of juvenile and adult dcssc and ls pbmc supernatants on mmp-1 production by ssc fibroblasts .
pbmc isolated from patients with dcssc ( n = 4 ; solid bars ) and ls ( n = 5 ; hatched bars ) were stimulated with and without ci for 6 days , and the individual supernatants were tested for their effect on the mmp-1 production by ssc fibroblasts .
dermal fibroblasts from a patient with ssc ( ssc008 ) were cultured for 21 days each with pbmc supernatants with ( a ) and without ci ( b ) after stimulation with tnf- for 24 h. the amount of mmp-1 accumulating in the culture supernatants is shown measured by western blot calculated as a percentage of mmp-1 from fibroblasts that were not co - cultured with pbmc supernatant , but were stimulated with tnf- ( control ) .
results are expressed as mean sem for mmp-1 content of the medium from the fibroblast cultures the effect of juvenile and adult dcssc and ls pbmc supernatants on mmp-1 production by ssc fibroblasts .
pbmc isolated from patients with dcssc ( n = 4 ; solid bars ) and ls ( n = 5 ; hatched bars ) were stimulated with and without ci for 6 days , and the individual supernatants were tested for their effect on the mmp-1 production by ssc fibroblasts .
dermal fibroblasts from a patient with ssc ( ssc008 ) were cultured for 21 days each with pbmc supernatants with ( a ) and without ci ( b ) after stimulation with tnf- for 24 h. the amount of mmp-1 accumulating in the culture supernatants is shown measured by western blot calculated as a percentage of mmp-1 from fibroblasts that were not co - cultured with pbmc supernatant , but were stimulated with tnf- ( control ) .
results are expressed as mean sem for mmp-1 content of the medium from the fibroblast cultures the inhibition of mmp-1 described above is very likely induced by cytokines or growth factors secreted by peripheral blood cells . in order to determine the cytokine profile of supernatants from culture of ci - stimulated dcssc pbmc , we pooled ci - stimulated pbmc culture supernatants from ten adult patients with dcssc and incubated these supernatants on raybioplex membrane arrays to test for presence of individual cytokines / growth factors .
the pooled supernatants were tested on three different cytokine or growth factor arrays and were found to be abundant in platelet - derived growth factor ( pdgf)-aa , pdgf - bb , pdgf - ab , epidermal growth factor ( egf ) , insulin - like growth factor binding protein 2 ( igfbp-2 ) , hepatocyte growth factor ( hgf ) , macrophage colony stimulating factor receptor ( mcsfr ) , and interleukin-13 ( il-13 ) when compared with the culture medium alone ( fig . 2 ) .
we further evaluated the cytokine profile of supernatants from ci - stimulated pbmc from one pediatric dcssc patient ( fig . 3 , p003 ) and two pediatric ls patients ( fig . 3 , p001 , p002 ) .
we cultured pbmc with ci for 6 days from these patients , harvested the supernatant , and incubated these supernatants on raybioplex membrane arrays as per manufacturer 's instructions .
as shown in fig . 3 , the cytokine profile of supernatants from ci - stimulated pbmc from the juvenile dcssc patient revealed an increase in pdgf - aa , pdgf - bb , il-13 , tnf- , and egf when compared to the supernatant from ci - stimulated pbmc from patients with ls .
although the numbers are small , the pbmc from the dcssc patient clearly secreted greater amounts of pdgf - aa , pdgf - bb , il-13 , tnf- , and egf when compared to supernatants collected from the culture of ci - stimulated pbmc from ls patients .
these results compare favorably to the cytokine profile in supernatants from the culture of ci - stimulated pbmc from adult patients with dcssc ( figs . 2 and 3).fig .
2raybio human cytokine antibody array of pooled culture supernatants from pbmc from ten adult patients with dcssc stimulated for 6 days with 10 g / ml native bovine ci .
after 6 days of incubation of pbmc plus 10 g / ml ci , culture supernatants were pooled and analyzed , along with the culture medium alone ( complete dmem ) as a control , in a raybio cytokine and growth factor antibody array assay .
the assays used contained antibodies to 120 cytokines , and receptors and 41 growth factors impregnated in small circles on membranes along with positive and negative controls .
pbmc from one patient with dcssc ( p003 ) and two patients with ls ( p002 and p001 ) were cultured individually for 6 days with ci , and the supernatants were collected and analyzed to be tested using raybio cytokine and growth factor antibody array assay .
the patient with dcssc had increased pdgf - aa , pdgf - bb , il-13 , tnf- , and egf as compared to pbmc from ls patients ( p002 and p001 ) .
comparisons are made to the positive endogenous control provided by the manufacturer raybio human cytokine antibody array of pooled culture supernatants from pbmc from ten adult patients with dcssc stimulated for 6 days with 10 g / ml native bovine ci .
after 6 days of incubation of pbmc plus 10 g / ml ci , culture supernatants were pooled and analyzed , along with the culture medium alone ( complete dmem ) as a control , in a raybio cytokine and growth factor antibody array assay .
the assays used contained antibodies to 120 cytokines , and receptors and 41 growth factors impregnated in small circles on membranes along with positive and negative controls .
unstimulated pbmc produce small amounts of cytokines spontaneously thereby preventing their use as controls cytokine profile supernatants from juvenile dcssc and ls pbmc stimulated with ci .
pbmc from one patient with dcssc ( p003 ) and two patients with ls ( p002 and p001 ) were cultured individually for 6 days with ci , and the supernatants were collected and analyzed to be tested using raybio cytokine and growth factor antibody array assay .
the patient with dcssc had increased pdgf - aa , pdgf - bb , il-13 , tnf- , and egf as compared to pbmc from ls patients ( p002 and p001 ) .
comparisons are made to the positive endogenous control provided by the manufacturer in a separate experiment , pdgf - aa , pdgf - bb , il-13 , and egf were added for 14 days individually at varying doses to cultures of ssc fibroblasts to assess their effect on mmp-1 production induced by tnf-. although multiple concentrations were tested , the data shown in fig .
long - term exposure of ssc 008 fibroblasts to pdgf - bb and il-13 significantly inhibited mmp-1 production when the fibroblasts were subsequently stimulated with tnf-. these data suggest that each of these cytokines may be responsible for the inhibitory effect on fibroblast mmp-1 production induced by supernatants from ci - stimulated pbmc from patients with dcssc .
in contrast , long - term exposure of ssc 008 fibroblasts to pdgf - aa and egf resulted in enhanced tnf- stimulation of mmp-1 production ( fig .
although egf is known to upregulate tgf- via pi 3-kinase / akt signaling pathway in dermal fibroblasts , the upregulation of tgf- by egf in the present experiments would not impact mmp-1 production , as activation of latent tgf- does not occur spontaneously in culture , and active tgf- suppresses mmp-1 production by fibroblasts .fig .
4ssc dermal fibroblasts cultured for 14 days with pro - inflammatory cytokines followed by stimulation with tnf- for 24 h. inhibition of constitutively produced mmp-1 as well as tnf--stimulated mmp-1 production was observed when ssc 008 fibroblasts were cultured with pdgf - bb and il-13 when compared to ssc fibroblasts cultured with the medium alone for 14 days
tnf-. mmp-1 was increased when fibroblasts were cultured for 14 days with pdgf - aa or egf and then stimulated 24 h with tnf-. * p < 0.05 when compared to supernatants from fibroblasts cultured with the complete medium alone ( first bar on the left ) .
p < 0.05 when compared to supernatants from fibroblasts cultured with the complete medium plus tnf ( second bar from the left ) ssc dermal fibroblasts cultured for 14 days with pro - inflammatory cytokines followed by stimulation with tnf- for 24 h. inhibition of constitutively produced mmp-1 as well as tnf--stimulated mmp-1 production was observed when ssc 008 fibroblasts were cultured with pdgf - bb and il-13 when compared to ssc fibroblasts cultured with the medium alone for 14 days
tnf-. mmp-1 was increased when fibroblasts were cultured for 14 days with pdgf - aa or egf and then stimulated 24 h with tnf-. * p < 0.05 when compared to supernatants from fibroblasts cultured with the complete medium alone ( first bar on the left ) .
p < 0.05 when compared to supernatants from fibroblasts cultured with the complete medium plus tnf ( second bar from the left )
our results show that soluble mediators from pbmc from patients with dcssc inhibit collagenase expression in cultured ssc dermal fibroblasts .
supernatants of soluble ci - stimulated pbmc from dcssc patients exerted profound suppression of production of mmp-1 by ssc fibroblasts .
pooled supernatants from a group of adult dcssc patients and individual supernatants from juvenile and adult dcssc patients significantly reduced the expression of mmp-1 by ssc fibroblasts .
suppression of constitutive production as well as tnf--stimulated production of mmp-1 by ssc fibroblasts was observed when these fibroblasts were chronically exposed to supernatants from ci - stimulated dcssc pbmc .
in contrast , prolonged culture of ssc fibroblasts with supernatants of ci - stimulated pbmc from patients with ls did not induce the mmp-1 suppressive phenotype in ssc fibroblasts .
tnf- inhibits collagen synthesis and increases synthesis of mmp-1 when added to cultures of normal human fibroblasts .
unstimulated pbmc from patients with lc- or dcssc in culture produce greater amounts of tnf- than pbmc cultured from healthy volunteers , and the most tnf- was produced by unstimulated pbmc from patients with early ( < 3-year duration ) dcssc .
although tnf- is abundantly produced in ssc patients , our data in this report suggest that cytokines produced by ci - activated pbmc from patients with dcssc may render fibroblasts insensitive to tnf- upregulation of mmp-1 and thereby contribute to dermal fibrosis .
the pathogenesis of fibrosis in ls and ssc is still unresolved , but a role for autoimmunity in effecting fibrosis is suggested by early tissue infiltrates of mononuclear cells that have the capability of producing an array of cytokines and growth factors that are known to mediate fibrogenesis .
the histologic features of the lesional skin of patients with ls and ssc are largely indistinguishable and are characterized in the early stages by perivascular infiltration of predominantly mature lymphocytes , t lymphoblasts , immature plasma cells , mature plasma cells , fibroblasts , fibrocytes , fibroblast - like cells , macrophages , undifferentiated mesenchymal cells , and monocytes .
analyzed the infiltrates in the lesional skin of patients with ssc using monoclonal antibodies to cell surface markers and found the mononuclear cell ( mnc ) infiltrates were composed predominately of activated cd4 and cd8 t cells in a ratio of 2.4 to 1 , and few b cells and monocytes were observed .
importantly , in this larger cohort study of 115 patients with ssc , significant correlations were observed between the degree of mnc infiltration and both the degree and progression of skin thickening .
separate studies have shown that when pbmc from patients with lc or dcssc ( in contrast to healthy volunteers ) are cultured with soluble ci or constituent 1(i ) or 2(i ) chains , there is increased production of cytokines including il-2 , il-6 , ifn- , il-10 ; increased production of monocyte chemoattractants , and increased t cell proliferation [ 1318 ] .
in addition , warrington et al . labeled pbmc from patients with lcssc , dcssc , and rheumatoid arthritis and healthy volunteers with carboxyfluorescein diacetate succinimidyl ester ( cfse ) and cultured these cfse - labeled pbmc for 14 days with and without soluble native bovine ci and 1 , two chains [ dimers formed by 1(i ) and 2(i ) ] .
analysis by flow cytometry showed a t cell proliferative response to these ci chains occurring in 32% of ssc patients but only in 3.6% healthy volunteers ( 1 of 19 volunteers ) and in 0% ra patients ( 0 of 9 ) .
the proliferating t cells expressed cd4 , activated ( cd25 ) memory ( cd45 ro ) phenotype .
the t cell lines generated by prolonged culture ( 2030 days culture ) of sorted ci - reactive t cells with ci , irradiated autologous pbmc , and il-2 were analyzed after resting for 10 days and then stimulated for 72 h with plate - bound anti - cd3 and anti cd28 .
these t cell lines then produced abundant th1 cytokines , ifn- , il-2 , tnf- , lower amounts of th2 cytokines ( il-4 , il-6 , and il-10 ) , and abundant chemotactic chemokine il-8 .
while this study does not establish whether the diminished production of mmp-1 that we have observed is due to t cell autoimmunity to ci or due to a costimulatory effect of ci on activated t cells , we favor an antigenic role of ci in triggering production of cytokines . we have previously shown that ci - specific t cell clones can be grown from peripheral blood of ssc patients .
moreover , the fact that soluble ci was used rather than plate - bound ci in the pbmc culture favors the concept that ci functions as an antigen , which triggers the production of cytokines which cause ssc fibroblasts to assume a phenotype of impaired mmp-1 production .
the pathogenesis of ssc is marked by the overabundance of collagen and skin fibrosis where collagen fibers accumulate in the dermis .
uncontrolled production of collagen and other extracellular matrix proteins produced by fibroblasts contributes to the fibrosis .
although decreases in mmp-1 in fibroblasts from patients with early ssc have been reported , the results have been controversial .
our data support the concept that an important component of the pathogenesis of ssc is the diminished capacity for production of mmp-1 by fibroblasts .
our data are unique in indicating that the reduction of fibroblast mmp-1 is mediated by cytokines derived from pbmc stimulated by ci .
it is possible that ci is functioning as an autoantigen or a co - stimulator of t cells in eliciting these cytokines .
the expression of il-13 and its receptor complex is increased in ssc skin samples , correlating with modified rodnan skin scores ( aliprantis ; acr 2010 ) and with nail fold capillary patterns [ 2325 ] .
our studies demonstrate that pooled supernatants from adult ssc pbmc co - cultured with ci contain significant levels of many profibrotic cytokines compared to controls ( pdgf - aa , pdgf - bb , pdgf - ab , egf , igfbp-2 , hgf , mcsfr , and il-13 ) [ 6 , 2629 ] .
our studies of pediatric patients with ssc have shown that ci induces increased expression of pdgf - aa , pdgf - bb , egf tnf- , and il-13 .
the overlap of cytokines found in juvenile and adult ssc compared to that seen in localized disease may in fact be reflective of severity of skin and organ involvement between these two diseases . moreover ,
the functional importance of these cytokines is demonstrated by our results that prolonged incubation of pdgf - bb and il-13 significantly inhibited tnf- , induced mmp-1 production by ssc dermal fibroblasts , and highlight the importance of these cytokines in dcssc .
together , the interaction of pbmc with ci and the elicited cytokines stimulates a pathway inherent in ssc fibroblasts that inhibits mmp-1 expression and contributes to the fibrosis in this disease . in the present study ,
we have shown that cytokines produced by ci - stimulated pbmc from patients with dcssc suppress mmp-1 production .
these data suggest a role for activation of lymphocytes and/or monocytes in a subgroup of patients with dcssc and suggest a cytokine - mediated pathway involved in the pathogenesis of the extensive fibrosis seen in these patients .
since we have shown that exposure to oral ci may benefit late - phase dcssc , our new results have important implications for future treatments for ssc .
this study was conducted using protocols approved by the institutional review board of participating institutions .
juvenile patients with dcssc ( ages 16 years or less ) were included in this study who met the pres / acr / eular classification of juvenile systemic sclerosis .
adult patients ( aged 1870 ) met the american college of rheumatology preliminary criteria for diagnosis of ssc .
patients with ls met the classification criteria for morphea or linear scleroderma [ 2 , 32 ] .
homogeneity of ci and 1(i ) was confirmed using sds - page and by cyanogen bromide peptide mapping .
the purified ci was dissolved in cold 0.1 m acetic acid at 4 mg / ml and stored frozen at 70c .
human recombinant tnf- , il-13 , pdgf - aa , pdgf - bb , and egf were purchased from r&d systems ( minneapolis , mn ) .
the antibody to human mmp-1 ( rabbit ) was made to a latent and truncated peptide , expressed in escherichia coli , and purified in the laboratory .
mmp-1 was detected by elisa ( r&d systems ) and cytokines by raybio human cytokine antibody arrays ( raybiotech , inc . ) .
blood samples were collected in egta - containing glass tubes and the pbmc isolated over histopaque ( sigma chemical co. , st .
the pbmc were plated at 2 10 cells per well , cultured in dulbeccos 's high - glucose modified eagle medium ( dmem ) containing 10% fetal bovine serum ( fbs ) , penicillin ( 100 units / ml ) , streptomycin ( 100 ug / ml ) , and 100 glutamax ( invitrogen corp . )
cells were cultured at 37c with 5% co2 for 6 days with and without purified bovine collagen 1(i ) ( 25 g / ml ) after which the supernatants were collected , pooled , and stored in 80c until use . in one experiment ,
pbmc from ten adult patients with dcssc were collected and cultured for 6 days with native bovine ci ( 10 g / ml ) , prior to pooling and storing at 70c .
four normal and four ssc fibroblast lines ( two from biopsies of lesional and two from non - lesional skin of dsssc patients ) were grown for 23 weeks in eagle minimum essential medium , with 9% fetal calf serum ( fcs ) , 100 /ml penicillin , 100 g / ml streptomycin , and amphotericin b ( 1 g / ml ) hereafter referred to as complete medium . thirty percent ( by volume ) of supernatant from a culture of ci - stimulated dcssc pbmc ( from a pool of ten adult patients with dcssc , sterile filtered and aliquoted into individual vials ) or 30% medium ( by volume ) alone or plus native ci ( 10 g / ml ) of high - glucose dmem containing the same lot of fbs used in the ssc pbmc cultures was added to each plate containing each cell line .
the medium in the cultures was changed every 7 days , and a new ssc pbmc culture supernatant or medium control ( each 30% by volume ) was added at each refeeding .
cells were then trypsinized and passed into new 100-mm tissue culture plates and cultured for 3 days in the complete medium .
fibroblasts were then trypsinized and transferred to costar tissue culture plates at a density of 10 cells / well and grown for 3 days in the complete medium .
the medium was then changed to the complete medium containing 5% fbs for 24 h , changed again to a fresh complete medium with 5% fcs containing either 5 ng / ml human recombinant tnf- ( r and d systems , minneapolis , mn ) in pbs containing 0.1% bovine serum albumin ( bsa , sigma ) or pbs with 0.1% bsa as a control .
culture supernatants were assayed by elisa or western blot analysis to quantitate mmp-1 protein as previously described .
fibroblasts were grown from dermal biopsies from similar locations on the forearm of normal volunteers or patients with dcssc .
ssc fibroblast cell line 008 ( ssc 008 ) passages 515 , that had regained the ability to synthesize mmp-1 upon stimulation with tnf- , was also used for comparing the effect of the supernatant from the culture of pbmc from different donors .
this ssc fibroblast line , grown from the fibrotic skin on the volar forearm of a patient with dcssc , was resistant to tnf- stimulation of mmp-1 synthesis during the first few subpassages but became more responsive to tnf- after passage .
the ssc 008 fibroblasts were plated at 5 10 cells / well in costar 24 well and grown in high - glucose dmem containing 10% fcs .
supernatants from 6-day pbmc cultures were removed from 80c storage , allowed to thaw at 37c , and then centrifuged at 190 relative centrifugal force for 10 min .
additions to fibroblast cultures consisted of the following : collagen alone in complete dmem ( complete dmem incubated 6 days with 12.5 l ( 12.5 g ) of l(i ) without pbmc in wells ) , pbmc supernatant ( pbmc ; dmem incubated 6 days with pbmc from scleroderma patients ) , and collagen supernatant ( + ci / pbmc ; dmem incubated for 6 days with pbmc and 12.5 l of 12.5 g 1(i ) ) .
the pbmc supernatants or complete medium was added at 30% v / v to triplicate well cultures of ssc 08 fibroblasts .
the medium was changed every 3 days for a total of 21 days , then dmem supplemented with 5% fbs was placed on the fibroblasts for 24 h prior to adding tnf- 5 ng / ml for an additional 24 h. fibroblast cultures were then collected and stored at 4c until analysis by western blot or elisa to quantitate mmp-1 level .
fibroblasts were harvested for cell number quantification using cyquant ( invitrogen , eugene , or ) .
fibroblast culture supernatants were analyzed for mmp-1 protein by western blot analysis or by elisa .
supernatants were resolved on 9% sds - page and electrotransferred to a pvdf membrane , blocked in 5% powdered milk in tbs ( 1 m tris , ph 7.4 ; 4 m nacl ; deionized water ) for 1 h , then soaked in primary mmp-1 antibody . the membrane was washed and incubated with anti - mmp-1 antibody , and then , alkaline phosphatase - conjugated anti - rabbit igg was used to visualize immunoreactive bands with ecf substrate .
densities were normalized to cell proliferation values ( number of cells ) and calculated as a percent of the tnf- control value ( storm 860 molecular dynamics , sunnyvale , ca , and typhoon ge healthcare biosciences ab , sweden ) and analyzed using imagequant tl 7.0 ( ge healthcare , sweden ) . in some experiments , human total mmp-1 duoset ( r&d )
cytokine analysis was performed on 6-day complete dmem and + ci / pbmc pooled supernatants obtained from 6-day culture of pbmc from ten dcssc patients cultured with 10 g / ml native ci using raybio human cytokine antibody arrays vi , 6.1 , and vi , 7.1 ( raybiotech , inc . ) .
further analysis was done on ci - stimulated 6-day pbmc supernatants from two juvenile ls patients and one dsssc juvenile patient . for this analysis ,
membrane arrays were custom made for by the manufacturer for detection of pdgf - aa , pdgf - bb , il-13 , tnf- , egf , mcscr , insulin - like binding protein 2 ( igfbp-2 ) , il-1 , hgf , and il-17 .
these cytokines were selected based on the preliminary cytokine data obtained from pooled supernatants from dcssc patients .
all procedures for this part of the experiment were followed according to the manufacturer 's instructions .
each blot of cytokine array membranes was normalized to irrelevant endogenous controls included on the blot by the manufacturer to allow comparisons between blots and analyzed using typhoon chemiluminescence . to study the effect of long - term exposure of fibroblasts to cytokines / growth factors
, fibroblasts were plated in 100-mm tissue culture plates at 4 10 cells per plate and then cultured with human recombinant pdgf - aa , pdgf - bb , il-13 , and egf for a total of 14 days .
the medium was changed every 72 h with addition of fresh medium containing the specific cytokine / growth factor .
fibroblasts were passed by trysinization and then plated with the complete medium containing 10% fcs in costar 24-well tissue culture plates at 5 10 per well .
these fibroblasts were then grown in the complete medium for 1 week with medium change every 72 h. fibroblasts were then grown in dmem containing 5% fbs for 72 h , followed by 24 h with tnf- stimulation .
anova and fisher 's exact test were used for statistical analysis due to a small sample size .
Output:
| systemic sclerosis ( ssc ) is a chronic fibrosing disease characterized by vasculopathy , autoimmunity , and an accumulation of collagen in tissues .
numerous studies have shown that compared to healthy or diseased controls , the peripheral blood mononuclear cells ( pbmc ) from patients with ssc produce a variety of cytokines or proliferate when cultured with solubilized type i collagen ( ci ) or constituent 1(ii ) and 2(i ) polypeptide chains .
the purpose of this study was to determine whether pbmc isolated from patients with ssc and cultured in vitro with soluble ci elaborated soluble mediators that inhibit the production of collagenase ( i.e. , matrix metalloproteinase , mmp-1 ) by fibroblasts .
supernatants of ci - stimulated pbmc from juvenile and adult diffuse cutaneous ( dc)ssc patients significantly reduced mmp-1 production by ssc dermal fibroblasts , while supernatants of ci - stimulated pbmc from patients with localized scleroderma ( ls ) did not .
ci - stimulated pbmc culture supernatants from patients with dcssc in contrast to patients with ls exhibited increased levels of platelet - derived growth factor ( pdgf)-aa , pdgf - bb , tnf- , il-13 , and egf .
prolonged culture of ssc dermal fibroblasts with recombinant pdgf - bb or il-13 inhibited the induction of mmp-1 in response to subsequent tnf- stimulation .
these data suggest that therapies aimed at reducing these cytokines may decrease collagen accumulation in ssc , preventing the development of chronic fibrosis . |
PubmedSumm118542 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
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the input is a biomedical literature
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the output is the summary of an input biomedical literature in six sentences
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Input: transthyretin ( ttr)related familial amyloid polyneuropathy ( fap ) is an inherited systemic amyloidosis caused by ttr gene mutations , and is characterized by peripheral and autonomic neuropathy in association with the involvement of many visceral organs 1 . as the liver is the main source of circulating ttr , including a variant form of ttr with one amino acid substitution 2 ,
the liver of an fap patient is anatomically and functionally normal apart from the production of variant ttr , and the fap liver has therefore been used as a graft donor in domino liver transplantation ( dlt ) to overcome organ shortages .
dlt was first carried out in 1995 4 , and more than 1000 patients have since undergone dlt using grafts from fap patients 3 .
one of the most serious complications in domino recipients is the development of de novo ttr amyloidosis , ie iatrogenic transmission of amyloidosis 5 .
clinical symptoms associated with de novo ttr amyloidosis usually begin 610 years after the operation 5 , 6 , 7 . to prevent the development of de novo amyloidosis , it is important to gain an understanding of the pathophysiology of initial amyloid formation .
however , the pathomechanism of initial amyloidogenesis in domino recipients remains unclear , as the biochemical characteristics of the amyloid fibril protein have not yet been investigated in preclinicalstage domino recipients .
in addition , so far , it has been nearly impossible to extract amyloid fibril proteins from extremely small amyloid deposits in asymptomatic patients , including domino recipients as well as fap patients , with conventional amyloid extraction methods by tissuehomogenization 8 . in this study , we successfully isolated and biochemically analyzed very tiny amyloid lesions on the gastroduodenal mucosae from two asymptomatic domino recipients using a laser microdissection ( lmd ) system . here , we report the biochemical features of initialstage amyloid lesions , possible seedlesions , of transmitted amyloidosis . in addition , serial changes in biochemical composition of initial amyloid lesions were identified in one recipient , in whom amyloid deposition was first detected only 14 months after dlt .
this is the first demonstration of an initial fap lesion in a human subject in addition to the unexpectedly rapid transmission of amyloidosis in a domino recipient after receiving an fap liver graft .
two dlt recipients were examined ( patient 1 : a 67yearold woman ; patient 2 : a 44yearold man ) .
both received dlt from fap patients with a val30met ttr variant ( patient 1 ) and a val30leu ttr variant ( patient 2 ) , respectively . the clinical picture by dlt of patient 2
dna analysis of the ttr gene 10 confirmed no mutations in either patient , although mass spectrometric analysis of serum ttr 11 showed a mutant ttr peak in addition to the wildtype ttr peak ( data not shown ) .
tacrolimus was used as immunosuppressant therapy in both patients . medical evaluation , including gastroduodenal mucosal biopsy , was carried out almost every year since dlt to monitor the development of de novo amyloidosis .
amyloid deposits were histopathologically evaluated with congo red staining and by immunohistochemistry using antittr antibody 12 . for biochemical analysis , deposited amyloid was extracted using an lmd system ( lmd 7000 ; leica microsystems inc . ,
however , due to the extremely small size of the amyloid lesions , extraction of amyloid was impossible using this lmd system in patient 1 .
we , therefore , isolated the amyloid using an advanced lmd system , which was specially developed for isolation of intracellular inclusions by hachiya and kaneko 13 .
extracted amyloid was solubilized in 50 l of 10 mm tris/1 mm edta/0.002% zwittergent buffer 14 .
microdissected amyloid proteins were digested with trypsin overnight , and the composition ratio of wildtype ( val30 ) and variant ( met30 or leu30 ) ttr in the amyloid was analyzed by liquid chromatography tandem mass spectrometry ( lcms / ms ) ( nano lc dina ; kya technologies co. , tokyo , japan and qexactive ; thermo fisher scientific inc . , waltham , ma ) as reported previously 15 .
the investigation was repeated twice and the mean composition ratio was calculated , except for the sample obtained at 14 months after dlt in patient 1 because the amount of the extracted amyloid was too small .
this study was performed with the approval of the institute review board of shinshu university ( 3088 ) and with written informed consent from both patients .
this domino recipient was a 67yearold japanese woman who had received dlt from a 35yearold female fap patient with val30met ( p.val50met ) at age 65 due to liver cirrhosis with hepatocellular carcinoma .
fourteen months after the operation , she was admitted to our hospital for the first check for amyloidosis .
biopsy of the gastroduodenal mucosa was performed under endoscopic control , and one tiny congo redpositive deposit , showing strong applegreen birefringence under polarized light , was detected on the lamina muscularis mucosa of the duodenum in only one tissue section among five different biopsy samples ( figure 1a c ) . for immunohistochemical analysis using antittr antibody 12 , we prepared 235 consecutive tissue sections from the same paraffinembedded tissue block ; no amyloid deposition was detected and we failed to detect ttrdeposited lesions . after obtaining informed consent , biopsies were taken from an additional five different portions of the duodenal mucosa .
of the five samples , two were fixed in 10% formalin , embedded in paraffin , and cut into sections , while the remaining three were stored at 80c and used to prepare frozen sections .
we prepared 258 consecutive tissue sections from the paraffinembedded tissue block , and no amyloid was detected .
however , we found small amyloid deposits in the duodenal mucosa in 3 of 465 consecutive tissue sections prepared from the three frozen samples ( figure 1d , e ) .
we carried out dual staining with congo red and immunohistochemical staining with antittr antibody 12 on the same tissue sections , and positive staining of the amyloid deposits was observed ( figure 1f ) .
the area positive with antittr antibody was somewhat widely expanded compared to the congo redpositive area .
we isolated amyloid fibril protein using the advanced lmd system from the two tissue sections dualstained with congo red followed by immunostaining with antittr antibody . in lcms / ms analysis of ttr 2234 tryptic peptides , only peptide derived from variant ttr ( met30 )
( f ) dual staining with congo red ( d , e ) followed by immunohistochemistry ( f ) on frozen duodenal mucosa . ( a c ) at lower magnification
, a small congo redpositive spot was seen on the lamina muscularis mucosae ( arrow ) ( a , bar = 100 m ) . at higher magnification ,
the amyloid was clearly positive for congo red ( b ) , showing strong applegreen birefringence under polarized light ( c ) ( b , c , bars = 5 m ) . formalinfixed and paraffinembedded tissue sections .
( d f ) frozen tissue sections were stained with congo red . after confirming the presence of amyloid ( d , e ) , the cover glass was removed in hemode solution ( falma co. , ltd .
after treatment with formic acid for 1 minute , immunohistochemical staining using antittr115124 peptide antibody ( 1:4000 dilution ) 12 was performed using the standard immunoperoxidase method ( vectastain abc kit ; vector laboratories inc . , burlingame , ca ) .
the deposited amyloid was positive for antittr antibody ( f ) ( d f , bars = 50 m ) .
( g ) a small congo redpositive spot was also present on the lamina muscularis mucosae at 24 months after dlt ( arrow , bar = 100 m ) .
serial changes in relative quantification of ttr 2234 tryptic peptide in lcms / ms analysis of amyloid isolated at 14 months ( a ) and 24 months ( b ) after dlt in patient 1 .
the area positive with both congo red and immunohistochemical staining of frozen biopsied samples ( figure 1d f ) was isolated using an advanced lmd system 13 .
selected mass range profiles obtained from the ion chromatograms of lcms / ms analysis are shown ( a , b ) .
the chromatograms were filtered with mass ranges , m / z 683.86683.90 , m / z 699.85699.89 and m / z 707.85707.89 .
these ranges correspond to ttr 2234 wildtype ( gspainvavhvfr , m / z 683.88 ) , variant peptide ( gspainvamhvfr , m / z 699.87 ) and variant peptide oxidized at met30 ( gspainvam(ox)hvfr , m / z 707.87 ) , respectively .
only ttr 2234 peptide peaks derived from variant ttr and oxidized variant ttr were detected at 14 months after dlt , and no clear peak derived from wildtype ttr was seen in the extracted amyloid ( sequence data of both variant and oxidized variant ttr on lcms / ms analysis are not shown ) .
we also investigated synthetic wildtype ttr peptide 2234 by mass spectrometry , and confirmed a peak derived from synthetic peptide at 29.97 minutes ( data not shown ) .
conversely , in amyloid isolated at 24 months after dlt , the mass peak of wildtype ttr became apparent and the composition ratio of wildtype versus variant ttr was 6:94% .
oral administration of tafamidis , a stabilizer of tetrameric ttr structure 16 , was started 20 months after dlt despite the preclinical stage of amyloidosis .
twentyfour months after dlt , she was again admitted to our hospital for the second check for amyloidosis .
duodenal mucosal biopsy was performed and very small amyloid deposits were seen in 5 of 300 consecutive paraffinembedded tissue sections ( figure 1 g ) .
we also prepared 200 consecutive frozen tissue sections , but no amyloid deposits were detected . in lcms / ms analysis of the isolated amyloid from paraffinembedded tissue sections , a small wildtype ttr peak became detectable and the composition ratio of wildtype ttr versus variant ttr was 6:94% ( figure 2b ) .
this recipient was a 45yearold japanese man with adultonset type ii citrullinemia , which developed at the age of 32 .
one month after onset , he received dlt from a 52yearold female fap patient with attr val30leu ( p.val50leu ) 9 .
however , his donor died of rapidly progressive amyloid cardiomyopathy 1 year after the operation due to paradoxical ongoing wildtype ttrderived amyloid deposition 17 .
therefore , the recipient has been carefully checked for the presence of de novo amyloid deposits almost every year , paying special attention to the development of amyloid cardiomyopathy as well as neuropathy .
in addition , he was started on oral intake of diflunisal ( 500 mg a day ) , a stabilizer of ttr structure 18 , 19 , from 4 years after dlt as a preventive step against de novo amyloidosis . to date , he has shown no clinical symptoms , including congestive heart failure or peripheral neuropathy , and no abnormal findings have been found on echocardiography . however , in nerve conduction studies , motor nerve compound muscle action potential of the tibial nerve and sensory nerve action potential of the sural nerve gradually decreased over the last 2 years ( from 9.9 to 1.1 mv , normal value > 6.2 mv ; from 14.7 to 4.4 v , normal value > 5 v , respectively ) , although the nerve conduction velocities were within the normal limits .
the presence of amyloid deposits has been checked almost every year with gastroduodenal mucosal biopsy , and amyloid deposits were first detected on both gastric and duodenal mucosae at 45 years old ( 12 years after dlt ) ( figure 3a c ) .
we investigated the gastroduodenal mucosal biopsy samples obtained at 11 years after dlt again , with preparation of 500 consecutive tissue sections , but no amyloid deposits were seen ( data not shown ) . in lcms
/ ms analysis of the amyloid microdissected from formalinfixed paraffinembedded tissue sections , the composition ratio of wildtype ttr versus variant ttr was 5:95% ( figure 3d ) .
congo redstained duodenal mucosa ( a c ) and relative quantification of ttr 2234 tryptic peptide in lcms / ms analysis of amyloid isolated ( d ) at 12 years after dlt in patient 2 .
( a c ) a small congo redpositive spot was seen on the lamina muscularis mucosae ( arrow ) ( a , bar = 100 m ) . at higher magnification ,
the amyloid was positive for congo red ( b ) , showing strong applegreen birefringence under polarized light ( c ) ( b , c , bars = 10 m ) . formalinfixed and paraffinembedded tissue sections .
deposited amyloid was isolated with an lmd system ( lmd7000 ; leica microsystems inc . , tokyo , japan ) . in lcms
/ ms analysis , the chromatograms were filtered with mass ranges , m / z 683.86683.90 and m / z 690.86690.90 .
m / z 683.88 ) and variant peptide ( gspainvalhvfr , m / z 690.87 ) , respectively .
this domino recipient was a 67yearold japanese woman who had received dlt from a 35yearold female fap patient with val30met ( p.val50met ) at age 65 due to liver cirrhosis with hepatocellular carcinoma .
fourteen months after the operation , she was admitted to our hospital for the first check for amyloidosis .
biopsy of the gastroduodenal mucosa was performed under endoscopic control , and one tiny congo redpositive deposit , showing strong applegreen birefringence under polarized light , was detected on the lamina muscularis mucosa of the duodenum in only one tissue section among five different biopsy samples ( figure 1a c ) . for immunohistochemical analysis using antittr antibody 12 , we prepared 235 consecutive tissue sections from the same paraffinembedded tissue block ; no amyloid deposition was detected and we failed to detect ttrdeposited lesions . after obtaining informed consent , biopsies were taken from an additional five different portions of the duodenal mucosa .
of the five samples , two were fixed in 10% formalin , embedded in paraffin , and cut into sections , while the remaining three were stored at 80c and used to prepare frozen sections .
we prepared 258 consecutive tissue sections from the paraffinembedded tissue block , and no amyloid was detected .
however , we found small amyloid deposits in the duodenal mucosa in 3 of 465 consecutive tissue sections prepared from the three frozen samples ( figure 1d , e ) .
we carried out dual staining with congo red and immunohistochemical staining with antittr antibody 12 on the same tissue sections , and positive staining of the amyloid deposits was observed ( figure 1f ) .
the area positive with antittr antibody was somewhat widely expanded compared to the congo redpositive area .
we isolated amyloid fibril protein using the advanced lmd system from the two tissue sections dualstained with congo red followed by immunostaining with antittr antibody . in lcms / ms analysis of ttr 2234 tryptic peptides , only peptide derived from variant ttr ( met30 )
( f ) dual staining with congo red ( d , e ) followed by immunohistochemistry ( f ) on frozen duodenal mucosa . ( a c ) at lower magnification
, a small congo redpositive spot was seen on the lamina muscularis mucosae ( arrow ) ( a , bar = 100 m ) . at higher magnification ,
the amyloid was clearly positive for congo red ( b ) , showing strong applegreen birefringence under polarized light ( c ) ( b , c , bars = 5 m ) . formalinfixed and paraffinembedded tissue sections .
( d f ) frozen tissue sections were stained with congo red . after confirming the presence of amyloid ( d , e ) , the cover glass was removed in hemode solution ( falma co. , ltd .
after treatment with formic acid for 1 minute , immunohistochemical staining using antittr115124 peptide antibody ( 1:4000 dilution ) 12 was performed using the standard immunoperoxidase method ( vectastain abc kit ; vector laboratories inc . , burlingame , ca ) .
the deposited amyloid was positive for antittr antibody ( f ) ( d f , bars = 50 m ) .
( g ) a small congo redpositive spot was also present on the lamina muscularis mucosae at 24 months after dlt ( arrow , bar = 100 m ) .
serial changes in relative quantification of ttr 2234 tryptic peptide in lcms / ms analysis of amyloid isolated at 14 months ( a ) and 24 months ( b ) after dlt in patient 1 .
the area positive with both congo red and immunohistochemical staining of frozen biopsied samples ( figure 1d f ) was isolated using an advanced lmd system 13 .
selected mass range profiles obtained from the ion chromatograms of lcms / ms analysis are shown ( a , b ) .
the chromatograms were filtered with mass ranges , m / z 683.86683.90 , m / z 699.85699.89 and m / z 707.85707.89 .
these ranges correspond to ttr 2234 wildtype ( gspainvavhvfr , m / z 683.88 ) , variant peptide ( gspainvamhvfr , m / z 699.87 ) and variant peptide oxidized at met30 ( gspainvam(ox)hvfr , m / z 707.87 ) , respectively .
only ttr 2234 peptide peaks derived from variant ttr and oxidized variant ttr were detected at 14 months after dlt , and no clear peak derived from wildtype ttr was seen in the extracted amyloid ( sequence data of both variant and oxidized variant ttr on lcms / ms analysis are not shown ) .
we also investigated synthetic wildtype ttr peptide 2234 by mass spectrometry , and confirmed a peak derived from synthetic peptide at 29.97 minutes ( data not shown ) .
conversely , in amyloid isolated at 24 months after dlt , the mass peak of wildtype ttr became apparent and the composition ratio of wildtype versus variant ttr was 6:94% .
oral administration of tafamidis , a stabilizer of tetrameric ttr structure 16 , was started 20 months after dlt despite the preclinical stage of amyloidosis .
twentyfour months after dlt , she was again admitted to our hospital for the second check for amyloidosis .
duodenal mucosal biopsy was performed and very small amyloid deposits were seen in 5 of 300 consecutive paraffinembedded tissue sections ( figure 1 g ) .
we also prepared 200 consecutive frozen tissue sections , but no amyloid deposits were detected . in lcms / ms analysis of the isolated amyloid from paraffinembedded tissue sections , a small wildtype ttr peak became detectable and the composition ratio of wildtype ttr versus variant ttr was 6:94% ( figure 2b ) .
this recipient was a 45yearold japanese man with adultonset type ii citrullinemia , which developed at the age of 32 .
one month after onset , he received dlt from a 52yearold female fap patient with attr val30leu ( p.val50leu ) 9 .
however , his donor died of rapidly progressive amyloid cardiomyopathy 1 year after the operation due to paradoxical ongoing wildtype ttrderived amyloid deposition 17 .
therefore , the recipient has been carefully checked for the presence of de novo amyloid deposits almost every year , paying special attention to the development of amyloid cardiomyopathy as well as neuropathy .
in addition , he was started on oral intake of diflunisal ( 500 mg a day ) , a stabilizer of ttr structure 18 , 19 , from 4 years after dlt as a preventive step against de novo amyloidosis . to date , he has shown no clinical symptoms , including congestive heart failure or peripheral neuropathy , and no abnormal findings have been found on echocardiography . however , in nerve conduction studies , motor nerve compound muscle action potential of the tibial nerve and sensory nerve action potential of the sural nerve gradually decreased over the last 2 years ( from 9.9 to 1.1 mv , normal value > 6.2 mv ; from 14.7 to 4.4 v , normal value > 5 v , respectively ) , although the nerve conduction velocities were within the normal limits .
the presence of amyloid deposits has been checked almost every year with gastroduodenal mucosal biopsy , and amyloid deposits were first detected on both gastric and duodenal mucosae at 45 years old ( 12 years after dlt ) ( figure 3a c ) .
we investigated the gastroduodenal mucosal biopsy samples obtained at 11 years after dlt again , with preparation of 500 consecutive tissue sections , but no amyloid deposits were seen ( data not shown ) . in lcms
/ ms analysis of the amyloid microdissected from formalinfixed paraffinembedded tissue sections , the composition ratio of wildtype ttr versus variant ttr was 5:95% ( figure 3d ) .
congo redstained duodenal mucosa ( a c ) and relative quantification of ttr 2234 tryptic peptide in lcms / ms analysis of amyloid isolated ( d ) at 12 years after dlt in patient 2 .
( a c ) a small congo redpositive spot was seen on the lamina muscularis mucosae ( arrow ) ( a , bar = 100 m ) . at higher magnification ,
the amyloid was positive for congo red ( b ) , showing strong applegreen birefringence under polarized light ( c ) ( b , c , bars = 10 m ) . formalinfixed and paraffinembedded tissue sections .
deposited amyloid was isolated with an lmd system ( lmd7000 ; leica microsystems inc . , tokyo , japan ) . in lcms
/ ms analysis , the chromatograms were filtered with mass ranges , m / z 683.86683.90 and m / z 690.86690.90 .
m / z 683.88 ) and variant peptide ( gspainvalhvfr , m / z 690.87 ) , respectively .
this domino recipient was a 67yearold japanese woman who had received dlt from a 35yearold female fap patient with val30met ( p.val50met ) at age 65 due to liver cirrhosis with hepatocellular carcinoma .
fourteen months after the operation , she was admitted to our hospital for the first check for amyloidosis .
biopsy of the gastroduodenal mucosa was performed under endoscopic control , and one tiny congo redpositive deposit , showing strong applegreen birefringence under polarized light , was detected on the lamina muscularis mucosa of the duodenum in only one tissue section among five different biopsy samples ( figure 1a c ) . for immunohistochemical analysis using antittr antibody 12 , we prepared 235 consecutive tissue sections from the same paraffinembedded tissue block ; no amyloid deposition was detected and we failed to detect ttrdeposited lesions . after obtaining informed consent , biopsies were taken from an additional five different portions of the duodenal mucosa .
of the five samples , two were fixed in 10% formalin , embedded in paraffin , and cut into sections , while the remaining three were stored at 80c and used to prepare frozen sections .
we prepared 258 consecutive tissue sections from the paraffinembedded tissue block , and no amyloid was detected .
however , we found small amyloid deposits in the duodenal mucosa in 3 of 465 consecutive tissue sections prepared from the three frozen samples ( figure 1d , e ) .
we carried out dual staining with congo red and immunohistochemical staining with antittr antibody 12 on the same tissue sections , and positive staining of the amyloid deposits was observed ( figure 1f ) .
the area positive with antittr antibody was somewhat widely expanded compared to the congo redpositive area .
we isolated amyloid fibril protein using the advanced lmd system from the two tissue sections dualstained with congo red followed by immunostaining with antittr antibody . in lcms / ms analysis of ttr 2234 tryptic peptides , only peptide derived from variant ttr ( met30 )
( f ) dual staining with congo red ( d , e ) followed by immunohistochemistry ( f ) on frozen duodenal mucosa . ( a c ) at lower magnification
, a small congo redpositive spot was seen on the lamina muscularis mucosae ( arrow ) ( a , bar = 100 m ) . at higher magnification ,
the amyloid was clearly positive for congo red ( b ) , showing strong applegreen birefringence under polarized light ( c ) ( b , c , bars = 5 m ) . formalinfixed and paraffinembedded tissue sections .
( d f ) frozen tissue sections were stained with congo red . after confirming the presence of amyloid ( d , e ) , the cover glass was removed in hemode solution ( falma co. , ltd .
after treatment with formic acid for 1 minute , immunohistochemical staining using antittr115124 peptide antibody ( 1:4000 dilution ) 12 was performed using the standard immunoperoxidase method ( vectastain abc kit ; vector laboratories inc . , burlingame , ca ) .
the deposited amyloid was positive for antittr antibody ( f ) ( d f , bars = 50 m ) .
( g ) a small congo redpositive spot was also present on the lamina muscularis mucosae at 24 months after dlt ( arrow , bar = 100 m ) .
serial changes in relative quantification of ttr 2234 tryptic peptide in lcms / ms analysis of amyloid isolated at 14 months ( a ) and 24 months ( b ) after dlt in patient 1 .
the area positive with both congo red and immunohistochemical staining of frozen biopsied samples ( figure 1d f ) was isolated using an advanced lmd system 13 .
selected mass range profiles obtained from the ion chromatograms of lcms / ms analysis are shown ( a , b ) .
the chromatograms were filtered with mass ranges , m / z 683.86683.90 , m / z 699.85699.89 and m / z 707.85707.89 .
these ranges correspond to ttr 2234 wildtype ( gspainvavhvfr , m / z 683.88 ) , variant peptide ( gspainvamhvfr , m / z 699.87 ) and variant peptide oxidized at met30 ( gspainvam(ox)hvfr , m / z 707.87 ) , respectively .
only ttr 2234 peptide peaks derived from variant ttr and oxidized variant ttr were detected at 14 months after dlt , and no clear peak derived from wildtype ttr was seen in the extracted amyloid ( sequence data of both variant and oxidized variant ttr on lcms / ms analysis are not shown ) .
we also investigated synthetic wildtype ttr peptide 2234 by mass spectrometry , and confirmed a peak derived from synthetic peptide at 29.97 minutes ( data not shown ) .
conversely , in amyloid isolated at 24 months after dlt , the mass peak of wildtype ttr became apparent and the composition ratio of wildtype versus variant ttr was 6:94% .
oral administration of tafamidis , a stabilizer of tetrameric ttr structure 16 , was started 20 months after dlt despite the preclinical stage of amyloidosis .
twentyfour months after dlt , she was again admitted to our hospital for the second check for amyloidosis .
duodenal mucosal biopsy was performed and very small amyloid deposits were seen in 5 of 300 consecutive paraffinembedded tissue sections ( figure 1 g ) .
we also prepared 200 consecutive frozen tissue sections , but no amyloid deposits were detected . in lcms / ms analysis of the isolated amyloid from paraffinembedded tissue sections , a small wildtype ttr peak became detectable and the composition ratio of wildtype ttr versus variant ttr was 6:94% ( figure 2b ) .
this recipient was a 45yearold japanese man with adultonset type ii citrullinemia , which developed at the age of 32 .
one month after onset , he received dlt from a 52yearold female fap patient with attr val30leu ( p.val50leu ) 9 .
however , his donor died of rapidly progressive amyloid cardiomyopathy 1 year after the operation due to paradoxical ongoing wildtype ttrderived amyloid deposition 17 .
therefore , the recipient has been carefully checked for the presence of de novo amyloid deposits almost every year , paying special attention to the development of amyloid cardiomyopathy as well as neuropathy . in addition , he was started on oral intake of diflunisal ( 500 mg a day ) , a stabilizer of ttr structure 18 , 19 , from 4 years after dlt as a preventive step against de novo amyloidosis . to date , he has shown no clinical symptoms , including congestive heart failure or peripheral neuropathy , and no abnormal findings have been found on echocardiography . however , in nerve conduction studies , motor nerve compound muscle action potential of the tibial nerve and sensory nerve action potential of the sural nerve gradually decreased over the last 2 years ( from 9.9 to 1.1 mv , normal value > 6.2 mv ; from 14.7 to 4.4 v , normal value > 5 v , respectively ) , although the nerve conduction velocities were within the normal limits .
the presence of amyloid deposits has been checked almost every year with gastroduodenal mucosal biopsy , and amyloid deposits were first detected on both gastric and duodenal mucosae at 45 years old ( 12 years after dlt ) ( figure 3a c ) .
we investigated the gastroduodenal mucosal biopsy samples obtained at 11 years after dlt again , with preparation of 500 consecutive tissue sections , but no amyloid deposits were seen ( data not shown ) . in lcms
/ ms analysis of the amyloid microdissected from formalinfixed paraffinembedded tissue sections , the composition ratio of wildtype ttr versus variant ttr was 5:95% ( figure 3d ) .
congo redstained duodenal mucosa ( a c ) and relative quantification of ttr 2234 tryptic peptide in lcms / ms analysis of amyloid isolated ( d ) at 12 years after dlt in patient 2 .
( a c ) a small congo redpositive spot was seen on the lamina muscularis mucosae ( arrow ) ( a , bar = 100 m ) . at higher magnification ,
the amyloid was positive for congo red ( b ) , showing strong applegreen birefringence under polarized light ( c ) ( b , c , bars = 10 m ) . formalinfixed and paraffinembedded tissue sections .
deposited amyloid was isolated with an lmd system ( lmd7000 ; leica microsystems inc . , tokyo , japan ) . in lcms
/ ms analysis , the chromatograms were filtered with mass ranges , m / z 683.86683.90 and m / z 690.86690.90 .
these ranges correspond to ttr 2234 wildtype ( gspainvavhvfr , m / z 683.88 ) and variant peptide ( gspainvalhvfr , m / z 690.87 ) , respectively .
de novo amyloidosis associated with dlt was first reported in 2005 as transmission of amyloidosis in a 55yearold man who developed neuropathic symptoms 8 years after dlt 5 . since then
, similar cases of de novo amyloidosis have been described in a number of domino recipients 5 , 6 , 7 . to date , the shortest periods from dlt to identification of amyloid deposits have been reported as 3 years in skin 20 and 4 years in gastroduodenal mucosa 21 , and there have been no reports of amyloid deposition identified within 3 years after dlt 22
. of particular interest in this study was that very small and primitive amyloid lesions were first analyzed biochemically as well as histopathologically at such an early stage that we are not usually able to observe in human fap patients .
in addition , the serial changes in biochemical composition of the amyloid lesions could clearly be captured . in patient 1 ,
as the amyloid deposits were identified at an unexpectedly early postoperative stage , these deposits were initially thought to be preexisting wildtype ttrrelated amyloid produced preoperatively from the patient 's native liver as senile systemic amyloidosis .
however , the amyloid was purely composed of variant ttr , all of which was produced by the transplanted fap liver during the 14month postoperative period .
wildtype ttr is known to be inherently amyloidogenic , as shown in senile systemic amyloidosis 23 . in fap patients ,
the contribution of wildtype ttr to amyloid formation is significant in all visceral organs 17 , 24 , 25 and our previous study showed that large amounts of wildtype ttr were already present even in biopsy samples of fap patients in their 20s obtained soon after onset of the disease 25 .
however , the biochemical characteristics of amyloid fibrils of preclinical fap patients have not been investigated , and it remains unknown whether wildtype ttr can be deposited from the initial stage of amyloid formation .
our biochemical results showed that variant ttr alone can be strongly associated with initial amyloid formation , and wildtype ttr seems to be deposited later in the early stage amyloidogenesis of domino recipients . in the histopathological dual staining with congo red and antittr antibody in this study
, congo redpositive lesions seemed to be located at the centre of congo rednegative / antittrpositive lesions ( figure 1d f ) , which looked like an amyloid lesion in the process of initial fibril formation from nonfibrillar ttr aggregates .
amyloid seeds before the involvement of wildtype ttr in amyloid fibrils . in patient 2 ,
there have been no clinical symptoms of amyloidosis even 12 years after dlt , although abnormal findings on nerve conductions studies suggestive of amyloid neuropathy were observed .
thus , the extracted amyloid in this study also represented earlystage amyloid lesions , and these results support the importance of variant ttr in the initial stage of ttr amyloid formation , as in patient 1 .
in addition , our data may provide valuable information for understanding the pathogenesis of ttr amyloid formation . in current dogma of ttrrelated amyloidogenesis
, the dissociation into monomeric ttr due to instability of the ttr tetramer structure is thought to be important , as confirmed by in vitro studies 26 .
however , this has not been fully confirmed in vivo and it is still controversial whether dissociated monomeric ttr is really a precursor or dissociated dimer with one or two variant monomers may be the real precursor because amyloid fibrils commonly contain large amounts of wildtype ttr 27 . in this study ,
the contribution of wildtype ttr to earlystage amyloid formation was not significant , and therefore , our results indicate , as the first in vivo data , the importance of aggregation from monomeric variant ttr , not from dimeric forms , in amyloid formation .
the precise pathomechanism underlying the difference in time from dlt to identification of amyloid deposits between patients 1 and 2 remains unclear .
however , our data strongly suggest that blocking of amyloid formation of variant ttr in the early postoperative stage may be a key to preventing the development of this transmitted amyloidosis . in patient 2 , administration of diflunisal 18 ,
19 was begun in the preclinical stage of amyloidosis , and it is , therefore , possible that diflunisal delayed the onset of transmission of amyloidosis associated with dlt .
Output:
| abstractthe most serious issue in domino liver transplantation ( dlt ) using liver grafts from patients with transthyretin ( ttr)related familial amyloid polyneuropathy ( fap ) is the development of iatrogenic transmitted amyloidosis ( de novo amyloidosis ) in dltrecipients .
however , little is known regarding the mechanisms of the initial stage of amyloid formation in these recipients .
we detected initial lesions ( possible seedlesions ) of this iatrogenic amyloidosis in two recipients following liver grafting from fap patients .
patient 1 underwent dlt at age 65 from an fap patient with a val30met ttr variant and patient 2 received dlt from an fap patient with a val30leu ttr variant at age 32 .
patient 2 was started on diflunisal administration from 4 years after dlt .
while neither patient had symptoms of fap , small amyloid deposits were detected on the gastroduodenal mucosae 14 months and 12 years after dlt in patient 1 and patient 2 , respectively .
the amyloid was analyzed using a laser microdissection system and tandem mass spectrometry .
biochemical analysis indicated that the amyloid was composed mostly of variant ttr produced from the transplanted liver in both patients . in patient 1 , wildtype ttr amyloid was detectable in the duodenal mucosa obtained 2 years after dlt .
this is the first study to successfully capture the pathological and biochemical features of initialstage amyloid lesions in dlt recipients .
the findings clearly indicate that amyloid deposition can start by deposition of variant ttr followed by deposition of wildtype ttr , and blocking of amyloid seed formation from variant ttr may be a key to prevent or delay the development of dltassociated amyloidosis . |
PubmedSumm118543 | ***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: genetic association studies take advantage of the fact that we can measure genotypes directly via either protein electro - phoretic or molecular genetic methods .
the goal is to explain the variation in the disease trait of interest using an individual 's genotype as a genetic marker .
there are two basic types of study design that are used in genetic association analysis : standard ( population - based , case - control or cohort ) and family - based .
for one , the design protects against a finding of spurious association , due to population admixture or stratification .
the reason for robustness is that the analysis uses parental genotypes to determine the distribution of the test statistic .
the analysis can not be biased by admixture or stratification because the case and control alleles are drawn from the same subjects ; therefore , they have the same genetic background .
the other key advantage of family - based studies is the way the multiple testing problem can be handled . using the conditional mean model approach ,
[ 1 - 3 ] the data are first analysed in a ' screening step ' .
the analysis of the screening step does not bias the significance level of sub - sequently computed tests . in this screening step
, the scientist can look at all possible associations between the markers and traits and select a subset of ' promising ' marker - trait combinations -- typically five combinations .
a general paradigm for testing the association between a response variable ( disease trait ) and a predictor ( genotype as a marker ) is a regression analysis , since this can accommodate all types of outcomes and all types of predictors .
although regression analysis has many advantages and is widely used in epidemiological investigations , it does require specifying a model for how the trait depends upon the genotype . if the model is incorrect , the power may be reduced . depending upon study design and analysis , there may also be consequences for the validity .
cordell and clayton have described a unified approach to performing genetic association analysis with nuclear families ( or case / control data ) in a regression context .
case - parent trios are analysed via conditional logistic regression using the case and three pseudo - controls derived from the untransmitted parental alleles .
the beauty of the method is that it can be performed using standard statistical software and that additional effects , such as parent - of - origin , effects can be included .
the major drawback is that , to date , the technique has not been adapted to include extended pedigrees without splitting them up into nuclear families .
a large number of computer programs are available for family - based association tests , including afbac , qtdt , fbat , [ 7 - 11 ] transmit and pdt .
these software packages primarily focus on the computation of various test statistics , whereas the pbat software package also exhibits pre- and post - analysis features .
pbat is an interactive software package that provides tools for the design and data analysis of family - based association studies .
the newest version of pbat ( v2.5 ) includes many features that were not available in earlier versions , such as haplotype analysis tools that can be invoked using batch mode or user interface , more flexible specifications in power calculations and allowance for discrete trait distribution when applicable . in particular
, pbat incorporates the features of the family - based tests of association ( fbat ) package http://www.biostat.harvard.edu/fbat/fbat.htm but provides many additional options for designing association / linkage studies and analysing data with multiple continuous traits .
perhaps the most striking feature , which gives pbata unique advantage over most available software in the field , is its implementation of the screening techniques -- that is , the conditional mean model approach -- that allow the user to handle the multiple comparison problem at a genome - wide level .
further advantages of pbat are the analytical power and sample size calculations for family - based association tests .
the cornerstone of the package is the unified approach to fbat , introduced by rabinowitz and laird and laird et al . .
fbat builds on the original transmission disequilibrium test ( tdt ) method , in which alleles transmitted to affected offspring are compared with the expected distribution of alleles among offspring .
it has been generalised so that tests of different genetic models , tests of different sampling designs , tests involving different disease phenotypes , tests with missing parents and tests of different null hypotheses are all in the same framework . in particular , the fbat statistic is based on a linear combination of offspring genotypes and traits : ( 1)fbat = s - e[s]/v1/2,s= ijtij*xij where v = var(s ) and tij represents the coded phenotype ( ie the phenotype adjusted for any covariates ) of the j - th offspring in family i. xij denotes the offspring 's coded genotype at the locus being tested .
the expected distribution is derived using mendel 's law of segregation and conditioning on the sufficient statistics for any nuisance parameters under the null hypothesis , the null hypothesis being ' no linkage and no association ' or ' no association , in the presence of linkage ' .
pbat provides methods for a wide range of situations that arise in family - based association studies using fbat statistics .
more specifically , there are two main components : tools for the planning of family - based association studies and data analysis tools . in terms of study planning , pbat computes the power for study designs that consist of different family types with varying numbers of offspring , under different ascertainment conditions and allowing for missing parental genotypes .
the data analysis tools available in pbat provide options to test linkage or association in the presence of linkage , using ( bi - allelic or multi - allelic ) marker or haplotype data , single or multiple traits ( eg measurements recorded repeatedly over time ) that may be quantitative , qualitative or time - to - onset , with nuclear families as well as extended pedigrees .
furthermore , pbat can also be used for post - study power calculations and construction of the most powerful test statistic . for situations in which multiple traits and markers are given ,
pbat 's screening tools reduce the large pool of traits and markers and select the most promising combinations in terms of the fbat statistic . using pbat 's screening tools
the present authors have shown that genome - wide association studies using families are realisable in terms of data analysis .
the key concept of the implemented screening techniques is the conditional mean model approach , for which the data space is partitioned into two independent testing sets .
this allows one to control the type i error rates and to overcome one of the most important statistical hurdles when analysing genome - wide association studies with thousands of markers : the multiple comparison problem .
the screening technique maintains its protective character for extended datasets with a few hundred thousand snps .
it should be noted that , in general , adding more snps comes at the cost of power loss when corrections for multiple testing need to be applied ( eg bonferroni - type corrections to control type i error ) .
in addition , they are robust against effects of population stratification and admixture , since the final decision in the screening process is based on fbats , which guard against these confounding factors . finally , pbat 's screening tools are most successful in detecting common disease susceptibility loci .
this is particularly attractive in the light of the hapmap project , which aims to describe the common patterns of genetic variation in humans .
the problem of detecting rare disease - associated snps remains ; however , this is a general problem rather than a problem specifically related to the screening techniques of pbat .
applying the authors ' screening tools using the haplo - type features of pbat ( eg using sliding windows acknowledging the linkage disequilibrium structures present in the data ) may be more beneficial .
tran - smit is another program for transmission disequilibrium testing that uses marker haplotypes based on several closely linked markers .
by contrast with pbat , however , transmit leads to elevated false - positive rates in the presence of population admixture and does not handle quantitative traits .
moreover , it has no built - in functions for performing screening on a genome - wide level .
these include the data analysis tools using univariate and multivariate traits , multivariate / longitudinal fbat models , time - to - onset traits ( su ; personal communication ) , haplotype analysis ( randolph ; personal communication ) and genomic screening .
future developments include refined screening tools and guidelines that apply to haplotype - based genomic screening , power calculations for haplotype analysis and further effort towards a pbat compendium of commands and an extensive documentation for its users .
Output:
| the pbat software package ( v2.5 ) provides a unique set of tools for complex family - based association analysis at a genome - wide level .
pbat can handle nuclear families with missing parental genotypes , extended pedigrees with missing genotypic information , analysis of single nucleotide polymorphisms ( snps ) , haplotype analysis , quantitative traits , multivariate / longitudinal data and time to onset phenotypes .
the data analysis can be adjusted for covariates and gene / environment interactions .
haplotype - based features include sliding windows and the reconstruction of the haplotypes of the probands .
pbat 's screening tools allow the user successfully to handle the multiple comparisons problem at a genome - wide level , even for 100,000 snps and more . moreover , pbat is computationally fast
. a genome scan of 300,000 snps in 2,000 trios takes 4 central processing unit ( cpu)-days .
pbat is available for linux , sun solaris and windows xp . |
PubmedSumm118544 | ***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: colonic diverticular hemorrhage is the most common cause of massive hematochezia [ 1 , 2 ] . both colonoscopy with endoscopic treatment and angiography with embolization have been shown to be effective for definite diverticular bleeding [ 3 , 4 , 5 ] .
these methods , however , are not helpful for presumed diverticular bleeding , cases in whom the bleeding source is not visualized endoscopically and the bleeding is not brisk enough to be detected by angiography .
previous reports suggested that therapeutic barium enema could achieve hemostasis in refractory diverticular bleeding [ 6 , 7 ] .
we present the case of an elderly patient with presumed diverticular bleeding that could not be treated with endoscopic or angiographic measures .
her acute bleeding episode was presumably controlled by therapeutic diverticular impaction with high - density barium .
the patient , an 86-year - old woman with alzheimer 's dementia and hypertension , was chronically taking aspirin , amlodipine , and donepizil .
she was admitted after an episode of hematochezia with orthostatic hypotension and a hemoglobin of 6.8 mg / dl . her baseline hemoglobin
she received intravenous fluids and a total of five units of packed red blood cells for resuscitation .
she was started on continuous pantoprazole intravenous drip for possible upper gastrointestinal bleeding and prepared for upper and lower endoscopy with polyethylene glycol - electrolyte solution .
the upper endoscopy showed multiple small ( 13 mm ) antral erosions with no evidence of bleeding , and colonoscopy showed many diverticula scattered throughout the colon , but no blood was seen in the lumen or in the diverticula .
she was discharged to a nursing home with a hemoglobin of 12.8 mg / dl and aspirin was restarted the day after discharge .
the patient was re - admitted three days later ( day 6 ) with recurrent hematochezia and a hemoglobin of 10.5 mg / dl .
enteroscopy , performed on day 7 after the initial bleeding event , was normal to 50 cm past the pylorus with no evidence of bleeding .
colonoscopy showed multiple diverticula , none specifically bleeding , but maroon blood throughout the colon and maroon blood pooling in the cecum . the terminal ileum was not examined .
continued hematochezia led to a tagged rbc scan which showed increased tracer activity throughout the colon , specifically the ascending , transverse , and descending colon on delayed images at 6 h. the actual site of bleeding was not identified .
it was felt by interventional radiologists that angiography would not localize the bleeding site as the bleeding rate was too slow .
capsule endoscopy was performed to further assess the small intestine as the patient continued to pass red blood and clots from the rectum .
it showed two 2 mm angiodysplastic lesions not actively bleeding at 43 and 81 min , a small mucosal break at 89 min , and a few small submucosal hemorrhagic lesions at 120 min , all of which were not actively bleeding .
eight hours after the capsule endoscopy was completed , the patient had another episode of bright red blood per rectum .
it showed diverticulosis throughout the colon with trace amounts of old blood , but no bleeding site could be identified .
given persistent rectal bleed without evidence of blood in the small intestine or bleeding arteriovenous malformations on capsule endoscopy , we felt that the most likely source of bleeding was colonic diverticula .
our therapeutic options were limited since she was a poor surgical candidate given her age and dementia and since she had not been bleeding briskly enough on the tagged rbc scan for angiography to be helpful .
previous case reports have shown that therapeutic barium enema can successfully stop bleeding in patients diagnosed with presumptive diverticular bleed .
for this reason , our patient was taken to the radiology suite for therapeutic high - density barium enema .
1,400 g of e - z - hd barium sulfate ( 98% w / w , e - z - em , westbury , n.y . , usa ) were dissolved in 300 ml of tap water to prepare a final volume of 800 ml of 171.5% w / v suspension in water , and a lafayette aircon xl 3000 disposable air contrast enema kit ( mallinckrodt inc . , st .
usa ) was used to instill the high - density barium by gravity into the colon .
contrast was seen to reach the cecum , and numerous diverticula were noted scattered from the sigmoid colon to the cecum .
the patient was asked to change position every 5 min by rolling 90 degrees to the next of four positions over a two - hour period , and at the end of the examination none of the barium could be expelled by the patient ( fig .
no anti - motility agent such as glucagon was given prior to or during the procedure .
eighteen hours after the procedure , treatment with polyethylene glycol 17 g mixed in 8 ounces of water p.o .
bid and liberal oral fluids were added in an effort to clear the intraluminal barium and minimize any risk of colonic impaction .
she continued to pass large amounts of barium per rectum for 48 h and was able to tolerate clear liquids without any nausea , vomiting , or abdominal pain .
she remained free of symptoms worrisome for obstruction , and daily abdominal films were obtained .
the abdominal x - ray done 48 h after treatment showed barium remained in the diverticula throughout the colon but was largely cleared from the lumen proper ( fig .
follow - up in the outpatient clinic two weeks later showed her to be doing well with no recurrence of hematochezia , and her hematocrit was stable at 12.1 mg / dl on day 16 ( fig .
follow - up blood counts on days 60 , 76 and 120 showed no drop in hemoglobin , and the patient , the assisted living center staff , and the patient 's children reported no further episodes of bleeding .
diverticulosis is primarily a disease of the elderly , a population with greater incidence of both comorbidities and poor outcomes after surgical resection .
although this bleeding is usually of minor clinical significance , massive bleeding from colonic diverticula may occur in 5% of patients who have diverticulosis . bleeding stops spontaneously in 75% of episodes and in 99% of patients who are transfused less than four units per day . however , the risk of rebleeding remains 1453% [ 2 , 3 , 11 , 12 ] . a previous study by jensen et al .
has shown that urgent colonoscopy with endoscopic submucosal injection of epinephrine and bipolar coagulation can prevent recurrent hemorrhage in patients with definite diverticular bleeding . in jensen et al .
's study , patients who were treated without endoscopic intervention had a rebleeding rate of 53% .
barium enemas employed for the diagnosis of lower gastrointestinal bleeding were noted by adams in the early 1960s to coincide in some cases with bleeding cessation .
the barium was thought to inspissate in the diverticula and the resulting concretions to tamponade the source of diverticular bleed .
a subsequent prospective case series of 22 patients published in 1970 showed 26 of 28 cases of suspected diverticular bleed with a source proximal to the extent of sigmoidoscopy to be acutely controlled by therapeutic barium enema .
thus , before the advent of therapeutic colonoscopy , therapeutic barium enema presented an alternative to conservative management or emergent subtotal colectomy for cases of unrelenting colonic diverticular bleeding .
recently , interest in therapeutic barium enema has been rekindled for patients with presumed diverticular bleeding .
koperna et al . , in a prospective study of 102 patients published in 2001 , described therapeutic barium enema in conjunction with sigmoidoscopy as resulting in fewer cases of rebleeding than conservative management in cases where surgery was not indicated or was contraindicated .
she had suffered from a refractory presumed diverticular bleed requiring multiple hospital admissions and blood transfusions over a 15-day period .
multiple endoscopic procedures were performed , but failed to demonstrate a definite site of bleeding . due to her age and medical comorbidities , it was determined that she would be a poor surgical candidate .
in addition , it was not possible to localize the bleeding artery by angiography as she was not bleeding briskly on the tagged rbc scan .
capsule endoscopy revealed no actively bleeding lesions in the small bowel and no fresh or old blood was seen in the lumen .
it is difficult to exclude the possibility that one of the non - bleeding lesions in the small bowel caused the bleeding , particularly in the setting of recent aspirin use .
however , if the small bowel was the source of acute rectal bleed in this case , we would expect the capsule endoscopy to demonstrate old or fresh heme in the lumen as the patient passed bloody bowel movements and blood clots several hours after the study was performed .
we used a therapeutic high - density barium enema based on previous case reports by chorost and matsuhashi .
we did not add epinephrine to the high - density barium ( 171.5% w / v ) as used by matsuhashi .
however , the use of barium could potentially limit subsequent diagnostic or therapeutic modalities such as angiography .
the presence of significant amount of retained barium within the bowel lumen may decrease the sensitivity of angiographic examination due to an overlap of the luminal contrast with bowel wall perfusion .
this problem could be minimized by a technique called masking where an initial spot image is used as a subtraction image from all the consequent runs .
the efficacy of this technique , however , may be limited when high - density barium is used .
the fact that the patient did not rebleed for 4 months after the first bleeding event could probably be attributed to long - term discontinuation of aspirin or the natural history of lower gastrointestinal bleed as it is less likely that the effect of the barium enema would last that long .
possible complications of barium enema include colonic perforation , mucosal irritation , and thrombosis of the involved vessels ; the reported incidence of colonic perforation after barium enema is very low ( 0.04% ) , and the connection between thrombosis and barium enema is tenuous [ 7 , 16 , 17 ] .
a colon weakened by iatrogenic trauma or disease is more likely to perforate than is a normal healthy colon .
in addition , tensile strength is impaired in elderly patients , patients receiving long - term steroid therapy , and disease states such as diverticulitis , ischemic bowel , neoplasm , and inflammatory bowel disease .
we propose that barium impaction therapy is considered as a therapeutic option in elderly patients with uncontrolled presumptive colonic diverticular bleeding who have failed conservative therapy , particularly for those who are poor surgical candidates .
this procedure appears to be safe , tolerable to patients , and easy to perform .
Output:
| many patients with lower gastrointestinal bleeding do not have an identifiable source of bleeding at colonoscopy .
a significant percentage of these patients will have recurrent bleeding . in many patients ,
the presence of multiple diverticula leads to a diagnosis of presumed diverticular bleeding .
current treatment options include therapeutic endoscopy , angiography , or surgical resection , all of which depend on the identification of the diverticular source of bleeding .
this report describes a case of recurrent bleeding in an elderly patient with diverticula but no identifiable source treated successfully with barium impaction therapy .
this therapeutic modality does not depend on the identification of the bleeding diverticular lesion and was well tolerated by our 86-year - old patient . |
PubmedSumm118545 | ***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: there has been much controversy over the baseline heart rate for a normal term fetus ( 1 - 6 ) .
gibb and arulkumaran ( 2 ) and spencer ( 3 ) proposed that the baseline fetal heart rate ( fhr ) range should lie between 110 and 150 beats per minute ( bpm ) and emphasized the possibility of serious problems resulting from tachycardia ( > 150 bpm ) or bradycardia ( < 110 bpm ) .
in contrast , it was pointed out that a rate of 100 - 119 bpm in the absence of other non - reassuring patterns is not the usual sign of fetal compromise ( 4 ) . according to sweha et al .
( 5 ) , fetal tachycardia is considered a non - reassuring pattern defined by a baseline heart rate greater than 160 bpm .
chan et al . ( 6 ) also defines fetal tachycardia as a heart rate greater than 170 bpm .
recently , new standards for electronic fetal monitoring were proposed at the national institute of child health and human development ( nichd ) workshop ( 7 ) .
these new standards are as follows : 1 ) fhr tracings are normal when the baseline fhr lies between 110 and 160 bpm , 2 ) bradycardia is defined by a baseline fhr less than 110 bpm , and 3 ) tachycardia is defined by a baseline fhr greater than 160 bpm .
a normal cardiotocography ( ctg ) is associated with a low probability of fetal compromise and has the following features ( 8) . an abnormal ctg trace ( non - reassuring ctg trace ) is when two of the features described for a non - reassuring ctg trace are present , or when the baseline fhr is less than 100 bpm or greater than 170 bpm .
however , most fetuses that had records of mild bradycardia or tachycardia without non - reassuring patterns did not have abnormal postnatal outcomes .
the nonstress test ( nst ) and vibroacoustic stimulation test ( vast ) are both fhr tests that can be used to predict antepartum fetal status ( 9 , 10 ) .
the reference ranges for the fhr parameters after vibroacoustic stimulation ( vas ) were reported in 2009 ( 11 ) . as shown in fig .
2 , baseline fhr after vas displayed different patterns and fhr ranges were unstable with an upward trend in the movement of fhr position . in the present study we investigated whether baseline fhr ranges reported by previous research studies differ from those reported in the aforementioned studies . to achieve the aim of our research ,
we investigated the different baseline fhr ranges established by various researchers and the nature of mild bradycardia and/or tachycardia without non - reassuring patterns through statistical methods and the heredity ( regress ) method designed by francis galton ( 1886 ) ( 12 , 13 ) .
gestational ages were distributed between 30 and 42 weeks old for the non - stress test ( nst ) and subjects were chosen from 4,589 pregnancies resulting in singleton live births ( between 1999 and 2008 ) .
the 1st and 2nd 20 min intervals of the nst were routinely performed followed by the fetal vast for 10 min immediately after completion of the nst ( 11 ) .
fhr data from antepartum fhr tracings taken 10 min before ( nst ) and 10 min after vas testing were analyzed using the han yang fetal monitoring ( hyfm ) system ( 14 ) .
vast was performed using a fetal vibroacoustic stimulator ( corometrics model 146 , wallingford , ct , usa ; audible sound 20 - 9,000 hz , vibrations between 67 and 83 hz , sound level 74 db at 1 m in air ) applied to the maternal abdomen above the fetal head .
regression analysis is widely used in biological and behavioral sciences to describe possible relationships between variables ( 15 , 16 ) .
more specifically , regression analysis helps us understand how the value of the dependent variable changes when any one of the independent variables is varied while the other independent variables are held fixed .
francis galton was interested in the relationship between a child 's height and the height of the child 's parents .
he questioned why the mean height of children remained stable even though the children of tall parents were tall and the children of short parents were short .
today , the characteristic of reverting from extreme values toward the average of the full population is well recognized and termed ' regression toward the mean ' .
fhr data was divided into the following three ranges : 1 ) a normal range ( 120 - 160 bpm , n = 4,404 ; 95.97% ) , 2 ) mild bradycardia ( 100 - 119 bpm , n = 46 ; 1.00% ) , and 3 ) mild tachycardia ( 161 - 180 bpm , n = 139 ; 3.03% ) .
for all 3 groups , simple linear regression analysis was performed using fhr data from the vast as the dependent variable and the nst as the predictor . for the linear regression plot ,
fhr data from the vast and the nst were used as the dependent variable and as the predictor , respectively .
in addition , a nonlinear regression model was used to analyze the fhr parameters , acceleration for 15 bpm-15 seconds ( acc1515 ) and deceleration for 15 bpm-15 seconds ( dec1515 ) in the nst .
the normality of baseline fhr ( nst data ) after vas testing was assessed using the shapiro - wilk test .
the plot of nst vs vast was used to estimate the best - fit regression line through the fhr data .
a chi - square test was performed to calculate differences in the rate of change of baseline fhr after vast among the three groups .
mean baseline fhr , acc1515 , and dec1515 were categorized into three groups according to fhr range and analyzed using a linear regression model . a p value less than 0.05 was considered a statistically significant difference among the three groups .
all statistical analyses were performed using sas for windows , release 9.1 ( sas institute , cary , nc , usa ) .
this study was approved by the institutional review board of hanyang university hospital , seoul , korea ( irb approval number : hyirb-201010 - 10 ) .
gestational ages were distributed between 30 and 42 weeks old for the non - stress test ( nst ) and subjects were chosen from 4,589 pregnancies resulting in singleton live births ( between 1999 and 2008 ) .
the 1st and 2nd 20 min intervals of the nst were routinely performed followed by the fetal vast for 10 min immediately after completion of the nst ( 11 ) .
fhr data from antepartum fhr tracings taken 10 min before ( nst ) and 10 min after vas testing were analyzed using the han yang fetal monitoring ( hyfm ) system ( 14 ) .
vast was performed using a fetal vibroacoustic stimulator ( corometrics model 146 , wallingford , ct , usa ; audible sound 20 - 9,000 hz , vibrations between 67 and 83 hz , sound level 74 db at 1 m in air ) applied to the maternal abdomen above the fetal head .
regression analysis is widely used in biological and behavioral sciences to describe possible relationships between variables ( 15 , 16 ) .
more specifically , regression analysis helps us understand how the value of the dependent variable changes when any one of the independent variables is varied while the other independent variables are held fixed .
francis galton was interested in the relationship between a child 's height and the height of the child 's parents .
he questioned why the mean height of children remained stable even though the children of tall parents were tall and the children of short parents were short .
today , the characteristic of reverting from extreme values toward the average of the full population is well recognized and termed ' regression toward the mean ' .
fhr data was divided into the following three ranges : 1 ) a normal range ( 120 - 160 bpm , n = 4,404 ; 95.97% ) , 2 ) mild bradycardia ( 100 - 119 bpm , n = 46 ; 1.00% ) , and 3 ) mild tachycardia ( 161 - 180 bpm , n = 139 ; 3.03% ) .
for all 3 groups , simple linear regression analysis was performed using fhr data from the vast as the dependent variable and the nst as the predictor . for the linear regression plot ,
fhr data from the vast and the nst were used as the dependent variable and as the predictor , respectively .
in addition , a nonlinear regression model was used to analyze the fhr parameters , acceleration for 15 bpm-15 seconds ( acc1515 ) and deceleration for 15 bpm-15 seconds ( dec1515 ) in the nst .
the normality of baseline fhr ( nst data ) after vas testing was assessed using the shapiro - wilk test .
the plot of nst vs vast was used to estimate the best - fit regression line through the fhr data .
a chi - square test was performed to calculate differences in the rate of change of baseline fhr after vast among the three groups .
mean baseline fhr , acc1515 , and dec1515 were categorized into three groups according to fhr range and analyzed using a linear regression model . a p value less than 0.05 was considered a statistically significant difference among the three groups .
all statistical analyses were performed using sas for windows , release 9.1 ( sas institute , cary , nc , usa ) .
this study was approved by the institutional review board of hanyang university hospital , seoul , korea ( irb approval number : hyirb-201010 - 10 ) .
fig . 1 shows typical fhr tracings for the three groups defined as : ( a ) mild tachycardia , ( b ) normal range , and ( c ) mild bradycardia . in the mild bradycardia group , the baseline fhr after vas testing increased from 109 bpm to 132 bpm and
the number of accelerations for 15 bpm-15 seconds ( acc1515 ) increased from 0 to 7 . on the other hand , in the mild tachycardia group ,
the baseline fhr did not change significantly after vas testing and the number of decelerations for 15 bpm-15 seconds ( dec1515 ) increased from 2 to 5 . as shown in fig .
2 , baseline fhr after vas testing displayed a variety of patterns and the rate of maintaining a fhr range was 26.1% , 66.0% , and 92.1% in the mild bradycardia , the normal range , and mild tachycardia groups , respectively ( p < 0.001 ) .
the rate of increase for a fhr range was 73.9% , 27.5% , and 0.0% in the mild bradycardia , normal range , and mild tachycardia groups , respectively ( p < 0.001 ) .
baseline fhr before ( nst data ) and after vas testing followed a normal distribution ( shapiro - wilk tests , p = 0.785 ) .
the linear relationships between baseline fhr before and after vas testing were plotted and compared by applying the regression model to all the data ( n = 4,589 , slope = 0.74 , correlation coefficients = 0.68 , p < 0.001 ) as shown in fig .
the regression slope was largest in mild bradycardia ( 1.14 ) and the smallest in the normal range ( 0.73 ) .
the regression slope gradually decreased with an increase in gestational age ( from 0.81 to 0.71 ) ( fig .
3 ) ; thus , implying that the slopes of the midpoints ( 34 - 37 weeks ) are similar to those of the overall average . as shown in fig .
4 , the mean of acc1515 did not change significantly ( p = 0.674 ) while the mean of dec1515 did significantly increase according to fhr range ( p < 0.001 ) .
regression to the mean occurs whenever a non - random sample is selected from a population and two imperfectly correlated variables are measured .
also , the more a value deviates from the population mean , the more room there is to regress to the mean .
it occurs whenever a group is selected with extreme values for one variable and another variable is then measured ( 12 ) . in this study
, the concept of ' fhr regression ' is based on the observation that fhr ( nst data ) changed after vas testing ( fig .
we found that the slope of the best - fit straight line was largest in the mild bradycardia group ( fig .
the larger slope value means there is more potential for regression to the mean . in other words ,
the mild bradycardia group has a greater potential for increased fhr ( that is , an increase towards the normal fhr range ) than the other two groups due to greater change in baseline fhr after vas testing . in the mild tachycardia group ,
the slope of the best - fit straight line was larger than that of the normal range group , but smaller than that of the mild bradycardia group .
thus , there is less potential for an increase in fhr in the mild tachycardia group compared with the mild bradycardia group .
in contrast , the mild tachycardia group showed the greatest increase of the three groups for dec1515 and no statistically significant change for acc1515 ( fig .
thus , the mild tachycardia group has a greater potential for a decrease in fhr compared with the mild bradycardia group .
the slope of the best - fit straight line was the smallest in the normal range group ; thus , implying that changes in fhr will be less extreme in this group compared with the other two groups .
in other words , the normal range group lies between the mild bradycardia and tachycardia groups due to its stability in fhr . in summary
, an arbitrary fhr value outside of the normal range will converge to a certain value ( the majority will regress toward the population mean ) within the normal range through mechanisms that increase or decrease baseline fhr .
these results imply that mild bradycardia and tachycardia have a tendency to regress toward the mean range for fhr . in other words , mild bradycardia and tachycardia
are not a fixed and/or abnormal fhr patterns but are capable of regressing toward the mean at any time . based on these results the differences among baseline fhr ranges established by various researchers may be reasonable and useful .
the inhibitory influence on heart rate is conveyed by the parasympathetic nervous system ( psns ) or vagus nerve , whereas the excitatory influence is conveyed by the sympathetic nervous system ( sns ) . in the present study ,
the mild bradycardia group had a greater potential to increase fhr than the other two groups indicating that the increase in fhr is facilitated by the sns rather than the psns .
in contrast , the increase for dec1515 observed in the mild tachycardia group indicates that , fhr is attenuated by actions of the psns .
the coexistence of the aforementioned properties correlates well with results reported by yang and coworkers ( 17 ) , in which they claim that normal pregnancy is associated with a facilitation of sympathetic regulation and an attenuation of parasympathetic influence of heart rate .
progressive vagal dominance occurs as the fetus approaches term and , after birth , results in a gradual decrease in baseline fhr .
stimulation of the peripheral nerves of the fetus by its own activity ( such as movement ) or by uterine contractions cause fhr accelerations ( 18 ) . in our study , the regression slope decreased with increasing gestational age ( 30 - 33 weeks , slope = 0.81 ; 34 - 37 weeks , slope = 0.73 ; 38 - 42 weeks , slope = 0.71 ) .
this finding also implies that fhr is controlled more by the sns in preterm and the psns in term pregnancy .
the fetuses of the mild bradycardia and tachycardia groups in this study did not show any clear evidence of non - reassuring patterns during the nst .
however , following up with a longer term study is recommended for the detection of an abnormal postnatal outcome . in general , the vas test offers several benefits including : 1 ) decreasing the frequency of nonreactive tests , 2 ) reducing test time , and 3 ) lowering the rate of false positives without changing the reliability of the nst .
however , in regards to our study , the number of acceleration ( nonreactive tests ) associated with vast in mild tachycardia cases had a tendency not to increase than that of normal and mild bradycardia cases .
it is thought to be the tendency to regress to the normal range , and thus may not coincide with the nonreactive tests .
therefore , the mild tachycardia cases should be evaluated with caution when interpreting vas test results . in conclusion
, we propose that both mild bradycardia and tachycardia of fhr are not regarded a pathologic signal for clinical use .
our findings may help to prevent unnecessary interventions in non - acute situations due to strict guidelines for a baseline fhr range between 100 and 180 bpm at 30 to 42 weeks of gestation .
Output:
| the purpose of this study was to investigate the feasibility of different fetal heart rate ( fhr ) ranges in the nonstress test ( nst ) and to better understand the meaning of mild bradycardia and/or tachycardia without non - reassuring patterns .
we employed the heredity to show that mild bradycardia ( 100 - 119 beats per minute , bpm ) and mild tachycardia ( 161 - 180 bpm ) regressed to the normal fhr range ( 120 - 160 bpm ) .
we used linear regression to analyze fhr data from fhr tracings recorded 10 min before ( nst , as the predictor ) and 10 min after vibroacoustic stimulation testing ( as the dependent variable ) .
acceleration for 15 bpm-15 seconds ( acc1515 ) and deceleration for 15 bpm-15 seconds ( dec1515 ) in the nst were also analyzed for each group .
the slope of the best - fit line was the largest in the mild bradycardia group and the smallest in the normal range group .
dec1515 was most prominent in mild tachycardia and both the mild bradycardia and tachycardia groups regressed towards the mean fhr range .
therefore , we propose that both mild bradycardia and tachycardia of fhr in non - acute situations ( range between 100 and 180 bpm ) are not regarded a pathologic signal for clinical use . |
PubmedSumm118546 | ***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 considerable number of natural and public disasters such as mass shootings , earthquakes , floods and hurricanes , and catastrophic accidents in the air and on the ground have occurred in recent years . notwithstanding the deep tragedy of these events , they offer opportunities for important research in the biosciences to better understand , prevent , and respond to such disasters in the future in a manner that minimizes human suffering .
however , research in this area is rife with inevitable ethical , legal , and policy challenges and implications .
fritz defines a disaster as an event concentrated in time and space , in which a society or one of its subdivisions undergoes physical harm and social disruption , such that all or some essential functions of the society or subdivision are impaired. as such , disasters provide real - world laboratories for the effects of harmful , irreversible loss , and damage requiring long - term recovery from their social , political , and economic repercussions .
agents of destruction vary , but in most traditional definitions of disaster research they fall into the category of natural forces .
a basic framework categorizes disaster effects into three impact conditions : hazard exposure , physical vulnerability , and social vulnerability .
research involving any of these conditions has , as at least one of its endpoints , the goal of reducing future risk .
disaster research began in the 1950s primarily in the usa , and has become increasingly international over time .
lindell 's studies of the aftermath of 2005 hurricane katrina , for example , revealed invaluable knowledge about the impact of failed management and care of affected persons forced to disperse from the epicenter of an event , and remedies for future disaster planning . prior to katrina ,
disaster research on the 1979 three mile island incident and 1996 catastrophe in chernobyl led to policy decisions about nuclear power accidents .
other research on disasters have also revealed important insights into coping strategies among emergency workers , impact of disasters on collective memory , the importance of culture and humor in recovery , and the cultural impact of terrorist attacks and religion in responsiveness .
the fundamental difference in doing disaster research compared to other forms of human subjects research is the context in which it is carried out .
indeed , studies have illustrated the ethical complexities of conducting disaster research for both participants as well as researchers .
separating disaster research from other forms of research and regulatory responses is the critical nature of timing of research , access to people , documents or other materials , and ultimately generalizability to other settings .
timing is especially key where arriving late to the disaster scene may yield poor or incorrect research results or be a missed opportunity to take advantage of unfolding events data that quarantelli describes as ephemeral or bourque et al . as perishable . the pressure of time for rapid interventions required of research teams may also preclude the usual formal institutional ethics board review .
while some scholars have questioned whether reduced research ethics scrutiny may justifiably apply in disaster research settings , minimal risk standards which still require oversight by an external research ethics body are expected .
for example , wendler considers whether the standard of minimal risk can be applied in these rapid response situations , and proposes a charitable participation standard where individuals should be enrolled in research only when the risks do not exceed the risks of charitable activities deemed acceptable for these individuals. similarly , jesus et al .
address the minimal risk question by advancing the need for flexible study designs that can be used across a wide variety of disasters but reviewed prior to implementation .
disaster researchers , sometimes described as action researchers , come to a crisis setting seeking access to a purposive sample of respondents or informants .
they bring courage to a scene , but often do so alongside other researchers who bring their own disciplinary methodologies , perspectives , and biases .
whether researchers are operating in collision or convergence with others , their presence can challenge the fundamental principle of non - maleficence by intruding on participants lives at a critical time .
, for example , reviewed research carried out on survivors of the bangladesh tsunami in 2004 , and found that numerous studies were conducted without proper approval or standards .
they attributed the sources of this lapse to the leniency of local standards , the vulnerability of victims , and the collapse of infrastructure that occurred after this mass natural disaster . even in the face of a stable infrastructure for research
while anonymity may be preserved in data aggregated from large pools of respondents , the identity of sole or small numbers of informants , such as first responders or community leaders , may be difficult to conceal without jeopardizing the integrity of the data or attribution to such experts .
the price of knowledge accumulation in any of these scenarios is borne disproportionately by subjects . in 2004 ,
the new york academy of medicine and the us national institute of mental health identified four critical areas of importance to research protocols in disaster settings : ( 1 ) decision - making capacity of potential participants , ( 2 ) vulnerability , ( 3 ) risks and benefits of participation , and ( 4 ) informed consent .
their conclusions highlight that existing guidelines and norms pertaining to research on human participants may not be sufficient to address all situations that arise during disasters , and that real vigilance is necessary [ ] to ensure that general ethical principles are adhered to and participants are protected. extreme life circumstances simultaneously and abundantly challenge decisions about life and death , valuing and foregoing , speed and patience , trust and distrust . given the press and urgency of these situations , the ability of researchers to obtain informed consent by fully delivering information about the purpose of a study , risks , benefits , and alternatives may be compromised . as such ,
we offer a new model of consent , in complement to existing methodologies , for the disaster research setting .
the basic tenet of the consent in escrow model is that data collection takes place under the time course of conventional procedures ( table 1 ) , but consent for data use is held in escrow until the acute post - disaster window has closed .
this two - tiered model places opt - in at the core of the research ethics process unlike , for example , the single - tier approach articulated by the american psychological association and us federal code 45cfr46.116 that assert and protect participants right to withdraw at any time , but according to which , consent allows for immediate data utilization . by holding data that are not time sensitive in escrow for later use , the model provides a layer of protection for individuals without compromising initial stage of data collection .
the model also supports the ethical concept that consent should not be a single point in time event , but rather be viewed as an ongoing process throughout the course of a research study .
summary of traditional models of informed consent and limitations for the disaster context . in canada ,
the usa , and in other developed states , policies for protecting human subjects acknowledge that there are times when modification to standard research ethics board processes is justified , provided that exceptions and the means to implement them are not unduly broad , overreaching , or unjustifiably invasive. this guidance applies specifically to and enables research in the disaster setting .
these policies also widely acknowledge that research participants in the midst of a disaster or an emergency are vulnerable , and that pre - existing vulnerabilities are potentially exacerbated under these extreme circumstances .
gender , race , and class are all factors correlated with vulnerability during disaster events , including those such as hurricane katrina . while traditional notions of informed consent make allowances for the exposure of research participants or groups through mechanisms such as assent for children or community consent in the case of indigenous peoples , a model that enables individuals to opt out of participating in a study to which they contributed data under acute circumstances has not been broached . in this way ,
consent in escrow builds on the two - stage model for retrospective clinical research proposed by norris et al .
, that provides the opportunity for subsequent research and is sensitive to participant recovery with a lengthened timeline , but that is not a prerequisite to release of data for analysis and utilization .
using the consent in escrow approach , initial informed consent from participants for the collection of data is obtained in the acute setting , but the data are held unexamined in escrow by a data steward until contributors can be recontacted and the second tier of informed consent is obtained for data release ( figure 1 ) .
respect for the autonomy of research participants is promoted through the opportunities afforded by the passage of time and the post - acute setting , and upheld by enabling them to re - evaluate their contribution .
multiple attempts for recontact are built into the protocol ex ante following other established ethics procedures where future attempts at recontact must be justified .
limits to repeated attempts must be factored into any protocol to preserve the benefit - risk balance with respect to autonomy and the right to refuse recontact . as with the model proposed by norris et al .
, researchers using the consent in escrow model may invite participants to provide information for kin through whom recontact is pursued secondary to primary contact at the future timepoint .
the significance and effectiveness of the kinship resource depends on the proximity of the kin to the affected person , the closeness of the tie , and the extent to which the kin is also affected .
nonetheless , it is common for study teams to collect information about relatives and friends of participants during the informed consent process for clinical trials when longer term follow - up is desired .
temporal dimensions of traditional models for informed consent and new model for consent in escrow .
the timing of the second stage of consent for release of data held in escrow will vary by context , but we anchor it in the period of time when the lives of research participants can reasonably be expected or observed to have stabilized such as when social , economic , and political routines have been restored .
new data may be collected under conventional procedures to compare or augment data collected at the acute timepoint , but originally collected data may not be modified post hoc . should a recontacted participant desire the latter , the conditions for release of data under the consent in escrow model are not satisfied and the data are destroyed .
the requirement to obtain community consent such as research with indigenous populations should not be circumvented in the first tier , and must be explicitly respected in the second . under conditions
when assenting youth attain age of majority during the data holding period , consent in the second tier is not required from the originally consenting surrogate . under conditions
in which competence of the participant is compromised over time after first - tier consent , proxy consent must be invoked at the second tier . in the case of participant 's death ,
an advanced directive for research or the instructions of the executor of the estate to which data may become property prevail . alternatively , the data are destroyed .
a limited version of this model is currently being applied successfully in a pediatric emergency research setting in british columbia , canada . here ,
verbal consent for research is acquired at the time of tissue biopsy by a treating physician , and then confirmed at a later time when the research study can be explained in greater detail and at time of reduced stress by an arm 's length researcher to avoid potential coercion .
situating consent in escrow in broader world events , the model would apply , for example , to a comparative study of emotional differences and long - term psychological changes between the families of those who vanished in flight mh370 , which disappeared presumably off the western coast of australia , and flight mh17 , which was shot down over ukraine .
while the location of the former flight and , most significantly , the victims bodies remain a mystery , families associated with the latter tragedy have the opportunity for closure and healing . in what disaster or emergency research settings situations will consent in escrow not be suitable ?
for one , it can not be applied to research with an immediate health intervention or short - term goal .
, it can not be applied to studies of war refugees , for example , where recontact would be too burdensome or simply a ludicrous requirement during times of political instability .
pre - reviewed , minimal risk research , as conceptualized and described above by wendler and jesus et al .
the collection of hair samples , for example , would qualify for such an exemption .
indeed , as with all research conducted in disaster and emergency settings , the consent in escrow model should be evaluated for its appropriateness to the specific research situation and for the associated risks and benefits it offers .
other complexities in applying the model will derive from heterogeneity in methods to determine return - to - life stability by research teams , and the inherent variability in progress along this continuum among people and populations .
recontact information may be unavailable at time of disaster or later invalidated due to a change in anticipated participant location .
participants may also feel burdened by the two - stage model and not wish to be reminded of the traumatic event in question .
use of the model may compound or extend fear of retaliation experienced by disaster researchers who are confronted with pressures to reveal informants identities , such as those reported after the 1989 exxon valdez oil spill .
two - tiered consent imposes pressures on funding streams , on researchers who rely on sufficient data to be released from escrow to power their analyses , and is complicated by changes in research leadership and personnel that inevitably occur over time .
decisional capacity and the ability to provide truly informed consent rely on durable and ongoing competence of research participants , and must neither be impulsive or be made under duress .
these conditions are difficult to achieve in disaster and emergency situations , and increasingly so in this era of instant messaging and social media , in which the right to privacy has been all but lost .
still , human societies are remarkably resilient in the face of large - scale crises , and disaster victims do not become irrational , self - destructive , necessarily hopeless , or dependent .
disaster victims may well be able to provide consent for immediate or long - term data use , but our model alleviates the extra burden of decision - making and choice in situ , and privileges time for participant reflection .
the model still needs to be tested , but we submit that when applied judiciously , consent in escrow will mitigate an extra strain that research brings to an already challenged setting , offer a welcome extra layer of protection to participants , and foster the completion of the research cycle for the advancement of the health and well - being of survivors .
Output:
| disasters such as flash flooding , mass shootings , and train and airplane accidents involving large numbers of victims produce significant opportunity for research in the biosciences .
this opportunity exists in the extreme tails of life events , however , during which decisions about life and death , valuing and foregoing , speed and patience , trust and distrust , are tested simultaneously and abundantly . the press and urgency of these scenarios
may also challenge the ability of researchers to comprehensively deliver information about the purposes of a study , risks , benefits , and alternatives . under these circumstances
, we argue that acquiring consent for the immediate use of data that are not time sensitive represents a gap in the protection of human study participants . in response , we offer a two - tiered model of consent that allows for data collected in real - time to be held in escrow until the acute post - disaster window has closed .
such a model not only respects the fundamental tenet of consent in research , but also enables such research to take place in an ethically defensible manner . |
PubmedSumm118547 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
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the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: magnetoencephalography ( meg ) records the extracranial magnetic field generated by the electrical activity of the brain ( 1 ) . because meg records continuous magnetic activity through multiple sensors that cover the entire brain , it has excellent temporal and spatial resolution compared with other modalities used to evaluate epilepsy . important advantages of meg over electroencephalography ( eeg ) are that the magnetic field detected from the scalp is not distorted or attenuated ( 2 ) and that accurate localization of the epileptic spike source is possible .
overlaying this localized spike source in the patient 's structural imaging ( magnetic source imaging , msi ) provides valuable information about the localization of the epileptogenic foci ( 3 ) .
the usefulness of meg as a presurgical evaluation tool has been demonstrated in previous studies .
the accuracy of meg spike source localization was satisfactory in a study of 455 patients ( 4 ) .
meg spike sources localized well in temporal and extratemporal lesional epilepsy , and sometimes provided additive localization information to brain mri or interictal scalp eeg ( 5 ) .
meg also added diagnostic yield to scalp video - eeg ( 6 , 7 ) . although the usefulness of meg has been well demonstrated and its application has yielded numerous promising results , the superiority of meg over eeg is not widely accepted .
moreover , there is no solid evidence that meg can be substituted for invasive intracranial eeg in epilepsy surgery ( 8) .
although the number of reports on the use of meg in pediatric epilepsy surgery in asia is increasing , there is no report on the use of meg in korean pediatric patients with epilepsy .
we examined the usefulness of meg in evaluating korean pediatric patients with lesional localization - related epilepsy .
we also sought to analyze the pattern of meg spike source distribution in relation to the lesions found by brain magnetic resonance imaging ( mri ) and the surgical outcomes .
of 41 pediatric patients who underwent meg spontaneous magnetic activity analysis at the meg center of seoul national university hospital between may 2005 and december 2010 , 13 patients ( 6 boys and 7 girls ) received epilepsy surgery for the diagnosis of lesional localization - related epilepsy and were included in the analysis .
data about sex , age , onset age , age at meg examination , seizure semiology , pre- and post - operative seizure frequency , brain mri , brain fluorodeoxyglucose positron emission tomography ( fdg pet ) and the pathology report were reviewed .
a 128-channel grass telefactor digital eeg was used for the interictal scalp and long - term video - eeg monitoring .
scalp electrodes were placed according to the international 10 - 20 system . if necessary , electromyography ( emg ) electrodes were also placed during the long - term video - eeg monitoring .
interictal eegs , video - eegs , and intracranial eegs were reviewed independently by three pediatric epileptologists .
the seizure semiology was described based either on the parents ' or the caregiver 's reports or on the video - eeg monitoring findings .
the seizure semiology description and classification were based on the international league against epilepsy classification of epileptic seizures ( 9 , 10 ) .
spontaneous brain magnetic activity was recorded using a helmet - shaped , 306-channel , whole - head neuromagnetometer ( vectorview ; elekta neuromag oy , helsinki , finland ) . the meg sensors comprised 2 planar gradiometers and 1 magnetometer .
the recording time was 50 - 90 min and most of the recordings comprised of spontaneous or sedated sleep records .
the sampling rate for data acquisition was 600 hz . a band - pass filter ( 0.1 - 200 hz ) and a notch filter ( 60 hz ) were applied .
chloral hydrate ( 50 mg / kg ; maximum , 1,500 mg ) was used when conscious sedation was required for infants and preschool - aged patients .
the meg recordings were analyzed and the spike sources were localized using the equivalent current dipole method and current density imaging .
the data was processed using us fda - approved neuromag software ( elekta neuromag oy , helsinki , finland ) . meg spike sources with goodness of fit values > 85% were considered significant .
when more than half of the sources were localized to the hemisphere with mri lesions , the results were considered concordant .
similarly , when more than half of the sources were localized to a certain lobe or the anatomical region of mri abnormality , the results were considered concordant .
meg spike sources were classified as clustered around the lesion with or without extension , clustered distant from the lesion , or scattered . the postsurgical seizure frequency noted in the outpatient visit
this study protocol was reviewed and approved by the institutional review board ( irb ) of the seoul national university hospital ( irb no.h-1111 - 052 - 386 ) .
waiver of informed consent was approved by the irb after reviewing the study design , which was a retrospective review of medical record and meg data .
this study protocol was reviewed and approved by the institutional review board ( irb ) of the seoul national university hospital ( irb no.h-1111 - 052 - 386 ) .
waiver of informed consent was approved by the irb after reviewing the study design , which was a retrospective review of medical record and meg data .
the mean age at the onset of epilepsy was 6.4 yr ( range , 10 months-12.1 yr ) and mean age at the examination was 8.4 yr ( range , 2.8 - 13.0 yr ) .
the most common seizure semiology was dialeptic or hypomotor seizure , followed by versive , focal tonic , focal clonic , hypermotor , and generalized tonic - clonic seizures .
the most common location of mri lesion was the temporal lobe ( n = 8 ; six medial and two lateral ) , followed by frontal lobe ( n = 3 ) and occipital lobe ( n = 2 ) ( table 1 ) .
the hemispheric concordance rate was 100% ( 13/13 patients ) and the lobar or regional concordance rate was 77% ( 10/13 patients ) .
the number of meg spikes analyzed was 2 - 52 ( mean , 18.8 ) .
more than eight spikes were analyzed in 10 patients , but only a few spikes were recorded in two patients ( patients 3 and 13 ) . with regard to distribution and location , the meg spike sources were clustered around or in proximity to the mri lesion in 10 patients ( 77% ) . among these patients ,
the meg spike sources were extended from the cluster in three patients and distant scatters coexisted in another three patients .
the meg spike sources were scattered in two patients and were clustered distant from the lesion in one patient ( table 2 ) .
meg spike source clusters were observed in 11 patients , and these clusters were located in the proximity of the lesion in 10 patients . in most patients ,
the meg spike sources were located on the margin of the lesion : superior ( patients 4 , 5 , and 6 ) , lateral ( patients 1 , 7 , and 8) , and superior and lateral ( patients 10 , 11 , and 12 ) . in patient 2 ,
distant scatters were also identified in the contralateral hemisphere in two patients and ipsilateral hemisphere in one patient ( fig .
2 ) . the meg spike source cluster was distant from the lesion in patient 3 . in the two patients without clusters ,
focal epileptiform discharges were present in 10 patients ( 77% ) , and the meg spike source locations were concordant with these eeg discharges . in two patients with a normal eegs ( patients 4 and 8) and in one patient with no focal epileptiform activity ( patient 1 ) , meg detected well - lateralized and localized meg spike sources .
meg spike sources were concordant in eight of the 10 patients whose pet findings were abnormal .
meg findings were concordant with the ictal onset zone identified by long - term video - eeg monitoring ( patients 7 , 11 , and 13 ) and invasive intracranial eeg monitoring ( patients 4 and 13 ) .
the surgeons determined the resection margin using the preoperative brain mri findings and intraoperative ultrasonograms .
an invasive intracranial eeg - based resection margin was applied in 2 patients ( patients 4 and 13 ) .
the pathology of the lesions included focal cortical dysplasia ( n = 7 ) , dysembryoplastic neuroepithelial tumor ( n = 4 ) , and ganglioglioma ( n = 2 ) .
the mean follow - up duration after the surgery was 39.2 months ( range , 26 - 64 months ) .
the postoperative seizure outcomes included engel class i ( n = 10 ) , class ii ( n = 1 ) , and class iii ( n = 2 ) .
identification and accurate localization of the epileptogenic area are critical for successful epilepsy surgery . in this study ,
localization was also satisfactory at the level of the anatomical region because the meg spike sources were distributed exactly at or in the vicinity of the lesion in most patients .
the hemispheric lateralization rate is similar to or higher than that reported for patients with intractable focal epilepsy in previous studies : 68% ( when compared to brain mri and intracranial ictal onset zone ) ( 12 ) , 82% ( lobar concordance to anatomical lesional in brain mri ) ( 7 ) , and 89% ( when compared to the final surgical decision ) ( 4 ) .
the lobar or regional localization rate is similar to the 72% rate reported in patients with intractable focal epilepsy ( 7 ) .
although the number of patients in this study is small , our data suggest that meg is useful in identifying the lateralization and localization of the structural lesions in pediatric epilepsy patients .
we observed good outcomes of 69% of patients free from seizures and 77% of patients with an engel class i outcome after a sufficient follow - up period .
favorable postsurgical seizure outcomes of meg have also been shown in previous studies ( 7 , 13 , 14 ) . although we did not compare the meg spike source foci with the intracranial eeg ictal onset in this study , complete seizure freedom after surgery can be considered as indirect evidence that the epileptogenic area was removed or the epileptogenic condition was resolved .
these findings allow us to infer that meg is effective in identifying the lateralization and localization of epileptogenic areas in patients with lesional epilepsy . in a study comparing the diagnostic sensitivity of presurgical evaluation modalities , msi had the highest sensitivity ( 58%-64% ) , as well as the highest predictive value for identifying the ictal onset zone ( 15 ) .
. reported additional benefits of msi for preoperative planning ( 16 ) . in our study , three patients had an interictal fdg pet result showing no decrease in glucose uptake . in two of these patients ( patients 1 and 2 ) , meg identified 13 and 20 meg spike sources that recognized the lesional hemisphere and localized the spike source clusters . in two patients with normal interictal scalp eegs ( patients 4 and 8)
, meg also identified the lesional hemisphere and the anatomical lobe that was concordant with the lesion .
it is well known that meg and eeg are not mutually exclusive in discriminating abnormal electrical activity ( 17 ) .
a recent study showed that a multimodality approach can improve surgical outcome even in pediatric patients with intractable nonlesional epilepsy ( 18 ) .
although we did not collect quantitative data , we demonstrated that meg provides additive information in patients with normal fdg pet or interictal scalp eeg results .
our findings suggest that meg should be performed in patients undergoing presurgical evaluation , especially in those with discordant or insufficient information on lateralization or localization . the distribution of meg spike sources in relation to the mri lesions varied and included clusters , clusters with extension , or scatters .
the clusters were located around the lesion or at the margin of the lesion . in most patients ,
the clusters were located on one side of the lesion and sometimes extended further to the same side .
similar findings were reported in previous studies that showed surrounding meg spike sources in patients with focal cortical dysplasia ( 13 , 19 , 20 ) . although we found no differences in the meg spike source distribution according to different pathologies , we observed the typical distribution of clusters located at the margin of the lesion either around the lesion or at one side of the margin .
this finding suggests that the irritative zone in lesional focal epilepsy may reside in the margin of the lesion , and hence indicates one possible pathophysiological mechanism underlying the epileptogenesis of lesional epilepsy .
this is the first study performed to assess the value of meg in pediatric patients from the tertiary epilepsy surgery center soon after utilizing magnetoencephalography . although we could not demonstrate the additional benefit of meg in lesional epilepsy surgery , this was shown in previous studies .
removal of the dysplastic cortex that has not been characterized by brain imaging but by meg was required for complete seizure freedom ( 13 ) . in cases of discordant presurgical evaluation ,
multiple meg spike source clusters required identification of the multiple or extensive epileptogenic zone prior to accurate localization and delineation of the resection margin ( 21 ) .
concordant lateralization and precise localization of interictal meg spike sources that were noted in this study may provide additional information in the presurgical evaluation and planning in lesional epilepsy surgery .
meg spike sources demonstrate and represent interictal irritative zone , this may partly explain the poor outcome of three patients in this study .
ictal onset zone should be verified by the intracranial eeg and interictal spike sources of meg may provide compensatory information .
meg and eeg are not mutually exclusive ( 17 ) , so both modalities should be used together to achieve the best information regarding the epileptogenic zone .
young patients were included in this study . the youngest patient reported to have undergone meg analysis was 5 months ( 12 ) , and another study included a patient who had received surgery at 4 yr of age ( 22 ) .
the age of patients included in the pediatric meg studies usually range from 4 to 18 yr , and the mean age of patients were usually 10 to 12 yr ( 13 , 20 , 22 ) .
the youngest patient in this study was 2.8 yr old when she underwent meg analysis , and other patients were 3.9 , 4.1 , and 4.4 yr old at the time of meg analysis .
conscious sedation with oral chloral hydrate , instead of general anesthesia or parenteral sedatives , was sufficient for these younger children and we found no limitations in processing and analyzing the meg data .
we emphasize that meg can be performed safely and effectively even in younger pediatric patients .
we could not demonstrate directly that the meg spike sources represent the ictal onset zone , and we found no difference between the meg spike source distribution and pathology of the epileptogenic lesion .
this should be verified in future studies . in conclusion , this is the first korean report of meg in the field of pediatric epilepsy surgery .
meg is safe and effective for analyzing pediatric patients with lesional localization - related epilepsy .
the favorable surgical outcomes in this study provide indirect evidence that the irritative zone defined by meg can provide valuable information about the epileptogenic area .
Output:
| this study was performed to assess the usefulness of magnetoencephalography ( meg ) as a presurgical evaluation modality in korean pediatric patients with lesional localization - related epilepsy .
the medical records and meg findings of 13 pediatric patients ( 6 boys and 7 girls ) with localization - related epilepsy , who underwent epilepsy surgery at seoul national university children 's hospital , were retrospectively reviewed .
the hemispheric concordance rate was 100% ( 13/13 patients ) .
the lobar or regional concordance rate was 77% ( 10/13 patients ) .
in most cases , the meg spike sources were clustered in the proximity of the lesion , either at one side of the margin ( nine patients ) or around the lesion ( one patient ) ; clustered spike sources were distant from the lesion in one patient . among the patients with clustered spike sources near the lesion , further extensions ( three patients ) and distal scatters ( three patients ) were also observed .
meg spike sources were well lateralized and localized even in two patients without focal epileptiform discharges in the interictal scalp electroencephalography .
ten patients ( 77% ) achieved engel class i postsurgical seizure outcome .
it is suggested that meg is a safe and useful presurgical evaluation modality in pediatric patients with lesion localization - related epilepsy . |
PubmedSumm118548 | ***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 wnt family comprises a group of secreted , lipid - modified , signaling glycoproteins . in mammalian systems , there are at least 19 members of the wnt protein family ( for more details , see the wnt homepage : www.stanford.edu/group/nusselab/cgi-bin/wnt ) .
wnt proteins transmit their signal across the plasma membrane through interactions with the frizzled ( fzd ) family of proteins and their co - receptors , the low - density lipoprotein receptor related protein-5 or protein-6 ( lrp5/6 ) .
the fzd receptors comprise at least 10 family members , all of which are composed of seven transmembrane domains .
the vast majority of wnts and fzd receptors are expressed or induced in the kidneys .
the reasons underlying the simultaneous expression of so many wnts and their receptors in a given tissue remain elusive .
wnts exert their biological functions via both canonical ( -catenin - dependent ) and non - canonical ( -catenin - independent ) pathways . in the canonical pathway , lrp5 or lrp6 ( lrp5/6 )
this triggers a series of downstream intracellular signaling events involving disheveled ( dvl ) , axin , adenomatosis polyposis coli , and glycogen synthase kinase-3 , ultimately resulting in dephophorylation of -catenin .
this leads to the stabilization and nuclear translocation of -catenin , where it binds to and activates transcription factors of the t - cell factor ( tcf ) and lymphoid enhancer
binding factor ( lef ) families to stimulate the transcription of target genes ( figure 1 ) .
in addition , wnt proteins may exert their activities through numerous non - canonical intracellular signaling routes .
one pathway helps to determine cell polarity during development and involves small rho gtpases and downstream c - jun n - terminal kinase activation .
this pathway still relies upon a cell surface complex involving wnt , fzd , and dvl , demonstrating that fzd and dvl can mediate both canonical and non - canonical pathways .
another pathway is dependent upon phospholipase c - mediated increases in intracellular calcium that in turn activates ca / calmodulin - dependent protein kinase , protein kinase c , and nuclear factor of activated t cells .
this pathway appears to be involved in mesenchymal - to - epithelial transitions during nephrogenesis .
other receptors for wnts are also known to exist , including ror2 and ryk , which act through c - jun n - terminal kinase and src , respectively .
the contributions of these non - canonical pathways in kidney disease are an area of active investigation .
regardless of the end result , signaling through wnt is tightly controlled in a multitude of ways .
there are several secreted antagonists of wnt signaling , including soluble frizzled - related proteins ( sfrps ) , wnt inhibitory factor , and the family of dickkopf ( dkk ) proteins .
sfrps , by virtue of their sequence homology with the fzd receptors , are capable of binding and sequestering wnts in the extracellular space to prevent binding to fzd receptors .
wnt inhibitory factor is a lipid - binding protein that binds to wnt proteins and prevents signaling . among the different wnt antagonists , dkk family proteins are unique in that they antagonize canonical signaling by binding and internalizing the lrp5/6 co - receptor that is vital for wnt signaling through fzd .
recent studies suggest that dkk1 blocks growth factor triggered mitogen - activated protein kinase and c - jun n - terminal kinase signaling cascades by mechanisms dependent on lrp6 and wnt ligands but not downstream -catenin signaling .
finally , not all proteins are negative regulators ; the protein cripto-1 was found to enhance wnt binding to lrp5/6 .
it is important to point out that -catenin can be activated by signals other than wnts .
one of the upstream regulators of -catenin is the integrin - linked kinase ( ilk ) , which is induced by transforming growth factor-1 ( tgf-1 ) , angiotensin ii , integrins , and other fibrogenic cues .
although there is controversy surrounding whether ilk is a true kinase , upregulation of ilk is reported to result in -catenin stabilization and activation in many cell types including podocytes .
we have shown that tgf-1 activates -catenin , either through the induction of wnt1 and ilk expression or through the activation of akt and p38 map kinase .
furthermore , matrix metalloproteinase-7 ( mmp-7)-mediated degradation of e - cadherin , the well - characterized cell adhesion receptor that can be found associated with -catenin , leads to -catenin release and activation .
therefore , apart from wnts , multiple pathogenic cues can lead to -catenin activation in diseased kidneys ( figure 1 ) .
despite being relatively silent in normal adult kidneys , wnt/-catenin signaling is re - activated after renal injury .
for instance , in acute kidney injury ( aki ) induced by folic acid or ischemia - reperfusion injury , -catenin is highly upregulated in renal tubular epithelial cells .
as wnt/-catenin signaling is essential for proper nephron formation and kidney development , one would speculate that activation of wnt/-catenin signaling might be reparative by promoting renal regeneration through recapitulating kidney developmental programs .
indeed , studies show that this upregulation of wnt/-catenin is advantageous , as tubule - specific ablation of -catenin in tubular epithelium was associated with increased renal injury , tubule cell apoptosis , and mortality after either ischemic or toxic aki .
similarly , it was found that wnt7b originating from macrophages is capable of stimulating renal repair in ischemia - reperfusion injury .
sustained activation of wnt/-catenin signaling , however , is detrimental and could lead to ckd progression .
chronic and progressive upregulation of -catenin appears to be a common pathologic feature in a wide variety of fibrotic ckds such as obstructive nephropathy , diabetic nephropathy , adriamycin ( adr ) nephropathy , remnant kidneys after 5/6 nephrectomy , polycystic kidney disease , and chronic allograft nephropathy .
a comprehensive survey demonstrated that 16 of the 19 wnts are induced at various time points in the obstructed kidneys after unilateral ureteral obstruction ( uuo ) , suggesting robust activation of wnt signaling in this model .
this induction was deleterious , as inhibition of wnt/-catenin signaling by a wide variety of approaches such as dkk1 , klotho , or small molecule -catenin inhibitor protected against myofibroblast activation and fibrosis .
therefore , it appears that the activation of this signaling is reparative in aki , but sustained activation is detrimental in ckd .
it remains unclear whether it is one specific wnt , or a group of wnts , that contribute to fibrosis development .
wnt/-catenin signaling elicits its actions through induction of its target genes . given that this signaling is implicated in regulating organ development and oncogenesis ,
it is not surprising that the well - characterized targets in the literature are predominantly the proliferation - related genes such as c - myc and cyclin d1 . over the last few years
, great efforts have been placed on identifying the wnt/-catenin unique target genes that are relevant to kidney injury and fibrosis .
several direct targets of wnt/-catenin are characterized , and include fibronectin , fibroblast - specific protein 1 ( fsp1 ) , snail1 , mmp-7 , plasminogen activator inhibitor-1 ( pai-1 ) , and components of the renin angiotensin system ( ras ) ( figure 2 ) . of them ,
fibronectin and fsp1 have well - known roles in fibrosis , as the former is an extracellular matrix component , whereas fsp1 is a marker for fibroblasts and myofibroblasts . in this section
, we will only discuss several recently identified wnt/-catenin targets in the setting of fibrotic ckd .
snail1 transcriptionally represses e - cadherin expression and leads to the disruption of epithelial cell
snail1 also induces id1 , a transcription antagonist that has a critical role in facilitating emt and renal inflammation .
both snail1 and -catenin are upregulated in the renal tubular epithelium in human and animal fibrotic kidneys , and activation of -catenin induces snail1 expression in tubular epithelial cells and glomerular podocytes in vitro .
interestingly , during embryologic development , the opposite occurs , as snail1 is downregulated when mesenchymal cells differentiate into the epithelium .
consistent with these findings , expression of snail1 and the epithelial marker e - cadherin are mutually antagonistic , and snail1 dominates in fibrotic disease .
a number of converging signals can lead to its upregulation , including wnt/-catenin , tgf- , and tumor necrosis factor ( tnf- ) .
it is worthwhile to stress that snail1 is not only a transcriptional target of -catenin but is also regulated post - translationally by glycogen synthase kinase-3 , the same regulatory protein governing -catenin activity .
therefore , when wnt signaling leads to the inhibition of glycogen synthase kinase-3 , both -catenin and snail1 can be potentially activated simultaneously , leading to additive or synergistic effects in promoting emt .
another downstream target of wnt/-catenin signaling is mmp-7 , a secreted zinc- and calcium - dependent endopeptidase that degrades extracellular matrix substrates such as elastin and syndecan .
it also cleaves additional substrates such as cell - associated fas ligand , promotes the release of tnf- , mediates e - cadherin ectodomain shedding , and activates other proteinases such as pro - mmp-1 , -2 , and -9 .
mmp-7 is preferentially expressed , at extremely low levels , in the epithelial cells of various normal tissues .
earlier studies documented an increased expression of mmp-7 in polycystic kidney disease , aki induced by folic acid , and obstructive nephropathy .
we have shown that mmp-7 expression is controlled by -catenin in kidney cells in vitro , that it is induced in injured kidneys , and that its level is closely correlated with renal wnt/-catenin in various models of ckd and in human kidney biopsies .
in fact , urinary mmp-7 level could serve as a surrogate biomarker for predicting the activity of renal wnt/-catenin , and it is associated with the severity of renal fibrotic lesions as well . given its ability to act on a broad spectrum of substrates including extracellular matrix , fas ligand , tnf- , and e - cadherin , mmp-7 is likely a critical factor in regulating a diverse array of cellular processes including matrix remodeling , apoptosis , inflammation , and emt .
pai-1 is a secreted acute - phase glycoprotein that is normally produced in low levels in the undamaged kidney .
however , in various human kidney diseases such as diabetic nephropathy , membranous nephropathy , focal and segmental glomerulosclerosis ( fsgs ) , and crescentic glomerulonephritis , its expression becomes highly upregulated .
as its name suggests , it is classically known for its ability to inhibit both tissue - type and urokinase - type plasminogen activators . experimental evidence from animal models
has shown that the upregulation of pai-1 is pro - fibrotic , through mechanisms as diverse as induction of tgf- and recruitment of inflammatory cells and myofibroblasts .
the promoter region of pai-1 contains a tcf / lef - binding site , suggesting that it is regulated by -catenin .
indeed , it was found that upregulation of -catenin via either tgf- or wnt stimulation could induce pai-1 expression in tubular cells , and disruption of the tcf / lef - binding site abolished this effect .
-catenin - induced modulation of pai-1 appears to be an important mechanism leading to fibrosis .
whereas ras is traditionally understood as a hormonal system with involvement of multiple organ systems , it has also been found that the kidney is capable of upregulating ras components in pathologic conditions ( intrarenal ras ) .
ras upregulation in turn leads to increased reactive oxygen species generation , nuclear factor kappa - b , and tgf- expression .
our studies have indicated that ras genes possess tcf / lef - binding sites , are upregulated by -catenin in vitro and in vivo , and ras upregulation can be blocked with -catenin inhibitors ( unpublished results ) . a link between -catenin and ras
glomerular fibrosis is often referred to as glomerulosclerosis and is the common outcome of various glomerular diseases such as fsgs and diabetic nephropathy .
recent studies have established that wnt/-catenin signaling also has a critical role in promoting podocyte injury and dysfunction , thereby contributing to the pathogenesis of proteinuria and glomerulosclerosis .
both wnt and -catenin are specifically activated in glomerular podocytes from patients with fsgs and diabetic nephropathy , suggesting the clinical relevance of the activation of this signal pathway to human proteinuric kidney disorders .
we further demonstrate that ectopic expression of the wnt1 gene aggravates podocyte injury and proteinuria in adr nephropathy , an experimental model for fsgs , whereas blockade of wnt signaling with its endogenous antagonist dkk1 reduced proteinuria and podocyte lesions .
genetic and pharmacologic activation of -catenin in podocytes is sufficient for causing proteinuria in mice , whereas podocyte - specific ablation of -catenin protects mice from developing albuminuria after adr injury .
studies also indicate that amelioration of kidney injury and fibrosis by paricalcitol is associated with its ability to inhibit wnt/-catenin . the mechanisms by which wnt/-catenin triggers podocyte injury could be multifactorial .
they often undergo a range of changes in response to injury , including hypertrophy , autophagy , dedifferentiation , detachment , and apoptosis .
podocyte depletion contributes to defective glomerular filtration , as a reduction of podocyte numbers in otherwise healthy kidneys induces proteinuria in experimental animal models .
however , numerous studies indicate that proteinuria precedes podocyte depletion , suggesting that podocyte dysfunction , rather than depletion , may be an initial cause of proteinuria in many circumstances . in this context , wnt/-catenin may lead to podocyte dysfunction through effects on regulatory molecules such as snail1 , trpc6 ( transient receptor potential cation channel , subfamily c , member 6 ) , angiotensin ii type i receptor , and wilms tumor 1 . just as in tubule cells , -catenin can induce snail1 expression , which in turn induces podocyte dedifferentiation and emt .
studies show that induction of snail1 in podocytes was associated with downregulation of nephrin and p - cadherin .
trpc6 is a calcium channel expressed in podocytes , for which mutations have been found in proteinuric renal disease .
it has been found that high glucose can activate trpc6 in a wnt/-catenin - dependent manner , which provides one explanation for how diabetes causes proteinuria .
a study also revealed that angiotensin ii exposure induces podocyte injury , whereas inhibition of wnt/-catenin by dkk1 attenuated this injury .
finally , wilms tumor 1 is a transcription factor that is exclusively expressed in glomerular podocytes in adult kidneys and is critical for maintenance of a differentiated podocyte phenotype , and can become downregulated in podocyte injury .
we recently found that wnt/-catenin signaling can target wilms tumor 1 by promoting its protein degradation via an ubiquitin - mediated pathway ( unpublished data ) .
these findings suggest that there are numerous ways in which wnt/-catenin signaling may perturb normal podocyte biology , leading to proteinuria and glomerulosclerosis .
in view of the importance of wnt/-catenin signaling in renal fibrosis , one would imagine that blockade of this signaling might be beneficial in fibrotic ckd .
indeed , investigators have used a variety of strategies to block this pathway at various steps ( table 1 ) .
for instance , sfrp4 was used in a uuo model and resulted in reduction of -catenin signaling and concomitant decreases in myofibroblast numbers and fibrosis .
similarly , klotho was shown to bind and sequester several wnts in kidney injury , leading to decreased -catenin activity and a reduction in both interstitial fibrosis and podocyte injury in different animal models of disease . both klotho and sfrps , by virtue of their wnt - sequestering mechanisms ,
dkk1 , as an inhibitor of the lrp5/6 co - receptors , has been used in a number of studies to interrupt canonical wnt signaling . in murine
it was similarly found that dkk1 was protective against podocyte dysfunction and proteinuria induced by adr .
however , as dkk1 may elicit actions by other pathways , it is unclear whether all of the protective effects of dkk1 are contributable to inhibition of wnt/-catenin .
inhibition of wnt/-catenin could be an explanation for the efficacy of existing drugs . in this
regard , vitamin d receptor ( vdr ) agonists , such as paricalcitol , have been shown to have potential renoprotective effects in ckd .
we showed that paricalcitol prevents podocyte injury and proteinuria in a mouse model of adr nephropathy .
the protective effect of this vdr agonist is at least partially attributable to its inhibition of wnt/-catenin signaling .
we found that paricalcitol triggered vdr activation and its translocation into the nucleus , where it physically interacts with nuclear -catenin and sequesters its ability to activate gene transcription .
similar vdr/-catenin interactions have also been shown to occur in tubular cells and can prevent emt under experimental conditions . as many wnts are induced in the diseased kidney , therapeutic strategies to target each individual wnt are neither practical nor efficient .
this speculation is recently confirmed by genetic approaches , in which wnt4 gene ablation in mice has no impact on renal fibrosis after uuo .
however , because all canonical wnt signaling converges on -catenin , it could be an ideal target for therapeutic intervention .
tubule cell specific and podocyte - specific knockout of the -catenin gene has no overt abnormality , suggesting that it is functionally dispensable in the kidney under normal physiological conditions .
these data provide a compelling rationale for targeting -catenin as a novel and effective approach for the treatment of fibrotic ckd .
recent studies show that icg-001 , a small molecule peptidomimetic , can selectively inhibit -catenin / tcf - mediated gene transcription .
when active -catenin translocates to the nucleus , it binds to tcf / lef transcription factors , leading to recruitment of co - activators , including cyclic amp response - element - binding protein - binding protein ( cbp ) or its closely related protein p300 , which creates a transcriptionally active complex .
icg-001 is unique in that it selectively disrupts the -catenin / cbp interaction by binding to cbp , rather than -catenin itself . although cbp and p300 are generally considered indistinguishable in terms of promoting their downstream gene expression , studies indicate that differential co - activator usage results in the selective expression of target genes . whereas -catenin
/ p300 signaling is instrumental in initiating normal cellular differentiation , -catenin / cbp - driven gene transcription is shown to be critical for inducing a dedifferentiated / proliferative state .
-catenin / cbp is also responsible for expression of fibrogenic genes such as mmp-7 , snail1 , fibronectin , pai-1 and fsp1 .
our studies show that icg-001 antagonizes tubular cell emt in vitro , while ameliorating renal fibrosis in vivo .
additional studies should confirm the therapeutic benefits of icg-001 in broader surveys of fibrotic kidney diseases .
the panoply of wnt/-catenin effects described in this review emphasizes the challenges to understanding the biological impact of this pathway on kidney disease . at this point ,
additional studies are required to further identify the exact temporal and spatial effects of this signaling in renal injury so as to properly harness therapeutic approaches to effectively treat kidney disorders .
it is , for instance , clear that while wnt/-catenin is pathologic in the development of interstitial fibrosis and chronic podocyte injuries in ckd , it also appears to be paradoxically protective in aki .
further , whereas canonical signaling has a clearly defined role in these processes , the relative contributions of non - canonical and non - traditional pathways need to be elucidated in both aki and ckd .
similarly , the exact contributions of the 19 different wnts have yet to be fully defined .
this could represent a daunting task , as genetic deletion of a particular wnt may not have a huge impact on the severity of ckd , as many wnts are simultaneously induced after kidney injury . in conclusion ,
the understanding of wnt/-catenin remains a significant challenge but one that carries immense opportunity for the therapy of kidney diseases .
Output:
| wnt/-catenin signaling is an evolutionarily conserved , highly complex , key developmental pathway that regulates cell fate , organ development , tissue homeostasis , as well as injury and repair .
although relatively silent in normal adult kidney , wnt/-catenin signaling is re - activated after renal injury in a wide variety of animal models and in human kidney disorders .
whereas some data point to a protective role of this signaling in healing and repair after acute kidney injury , increasing evidence suggests that sustained activation of wnt/-catenin is associated with the development and progression of renal fibrotic lesions . in kidney cells ,
wnt/-catenin promotes the expression of numerous fibrosis - related genes such as snail1 , plasminogen activator inhibitor-1 , and matrix metalloproteinase-7 .
recent studies also indicate that multiple components of the renin
angiotensin system are the direct downstream targets of wnt/-catenin .
consistently , inhibition of wnt/-catenin signaling by an assortment of strategies ameliorates kidney injury and mitigates renal fibrotic lesions in various models of chronic kidney disease , suggesting that targeting this signaling could be a plausible strategy for therapeutic intervention . in this mini review
, we will briefly discuss the regulation , downstream targets , and mechanisms of wnt/-catenin signaling in the pathogenesis of kidney fibrosis . |
PubmedSumm118549 | ***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 united states , there has been a movement to demand more accurate blood glucose meter performance for hospitalized patients .
food and drug administration ( fda ) in march 2010 , where many diabetes professionals requested a new two - track regulatory approach to distinguish the needs of patients who use meters at home from those of health care professionals ( hcps ) working in hospitals or other acute care settings where poc testing is performed . on 7 january 2014 ,
the fda released two draft guidance documents for blood glucose monitoring test systems . at the time this article was written ,
the two documents were being distributed for a 90-day public comment period and were not yet finalized .
one guidance is for prescription poc use by professionals in settings that include hospitals and acute and chronic care settings .
the other guidance is for over - the - counter ( otc ) self - monitoring devices used by laypeople .
the first guidance document is relevant to hospital monitoring of blood glucose in both critical and noncritical care settings .
before release of the prescription poc guidance , most blood glucose monitoring devices , including those intended for use by hcps in a hospital setting , were submitted to the fda based on accuracy claims for otc devices use by patients .
hospital - specific issues , including extreme states of hydration or blood pressure , imbalances of analytes , or severe undercurrent illnesses or other unusual physiological states associated with hospitalization , were not a significant part of the approval process . in this guidance
, the fda has specified that the performance of prescription blood glucose monitors must now be tested based on issues that arise in the intended - use population for which fda approval of the device is sought .
the proposed prescription poc blood glucose monitor guidance specifies that , to demonstrate that a blood glucose monitoring system is sufficiently accurate to be used safely by hcps , the manufacturer should demonstrate that 99% of all values are within a range of 10% of the reference method for glucose concentrations > 70 mg / dl and within 7 mg / dl at glucose concentrations < 70 mg / dl . also , to avoid crucial patient management errors ,
no individual result should exceed 20% of the reference method for samples > 70 mg / dl or 15 mg / dl for samples < 70 mg / dl.the previous standard , which the fda used for clearance of both otc and prescription poc devices was the 2003 international organization for standardization ( iso ) standard that required 95% of the measured glucose values to fall within 15 mg / dl of the average measured values of the reference measurement procedure at glucose concentrations < 75 mg / dl or within 20% at glucose concentrations 75 mg / dl .
iso 15197 - 2013 ( e ) is an international standard that delineates requirements for in vitro glucose testing measuring capillary blood glucose concentrations and performance validation by intended users ( e.g. , people with diabetes ) .
it should be noted that the latest iso standard , which was released in 2013 and is expected to be adopted by the european union in 2016 , does not specify separate accuracy requirements for patient systems and professional systems .
furthermore , the degree of accuracy required for both types of system in this iso standard is less stringent than the proposed fda requirements .
fda believes that the criteria set forth in the iso 15197 standard do not adequately protect patients using bgms [ blood glucose monitoring system ] devices in professional settings , and does not recommend using these criteria for bgms devices .
according to iso 15197 - 2013 ( e ) , also known as in vitro diagnostic test systems
requirements for blood glucose monitoring systems for self - testing in managing diabetes mellitus , the required accuracy is as follows : 95% of the measured glucose values shall fall within 15 mg / dl of the average measured values of the reference measurement procedure at glucose concentrations < 100 mg / dl or within 15% at glucose concentrations 100 mg / dl .
also 99% of individual glucose measured values shall fall within zones a and b of the parkes error grid for type 1 diabetes .
analytical accuracy is a quantitative method for describing how closely the result of a measurement by a device compares with a measurement by a reference method for this assay .
clinical accuracy is a qualitative metric for describing the clinical outcome of making a treatment decision using the result of a measurement from a device being assessed .
a blood glucose error grid is a graph that plots blood glucose monitor values on the y - axis and reference blood glucose values on the x - axis .
a set of risk zones is superimposed on the graph such that each zone represents a likely clinical outcome resulting from inaccuracy in the measured glucose values .
outcomes can range from appropriate treatment to slightly inadequate treatments requiring no corrections to serious errors causing life - threatening outcomes , with many gradations in between .
error grids permit a data set to be defined on the basis of the percentage of data points that fall into each zone of risk .
an error grid developed by the diabetes technology society in cooperation with the fda , the american diabetes association ( ada ) , the endocrine society ( tes ) , and the association for advancement of medical instrumentation ( aami ) , known as the surveillance error grid , was released this year and is discussed in more detail below .
this metric is expected to be used by the fda to assess the performance of cleared blood glucose monitors .
the recent 2014 guidance for prescription poc glucose monitors specifies five types of evaluation studies : 1 ) a precision evaluation , 2 ) a linearity evaluation , 3 ) a method comparison / user evaluation , 4 ) interference evaluations , and 5 ) flex studies .
the precision evaluation must express the precision as a mean value , standard deviation , and percentage coefficient of variation ( defined as the ratio of the standard deviation divided by the mean ) .
the linear evaluation should demonstrate adequate performance of the system across the range of glucose levels for which clearance is sought .
in addition to the percentage of data points falling within a percentage of the reference method , other methods for expressing the liner analytical accuracy of a blood glucose monitor include calculating the correlation with reference method based on the bias , slope , intercept , and r , as well as the extent of agreement or consistent bias comparing the monitor method to a reference method using a bland altman plot .
multiple - method comparison and user performance studies for blood glucose monitoring systems include multiple users and multiple devices .
an interference evaluation studies the effect of potentially interfering endogenous and exogenous substances on device performance .
these include icterus , hyperlipemia , and varying hematocrit levels , as well as some common medications .
such potential interfering medications include acetaminophen ( which is being increasingly used in hospitals for pain relief ) , ascorbic acid , l - dopa , and xylose .
flex studies stress the operational limits of a test system and should be used to validate the insensitivity of the test system to performance variation under stress conditions .
the fda recommends four types of flex studies , including 1 ) mechanical vibration testing , 2 ) shock testing , 3 ) electromagnetic compatibility , and 4 ) electrostatic discharge / electromagnetic interference testing .
next - generation poc devices will likely be required to meet stricter standards for fda clearance , especially if the 2014 draft guidance for professional poc devices is adopted .
no poc monitor is currently approved by the fda for critically ill patients , which includes patients who are typically in the intensive care unit , operating room , recovery room , or emergency room of a hospital .
this means that use of poc devices in these settings is considered an off - label use .
although use of poc devices is a standard of care in virtually every hospital in the united states , the off - label status of this practice is not in accordance with clia regulations .
therefore , a solution to this situation will be needed to permit continued legal use of these products in these settings .
hypoxemia , poor perfusion , and tissue edema can artificially alter the measured blood glucose results of poc devices .
blood glucose monitors require oxygen to complete the chemical reaction that generates an electric current that is proportionate to the blood glucose concentration .
the accuracy of some glucose meters is degraded by states of hypoxemia or low partial pressure of oxygen concentration .
therefore , venous samples ( compared to capillary samples ) will produce lower glucose results from many blood glucose monitors . during states of poor perfusion
therefore , blood glucose measurements from poc devices may be artificially lower in blood samples from patients with poor perfusion .
it is necessary to always follow the instructions on the label of the specific device used .
if a device is approved for capillary glucose testing , it should not be used on blood samples from other sources .
edematous patients might be subject to dilution of a capillary fingerstick sample by fluid in the edematous tissue overlying the capillary , which can artificially lower the measured blood glucose concentration .
critically ill patients may be affected by hypoxemia , poor capillary perfusion , or tissue edema . in these states ,
the accuracy of the poc blood glucose devices may be inadequate , and blood glucose readings in these situations can lead to insulin dosing errors .
little empirical research has been conducted in critically ill patients to assess the contribution of the above three risk factors or other potential risk factors for inaccurate performance of poc blood glucose monitoring devices .
food residue on fingers can contain glucose and lead to artificially high readings from poc testing .
therefore , hands should be cleaned with soap and water and dried ( rather than cleaned with alcohol ) before a fingerstick blood glucose test is performed .
as previously mentioned , the performance of blood glucose monitors can be described in terms of either their analytical or their clinical accuracy .
analytical accuracy describes how closely the result of the measurement method being assessed correlates to a measurement from a reference method .
clinical accuracy describes the clinical consequences of a treatment decision based on a result by the measurement method being assessed .
the need to consider clinical accuracy , especially in postmarketing analyses of specific scenarios of analytically inaccurate performance by an approved product or by a specific lot of an approved product by regulatory agencies , arises because not all blood glucose errors of a particular percentage range from the reference method have equal clinical significance .
analytical accuracy is measured by quantitative statistical metrics such as precision , bias , and percentage of data points lying within a certain percentage of the reference value .
the term reference value in assessment of a blood glucose monitor refers to a laboratory - based glucose measurement method that has been well validated for precision and accuracy and is traceable to a higher order , such as an internationally recognized reference material or method .
clinical accuracy is measured by comparing paired data points of the results of the measurement being evaluated , along with the results from a reference method as defined above , with the paired data points plotted on a grid , which is known as an error grid .
error grid analysis of blood glucose monitors was developed in 1987 by clarke et al . at the university of virginia to quantify the clinical accuracy of patient - determined blood glucose values .
this first error grid , known as the clarke error grid , analyzed the clinical relationship between a patient - generated blood glucose value and a reference blood glucose value when a treatment decision is based on the patient - generated blood glucose value . later in 1995 , parkes et al .
developed an updated error grid ( known as the parkes error grid or the consensus error grid ) , which they published in 2000 .
the good clinical accuracy of the glucowatch device , as determined by error grid testing , was an appealing feature of the product .
this contributed to its approval as this first continuous glucose monitor marketed in the united states .
as mentioned above , the diabetes technology society is working with the fda , ada , tes , aami , and representatives from the diabetes diagnostics industry on an updated error grid .
such a new metric is needed because new practices and treatments that are now standards of care were not well established when the earlier error grids were developed .
this new metric , which will be known as the surveillance error grid , will be based on work that started in 2012 and is expected to be published in 2014 .
the performance of blood glucose monitors can be adversely affected by preanalytical ( obtaining the sample ) , analytical ( performing the assay ) , or postanalytical ( reporting the results ) factors .
operator activities that affect preanalytical accuracy include overlooked food residue on the fingertips , site selection ( if arterial or venous blood is sampled instead of capillary blood , for which most monitors are indicated ) , improper lancing technique , and improper sampling of a hanging blood drop .
strip - related factors that can adversely affect preanalytical accuracy include product use past the expiration date , exposure to heat and humidity , or imprecision resulting from lot - to - lot variability .
in addition to any inherent inaccuracy of the blood glucose monitoring system itself ( e.g. , an inaccurate monitor , inadequate calibration process , or improper testing method ) , analytical factors can also adversely affect blood glucose monitoring accuracy .
these include 1 ) extreme physical environments ( e.g. , high altitude , humidity , heat , or cold , especially if vasoconstriction occurs ) , 2 ) nonstandard physiology of the patient ( e.g. , extreme hematocrit , extreme partial pressure of oxygen , or severe hypertriglyceridemia ) , and 3 ) concomitant use of certain medications , including in some cases ascorbic acid , acetaminophen , or d - xylose .
environmental , physiological , and pharmacological factors that affect monitor performance are known as interfering substances .
postanalytical factors that can adversely affect blood glucose monitor performance include display of incorrect units of glucose ( e.g. , mg / dl instead of mmol / l or vice versa ) , failure to upload data into an electronic database , incorrect data transmission to an electronic database , presentation of a misleading message , or failure to respond appropriately to glucose data . at a hospital in italy
, it was determined that , when 1,966 individual poc glucose test results were performed and then manually entered into an electronic database , there were errors of missing information ( 12.1% of measurements ) , missing time of testing ( 7.2% ) , and incorrect results ( 3.2% ) .
newer blood glucose monitors for hospital systems offer real - time electronic transfer of data , thus eliminating data entry errors .
the preanalytical , analytical , and postanalytical factors that are most likely to occur in a hospital setting are not the same as those that might typically occur during blood glucose testing in an outpatient setting .
plebani reported a series of hospital laboratory errors divided into preanalytical , analytical , and postanalytical categories . the causes and distributions of that hospital 's errors
because of the risk and liability of measurement errors , many hospitals have written policies prohibiting the use of information from otc blood glucose meters that patients bring into the hospital and operate themselves .
the fda has categorized the most common blood glucose monitor errors in terms of their potential sources ( e.g. , errors caused by monitor design , production , or use ) .
phases in diagnostic processing leading to missed diagnoses potential sources of error in blood glucose monitors based on fda experience
proper inpatient glycemic management requires timely blood glucose results with careful consideration of sample size , patient comfort , test time , nursing work flow , cost , and ability to automatically transfer results into the electronic medical record so they are readily available to clinicians to make treatment changes .
prescription blood glucose monitors for use by hcps at the bedside are already widely used for this purpose .
regulatory bodies in the united states and europe are requiring progressively greater levels of accuracy for these products . even with accurately performing monitors , it is necessary to follow proper procedures to avoid errors .
measurement errors caused by perturbations in patient s physiological state or interference from concomitant use of medications can result in analytical errors .
proper training for health care staff and knowledge of how these devices work are both necessary to get the highest quality and most useful information from blood glucose monitoring in the hospital setting .
Output:
| in briefpoint - of - care ( poc ) tests provide analytical information that can be used to make decisions at patients ' bedside , as opposed to laboratory tests that must be run at a central laboratory .
poc testing is a widely used tool to enable immediate determination of glucose levels in hospitalized patients and facilitate rapid treatment decisions in response to fluctuations in glycemia .
accurate poc glucose testing requires attention to various factors before , during , and after performance of tests .
these include 1 ) proper preparation of test sites to avoid preanalytical errors , 2 ) proper identification of tested patients whose physiological status permits sampled capillary specimens to correlate with central venous blood glucose levels to avoid analytical errors , and 3 ) proper documentation of the fidelity of meter results with the medical record to avoid postanalytical errors . |
PubmedSumm118550 | ***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 it was first described by semm in 1983 , laparoscopic appendicectomy has gained acceptance as a diagnostic and treatment method for acute appendicitis .
appendicitis constitutes a nosologie entity whose incidence is about 7% in industrialized countries ; a usa report shows approximately 300,000 cases / year , with the greatest incidence falling in the 2nd and 3rd life decade and with a rate of 3 - 4:1 among men and women during puberty .
about 40% of cases of appendicitis are incorrectly diagnosed in women during their reproductive years , and approximately 20 - 30% of patients submitted to surgical interventions do not show any inflammatory alterations of the appendix .
many surgeons have demonstrated that a videolaparoscopic approach ( vla ) to acute appendicitis is possible during several stages of the inflammatory process , depending upon the surgeon 's experience .
there are absolute and relative contra - indications given by surgeons , which include previous operations on the lower abdomen and situations where a pneumoperitoneum may have deleterious hemodynamic effects . as for traditional , or open , appendicectomy
nonetheless , they omit data regarding morbidity and mortality of davis and mcburney 's technique . regarding questions concerning the advantages and dis - advantages of a videolaparoscopic approach in the treatment of acute appendicitis ,
the authors propose establishing a comparative parallel study between videolaparoscopic and traditional appendicectomy , giving priority to duration of surgery , morbidity and mortality evaluation , costs and duration of hospitalization .
between january 1992 and march 1998 , 496 patients were admitted by the general surgery service of sao rafael hospital ( salvador city - bahia state , brazil ) with signs and symptoms of acute appendicitis and with indications for appendicectomy .
of the 496 patients , 332 ( 66.9% ) were submitted to the videolaparoscopic approach ( group 1 ) ; 164 ( 33.1% ) to the traditional , or open , technique ; and 18 ( 5.4% ) , initially to the videolaparoscopic technique , and a posteriori converted to the traditional technique ( group 2 ) , due to the occurrence of adherences , necrosis of the appendix stump or hemodynamic instability .
the traditional ( open ) appendicectomy technique involved utilizing a mcburney 's incision or a para - rectal incision .
videolaparoscopic surgery was performed with the patient in the dorsal decubitus position , slightly inclined to the left side , and securely bound to the operating table .
the surgery staff was positioned on the patient 's left side , while video equipment was positioned on the right .
the videolaparoscopic technique utilized three trocars placed 1 ) in the umbilical region with a 10 mm optic .
( after having acquired the 5 mm optics , we started using the 5 mm trocar . ) , 2 ) in the left - side fossa iliac ( 10 mm ) , and 3 ) 2 cm above the pubis ( 5 mm ) , after having initiated pneumoperitoneum with the aid of a veress needle .
the upper limit of induced intra - abdominal pressure was limited to 12 mm hg . after a general examination of the abdominal cavity ,
ties , two of the ties placed proximally near the base of the appendix , and a third on the distal part . stump invagination was not performed .
the appendix was deposited in an endobag or surgical glove when there was a possibility of rupture and extracted via a 10 mm trocar .
the studied variables were sex , age , signs and symptoms presented upon admission ( preoperative ) , antibiotic therapy , position and aspect of the appendix , cavity drainage and surgery duration ( intraoperative ) , time of presentation of flatulence and bowel sounds , postoperative complications , and postoperative length of stay
. statistical analysis of the results obtained from this prospective , non - randomized study was done by means of kruskal - wallis and mantel - haenszel tests , considering a difference among values whose p is less than or equal to 0.05 ( p 0.05 ) , as statistically significant .
among the 496 patients operated on , 251 ( 50.6% ) were males and 245 ( 49.4% ) were females , with a mean age of 29.8 years ( table 1 ) . via vs open - surgery : sex and age .
if symptoms referred upon admission are taken into account , 41 patients ( 8.3% ) presented with intestinal obstipation , 72 ( 14.5% ) had diarrhea , 253 ( 51% ) had a fever , and 313 ( 63.1% ) had nausea and vomiting ( table 2 ) .
blumberg 's sign was present in 342 patients ( 69% ) ; plastron was detected upon examination of 24 patients ( 4.8% ) , while 339 patients ( 68.3% ) presented with a leucocyte count > 10.000 ( table 3 ) . as regards anaesthetic risk , utilizing the american society of anesthesiologists ( asa ) criteria ,
365 patients ( 80.8% ) were asa 1 , 75 ( 16.6% ) were classified as asa 2 , 11 ( 2.4% ) patients were considered as asa 3 , and 1 case ( 0.2% ) was asa 4 .
table 4 shows the anaesthetic risk , taking into account both videolaparoscopic and traditional approaches .
the appendix was found in the subhepatic position in 5 cases ( 2.2% ) , in the iliac position in 10 cases ( 4.4% ) , in the pelvic position in 19 cases ( 8.5% ) , and in the fore ( anterior ) position in 22 cases ( 9.9% ) ; it was retrocecal in 66 cases ( 29.4% ) and internal lateral in 102 cases ( 45.5% ) ( table 5 ) . as regards anatomopathological aspects , 243 patients ( 50.5% ) presented with an edematous appendicitis , 120 ( 24.9% ) with a purulent appendicitis , 84 ( 17.5% ) with necrosis of the appendix , and 34 ( 7.1% ) with perforation .
fifteen cases were excluded as patho - logic references were not made ( table 6 ) .
drainage of the abdominal cavity was carried out in 30 patients ( 9% ) belonging to group 1 and in 43 patients ( 26.2% ) belonging to group 2 , this difference being statistically signifi - cant ( p = 0.006 ) .
the average surgical time of videolaparoscopic appendicectomy was 84.4 minutes , while the time referring for the traditional open procedure was 59 minutes .
antibiotic prophylaxis consisted of mefoxin ( 2 g intravenously as a single dose at induction of anesthetic ) and was utilized in 306 patients ( 92.2% ) from group 1 and in 153 patients ( 93.3% ) from group 2 ( table 7 ) .
postoperatively , 1.3 and 1.4 days were the average times required for the appearance of flatulence in patients submitted to appendicectomy through videolaparoscopy and the open traditional method respectively .
no statistically significant difference ( p = 0.78 ) could be verified between the two values . from group 1 ,
23 patients ( 6.9% ) presented with postoperative complications ( table 8) , while 30 patients ( 18.3% ) from group 2 presented with postoperative complications .
emphasis was given to abdominal wall infection , noted in three cases among patients submitted to the laparoscopic approach and in six cases among those submitted to the traditional procedure .
finally , patients submitted to appendicectomy through videolaparoscopy stayed in the hospital for an average of 3.9 days , while those submitted to the open procedure remained for an average of 5 days , the difference between these two values being statistically significant ( p = 0.006 ) .
the use of videolaparoscopy for treating acute appendicitis has gained acceptance after the development of laparoscopic cholecystectomy . since 1983 ,
when semm first described the laparoscopic removal of an appendix , a number of studies have been developed with the aim of clarifying the advantages and disadvantages of the laparoscopic surgical approach . in 1991 , for example , pier and colleagues , from linnich , germany , reported on 625 laparoscopic appendicectomies performed in that year , showing excellent results .
zaninotto et al and laine et al proved the advantage of using laparoscopy in female patients during their reproductive years . comparing traditional appendicectomy ( open surgery ) and the videolaparoscopic approach ,
several recent papers have identified areas of concern that included duration of the operation , length of hospitalization , global costs , as well as postoperative complications , with emphasis given to abdominal wall infection . from our results described above
, no statistically signifi - cant difference emerged relative to the age of patients submitted for videolaparoscopy or traditional open surgery .
most patients , either men or women , were able to undergo the videolaparoscopic procedure .
as regards surgical risk , there was no significant difference between the appendicectomized patients , be it through the laparoscopic procedure or the traditional method .
the conversion rate of laparoscopic appendectomy to laparotomy has averaged 9.3% ( 0 to 30.4% ) .
cox et al mention a 15% average , mcanena et al a 13.5% average , schroder et al and attwood et al a 7% conversion average .
these conversions took place in situations when there was appendiceal perforation , perforation with fecal soilage , retrocecal appendix , unclear anatomy , presence of plastron , abscess and intraoperative bleeding .
our conversion rate was 5.4% , somewhat better than the average quoted in the literature .
mcanena et al8 and schroder et al demonstrated that there is no statistically significant difference between the duration of videolaparoscopic appendicectomy and appendicectomy performed through open surgery .
attwood et al showed that , on average , 51 minutes were needed to complete an open procedure , while 61 minutes were needed to complete the laparoscopic approach .
our results demonstrated that traditional surgery was faster ( 59 minutes ) when compared to videolaparoscopy ( 84.4 minutes ) , with confirmation that a longer operative time is a disadvantage of the laparoscopic method .
there is evidence in the literature suggesting that laparoscopic appendicectomy reduces postoperative pain , since the trocar orifices are less traumatic than incisions with muscle division , and there is , therefore , a smaller amount of tissue trauma .
our results also showed that postoperative complications of patients submitted to laparoscopic surgery are less frequent than with those submitted to open surgery .
one should also point out that infection is significantly less , due to lack of contamination to the abdominal wall . on the other hand , richards et al do not confirm a reduction of intra - abdominal abscesses in patients who have been submitted to videolaparoscopic appendicectomy .
for some authors , laparoscopic appendicectomy for perforated appendicitis was associated with an increase of abscess formation .
we found a statistically significant reduction in the number of complications presented in patients belonging to group 1 ( 6.9% ) , when compared to patients of group 2 ( 18.3% ) .
patients who underwent videolaparoscopic appendicectomy typically had a shorter length of stay ( 3.9 days ) , according to our results .
mcanena et al , attwood et al , ortega et al , and cox et al presented similar results in their work . on the other hand ,
kum et al , zaninotto et al , and minne et al did not find any difference .
according to fritts / orlando , hospital costs for performing videolaparoscopic appendicectomy are us$6,711 , while hospital costs for open surgery amount to only us$6,369 .
schroder et al state us$6,213 and us$8,683 as the respective costs for open versus laparoscopic appendicectomy . in our area ,
hospital costs for performing open appendicectomy are approximately us$2,300 , while those for the videolaparoscopic approach correspond to approximately us$2,915 .
in short , we have demonstrated that laparoscopic appendicectomy is a safe alternative for treating acute appendicitis .
furthermore , it presents advantages such as a shorter hospitalization period and less morbidity , with a smaller rate of abdominal wall infection .
analyzing more recent studies , there is an indication that laparoscopy is becoming the first - choice method for management of acute appendicitis .
for this reason , disadvantages such as longer duration of surgery , higher costs , as well as technical limitations must be overcome .
Output:
| there are many questions regarding the advantages and disadvatanges of a videolaparoscopic approach in the treatment of acute appendicits .
the authors present the results of a non - randomized , prospective study with 496 patients admitted between january 1992 and march 1998 by the general surgery service of so rafael hospital -salvador - ba - brazil .
the patients were submitted for appendicectomy by video laparoscopy or by the traditional open method , and variables such as surgery duration , morbidity , mortality , costs , and length of stay ( los ) were compared .
the results demonstrate that laparoscopic appendicectomy is a safe alternative for treatment of acute appendicitis ; however , there are several disadvantages that gradually must be overcome . |
PubmedSumm118551 | ***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: panax ginseng meyer root has been considered as a medicinal plant in eastern countries for thousands of years , and has been widely used for its health promotion in various disease conditions .
panax ginseng can be classified by its processing methods and include fresh ginseng , white ginseng ( air - dried ) , red ginseng ( steamed ) , and sun ginseng .
notably , red ginseng , which is harvested at 6 yr , steamed , and then further dried , is well known for its elevated content of ginsenosides , which are bioactive compounds , .
red ginseng also exhibits various biological activities against chronic diseases , such as diabetes mellitus , cancer , and cardiovascular disease , .
red ginseng is composed of saponin ( generally known as ginsenosides ) and nonsaponin , including polysaccharides
. the main active components in red ginseng are ginsenosides containing triterpene and sugar moieties .
ginsenosides can be divided into three groups depending on their structures : ( 1 ) the panaxadiol group , including rb1 , rb2 , rb3 , rc , rd , rg3 , and rh2 ; ( 2 ) the panaxatriol group , including re , rf , rg1 , rg2 , and rh1 ; and ( 3 ) the oleanolic acid group , including ro , as shown in fig . 1
.
the amount of ginsenosides vary according to harvest time , storage condition , and processing methods .
although there are other panax species , such as panax notoginseng , panax japonicus , panax quinquefolius , panax pseudoginseng , and panax vietnamensis as shown in table 1 , this review focuses on the biological activities of panax ginseng .
certain levels of reactive oxygen species ( ros ) , such as superoxide , hydroxyl radical , and hydrogen peroxide , are necessary for crucial roles in differentiation , proliferation , and regulation of signal transduction in cells .
ros are constantly produced from mitochondria via the respiratory chain and the nicotinamide adenine dinucleotide phosphate ( nadph ) oxidase system , and can be eliminated by enzymatic and non - enzymatic ros scavenging factors , such as superoxide dismutase ( sod ) , catalase ( cat ) , glutathione peroxidase ( gpx ) , reduced glutathione ( gsh ) , thioredoxin , and nf - e2-related factor 2 ( nrf 2)-mediated expression of heme oxygenase 1 ( ho-1 ) , resulting in redox homeostasis , .
however , impaired redox homeostasis results in excessive ros , which is associated with the progression of several chronic diseases , such as diabetes , cancer , alzheimer 's disease , and cardiovascular diseases . for these reasons , reducing oxidative stress by increased antioxidant intake is an attractive strategy for the prevention of such chronic diseases .
proper biomarkers for oxidative stress validate the efficacy of red ginseng for evaluating the risk of chronic diseases .
ros determination in cells can be achieved by treatment with 2,7-dichlroflurescein diacetate ( dcf - da ) . oxidized dcf - da
is changed to 2,7-dichlroflurescein , which appears under fluorescence examination and can be detected by a microscope , flow cytometry , or microplate reader .
oxidative modification of macromolecules ( dna , lipids , proteins , and carbohydrates ) are used to assess levels of oxidative stress , because of the short - lived nature of ros .
oxidation of the eighth guanine of dna can be detected by 8-hydroxydeoxyguanosine ( 8-ohdg ) in serum , urine , and tissue .
additionally , phosphorylation of a histone h2a variant ( h2ax ) at ser19 , can be determined by immunoblotting and immunohistochemistry in tissues as a novel biomarker for dna damage by estimating the number of double - strand breaks .
comet assays ( single - cell gel electrophoresis ) also have been used for determination of dna damage , which is closely related to cancer incidence .
isoprostanes ( isops ) and malondialdehyde ( mda ) are by - products of lipid peroxidation from arachidonic acid and polyunsaturated fatty acid ( pufa ) , respectively .
measurement of isops in the plasma and urine can be performed by lc - ms , gc - ms , radioimmunoassay , and enzyme - linked immunosorbance assays ( elisa ) .
mda levels can be quantified through a reaction with thiobarbituric acid ( tba ) , resulting in an mda - tba adduct that appears as colored end products .
additionally , oxidized low - density lipoprotein ( oxldl ) is associated with oxidative stress , and 4-hydroxy-2-nonenal ( hne ) can be produced by oxygen attack on -6-pufa , which can make adducts with other macromolecules .
the hne forms a michael adduct with cys , lys , and his residues on proteins , and these adducts serve as advanced lipoxidation / glycation end products that are closely associated with various chronic diseases , such as cardiovascular diseases , chronic obstructive pulmonary diseases , and neurodegenerative diseases , , .
the advanced glycation end products can bind to their receptors , resulting in promotion of inflammatory factor production , which in turn produces oxidative stress and irreversible cellular dysfunction .
additionally , protein modifications , such as nitrotyrosine and s - glutathionylation , can also be used as biomarkers for oxidative stress ( fig . 2 ) .
red ginseng water extracts were shown to scavenge free radicals , such as 1,1-dipheny-2-picrylhydrazyl , hydroxyl , superoxide , and carbon - centered radical in vitro
. additionally , red ginseng water extract decreased ros - induced bacterial plasmid dna - strand breaks in vitro
.
due to the feasibility of diverse approaches , the antioxidant activities of red ginseng have been studied extensively in cells ( table 2 ) .
red ginseng has a protective effect against cisplatin - induce ototoxicity , and pretreatment with red ginseng extract ( 2.5 mg / ml , major constituents : rb1 , rg1 ) before inducing ototoxicity by cisplatin - attenuated apoptosis in hoi - oc1 auditory cells inhibited ros production . additionally , treatment with red ginseng extract ( 0.5 mg / ml ) upregulated nrf - induced ho-1 in polychlorinated biphenyl ( pcb ) 126-treated pc12 rat pheochromocytoma cells .
red ginseng also rescues cells from oxidative stress by increasing the concentration of antioxidant enzymes , such as sod , cat , and gpx in hydrogen peroxide - treated hepg2 hepatoma cells , indicating cytoprotective effects in the liver .
red ginseng ( 11,000 g / ml ) and its ginsenosides ( rg3 and rh2 at 130 g / ml ) mitigated to the hepatocytic injury by increasing its antioxidant capacity .
the underlying mechanism of antioxidant activities associated with red ginseng is due to the downregulation of ros - stimulated mitogen - activated protein kinase ( mapk ) and akt pathways , , .
when ros was induced by hydrogen peroxide , the saponin fraction of red ginseng ( 50100 g / ml ) significantly decreased ros detected by dcf - da assay and mda levels , as well as improved antioxidant enzyme activities . it was suggested that saponin in red ginseng prevents oxidative stress - induced hepatic diseases , and that the effects were stronger as compared with those of white ginseng extract .
additionally , red ginseng extract ( 1 mg / ml ) eliminated arachiodonic acid + iron - induced oxidative stress in hepatocytes from diverse origins , including hepg2 ( human ) , h4iie ( rat ) , and aml12 ( mouse ) cells .
the inhibition of lkb1/amp - activated protein kinases ( ampk ) was reported to be a major mechanism associated with red ginseng antioxidant activity .
red ginseng water extract ( 0.33 mg / ml ) blocked ros generation and neuronal apoptosis , which was stimulated by glutamate , n - methyl - d - aspartate , or -amyloid in rat cortical cells .
these results implied the potential of red ginseng to aid in the prevention of neuronal diseases .
additionally , red ginseng extract ( 0.011 mg / ml ; major constituents : rb1 , rb2 , rc , rd , re , rf , rg1 , and rg3 ) was reported to have a neuroprotective effect on primary rat hippocampal neurons , where toxicity was induced by kainite , a glutamate analogue .
helicobacter pylori has been studied as a causative bacteria that increases the risk of gastritis by triggering inflammation cascades . h. pylori - associated inflammation causes oxidative stress by recruiting neutrophils and macrophages to an infection site .
red ginseng extract ( 1100 g / ml ; major constituents : rb1 , rb2 , rc , rd , re , rf , rg1 , rg2 , rg3 , and rh1 ) reduced expression of inflammatory factors by suppressing nadph oxidase activity and jak2/stat3 in ags human gastric epithelial cells . furthermore , treatment with red ginseng ( 1050 g / ml ) was beneficial to enhancing cell survival under radiation exposure by inhibiting ros generation and activation of the mapk signaling pathways . in an in vitro model of vascular diseases ,
red ginseng extract ( 0.52 mg / ml ) exhibited a protective effect on oxidative stress - induced cell death in endothelial cells by upregulating thioredoxin reductase 1 and downregulating ros generation , p38 , and pkc- expression in endothelial cells damaged by ,-unsaturated aldehyde acrolein and hydrogen peroxide , . furthermore , red ginseng extract ( 0100 g / ml ) was effective at inhibiting cytokine - induced cell death by downregulating apoptosis cascades and ros production in min6n8 cells and pancreatic cells .
in particular , ginsenosides at low concentrations of 0.11.0 g / ml were responsible for such activity , introducing he possibility for red ginseng use in diabetic treatments .
therefore , various red ginseng studies evaluated biomarkers of oxidative stress in young versus aged animals , as well as sexual dysfunction and kidney dysfunction ( table 3 ) .
aged rats fed red ginseng water extract ( 200 mg / kg / d ; major constituents : rb1 , rb2 , rc , rd , re , rf , rg1 , rg3 , and rh1 ) exhibited a significant reduction in oxidative stress as determined by mda , as well as elevated concentration of antioxidant factors , such as sod , cat , gpx , glutathione reductase ( gr ) , glutathione - s - transferase ( gst ) , reduced glutathione , vitamin c , and vitamin e in various organs . as male adults become older , one physical problem is sexual dysfunction .
red ginseng intake ( 200 mg / kg / d ) in aged rats restored sexual function as estimated by enhancement of both sperm maturation and impaired testicular functions .
the underlying mechanism for these alterations was revealed to be due to the antioxidant functions of red ginseng .
rats fed with red ginseng also displayed reduced mda levels , while enzymatic and non - enzymatic antioxidants were elevated .
other symptoms observed in aging rats was renal dysfunction ; however one study showed that red ginseng treatment ( 200 mg / kg / d ; major constituents : rg1 , rb1 , rg3 , re , rc , rb2 , and rd ) rescued oxidative - stress damaged renal tissue as detected by 8-ohdg and advanced glycation end - product levels .
as listed in table 3 , red ginseng oil ( 1050 mg / kg / d)-fed mice exhibited improvements in carbon tetrachloride ( ccl4)-damaged liver tissue following upregulation of antioxidant capacity , as well as downregulation of the mapk pathway .
additionally , rats administered 250mg / kg / d red ginseng extract prior to injection of aflatoxin b1 to induce hepatocyte damage showed decreased apoptosis levels in liver tissue and elevated antioxidant enzyme levels .
red ginseng extract treatment ( 250500 mg / kg / d ) also relieved symptoms of fatty liver induced by chronic exposure to ethanol . in this study , lipid peroxidation as determined by 4-hne and oxidative - protein modifications evaluated by nitrotyrosine were both decreased .
furthermore , ampk / sirt1 levels were reported to be involved in the observed decrease in oxidative stress .
fermented red ginseng extract ( 100200 mg / kg / d ) treatment of diabetic rats exerted antioxidant effects , and red ginseng ( 0.20.4 mg / kg / d ; major constituents : rg1 , rb1 , rg3 , re , rc , rb2 , rd , rf , rh1 , and rg2 ) administration reduced cyclosporine - induced elevated 8-ohdg levels in mouse pancreas , , indicating anti - diabetic effects .
gastric ulcers can be induced by oral administration of hydrochloride in ethanol or indomethacin in mice .
red ginseng treatment ( 30300 mg / kg / d ) with these drugs resulted in a decrease in ulcer area and tbars .
interestingly , high temperature- and high pressure - treated red ginseng ( 100 mg / kg / d)-fed mice ameliorated exercise - induced oxidative stress as compared with commercial red ginseng extracts ( 100 mg / kg / d ) . when saponin was fractionated from red - ginseng crude extract and administered to mice with arthritis , the red ginseng saponin extract ( 10 mg / kg / d ; major constituents : rg3 , rk1 , and rg5 ) reduced not only inflammatory factors , but also lipid peroxidation and nitrotyrosine levels . additionally , the recovery of antioxidant enzymes in the liver and kidney that had been damaged by oxidative stress was also observed .
furthermore , red ginseng ( 25 mg / kg / d ; major constituents : rb1 and rg1 ) reduced incidence of skin cancer induced by 7,12-dimethylbenz(a)anthracene and croton oil through antioxidant mechanisms .
biomarkers that were utilized to determine antioxidant activities of red ginseng in humans are listed in table 4 .
three grams of red ginseng per day and 6 g / d of red ginseng were randomly allocated to healthy participants for 8 wk along with a placebo .
the participants that ingested red ginseng displayed elevated levels of antioxidant enzymes that were greater than the placebo group , along with decreased levels of dna damage ( detected by alkaline comet assay ) and lipid peroxidation ( detected as oxldl levels ) . reduced estrogen levels in postmenopausal women are associated with high - risk of cardiovascular diseases .
postmenopausal women who ingested 3 g / d of red ginseng for 12 wk displayed higher concentrations of antioxidant enzymes relative to the placebo group .
furthermore , serum mda levels were also reduced , although ingestion of red ginseng had no effect on serum 8-ohdg levels .
there have been limited studies on the antioxidant activity of red ginseng in humans . although ginseng has been regarded as safe , , several studies warned about adverse effects of red ginseng , including allergies and toxicity to the heart , kidney , liver , and reproductive organs .
additionally , depending on the processing method , the amount and type of ginsenosides vary .
therefore , application of red ginseng in humans requires development of a standard processing method and various other controlled conditions , such as proper daily dose duration and accurate determination of patient health status .
as previously described , red ginseng is produced through a process of steaming and drying of white ginseng , resulting in improved stability and elevated ginsenoside content . despite its reported health benefits , studies on red ginseng are still limited in asia , in contrast to worldwide studies on white ginseng .
therefore , further studies on the efficacy of red ginseng in western countries and direct comparison with white ginseng regarding their reported functions are necessary . in summary ,
red ginseng and ginsenosides , the major bioactive constituents in red ginseng , have biological functions ameliorating various disease symptoms via antioxidant mechanisms in cells and animals ( especially in rodents ) .
although , there are limitations with respect to human studies on the effect of red ginseng , ingestion of red ginseng has also been shown to improve antioxidant activities in humans determined by various biomarkers of oxidative stress . taken together , ingestion of red ginseng can be a preventive strategy against oxidative stress associated chronic diseases .
Output:
| the steaming process of panax ginseng has been reported to increase its major known bioactive components , ginsenosides , and , therefore , its biological properties as compared to regular panax ginseng . biological functions of red panax ginseng attenuating pro - oxidant environments associated with chronic diseases are of particular interest , since oxidative stress can be a key contributor to the pathogenesis of chronic diseases .
additionally , proper utilization of various biomarkers for evaluating antioxidant activities in natural products , such as ginseng , can also be important to providing validity to their activities .
thus , studies on the effects of red ginseng against various diseases as determined in cell lines , animal models , and humans were reviewed , along with applied biomarkers for verifying such effects .
limitations and future considerations of studying red ginseng were been discussed .
although further clinical studies are warranted , red ginseng appears to be beneficial for attenuating disease - associated symptoms via its antioxidant activities , as well as for preventing oxidative stress - associated chronic diseases . |
PubmedSumm118552 | ***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: secondary implications of malignancies are often more life - threatening than the malignancy itself and need early detection and urgent intervention .
we report a similar case of a young gentleman , with a bulky friable middle esophageal mass , which invaded the bronchus , resulting in a broncho - esophageal ( be ) fistula , resulting in lung abscess .
this highlights the importance of fdg pet / ct in detecting associated life threatening condition in an oncological setting .
he also had recent onset high grade fever with chills . nasogastric tube ( ngt )
upper gastro - intestinal endoscopy ( ugie ) showed friable mass in the middle third of esophagus , biopsy from which showed adenocarcinoma cells . staging fdg pet / ct study
maximum intensity projection image showed an hypermetabolic area in mid - thorax [ figure 1a - thick arrow ] with diffuse low grade uptake around it [ figure 1a - thin arrow ] .
axial fused pet / ct image [ figure 1b and c- arrow ] showed a large intensely fdg avid soft - tissue mass in the middle third of esophagus , closely abutting the right main and segmental bronchi , measuring 32 mm 32 mm , with maximum standardized uptake value of 27.2 . abutting this mass , a centrally necrotic ill - defined mass , with air pockets within and peripheral low intensity fdg uptake in the thick walls ; was seen in the right lung parenchyma , in the lower lobe [ figure 1b and c - arrow heads ] .
minimum intensity projection ( minip ) reformatted sagittal [ figure 2a ] and axial ct [ figure 2b ] images showed a definite communication ( arrow - head ) between the mass ( thick arrow ) and the right lower lobar bronchus ( thin arrow ) .
patient , when again asked for any complaints , said to have coughing immediately after swallowing . on collating history and imaging findings and also considering the fact that the patient underwent interventions like ngt placement and ugie , a diagnosis of lung abscess secondary to be fistula was made .
( a ) mip image showing intense fdg uptake in mid - thorax ( thick arrow ) with an area of low grade uptake abutting it ( thin arrow ) , ( b and c ) axial pet / ct images show large middle esophageal mass with bronchial invasion ( arrow ) with a centrally necrotic ill - defined mass adjacent to it ( arrow heads ) sagittal ( a ) and axial ( b ) reformatted ct images in minip window showing definite communication ( arrow head ) between the mass ( thick arrow ) and right lower lobar bronchus ( thin arrow )
they present as bouts of coughing while eating or drinking , known as ohno 's sign and sometimes with recurrent pulmonary infections .
difference in density and fdg uptake intensity of the two adjacent lesions on ct and pet images respectively and radiological features of central necrosis with few air - pockets in the lung parenchymal lesion , confirmed it to be an abscess .
following interventions , especially in the presence of a large tumor with friable margins in close proximity with bronchi , there is a greater risk of perforation and fistula formation .
this is of particular importance in cancers involving middle third of esophagus , where there is close proximity of primary mass to trachea and bronchus . since the entire focus is on tumor staging and management , specific symptoms as seen in our patient
however , proper assimilation of history and imaging findings , with use of reconstruction techniques on pet / ct helped us pick up this life threatening condition in a case of esophageal cancer , which led to urgent intervention and also a drastic change in the management of primary malignancy .
Output:
| sinister undesirable pathologies often accompany malignancies .
though the entire emphasis is on cancer management , these benign conditions are more life - threatening than the primary malignancy itself .
we report an interesting imaging finding of broncho - esophageal fistula leading to lung abscess on 18f fluoro - deoxy - glucose positron emission tomography / computed tomography ( fdg pet / ct ) in large middle esophageal cancer , which due to early detection , was promptly managed . |
PubmedSumm118553 | ***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 x - ray crystallography can be used to determine molecular structures at atomic resolution in principle , it is often not possible because of limitations in crystal quality .
due to their inherent flexibility and the relative sparsity of contacts with which to hold a crystal lattice together , the highest resolution where x - ray diffraction data are measurable is often worse than 3.5 .
the protein data bank currently contains 863 entries at resolutions lower than 3.5 and their number seems to be increasing rapidly .
one might ask why researchers bother to solve structures that clearly will not yield near - atomic level detail rather than focusing on projects where such detail can be revealed ?
it turns out that a large number of some of the most important questions that structural biology attempts to address involve determining how large macromolecules and their complexes assemble , and understanding how their components interact .
substantial insight into these issues does not necessarily require structures at near - atomic resolution , although if such structures were possible to obtain they would clearly be much more desirable .
given that biological interest is focused on large complexes , the crystallographer often has no choice but to compromise and accept and deal with the inherent experimental limitation of low resolution .
the road to a low resolution crystal structure is a difficult one to navigate , paved with potholes of frustrations and ambiguities , and it is in sharp contrast to what feels like driving on a well - lit multilane highway when resolutions better than 3 are available ; here , progress can be trusted to automated programs that require less and less human intervention as technology develops .
the principal difficulty in low resolution structure determination stems from the limited number of independent ( unique ) x - ray reflections . in principle , in order to determine a structure , one would need at least as many independent reflections as the number of flexible torsions in the molecule or assembly , so if diffraction data were available at least to about 5 , in most cases determination should be possible .
( the exact number varies depending on solvent content , as this relates to the sampling density of the molecular transform . )
diffraction data that are limited to low resolution also tend to be weak , and therefore the error in the intensity estimates could be high .
furthermore , data might be affected substantially by systematic errors such as radiation decay because experimenters tend to expose their crystals to large x - ray doses in order to get stronger diffraction .
since the experimental information is very limited compared to the number of degrees of freedom , redundancy is minimal or none , and the intensity errors are especially detrimental .
in addition , data quality can be further compromised if the final data set is the result of merging partial sets collected on a number of crystals that may be only approximately isomorphous .
in some cases , some relatively trivial measures have been used to improve data quality .
for example , in order to detect reflections beyond 4.5 in the case of crystals of the siv ( simian immunodeficiency virus ) gp12 envelope glycoprotein , it was important to make sure that a small beamstop was placed close to the crystal and to move the detector 400 mm back from it .
this served to minimize the background , as the diffraction limit is basically a signal to noise issue ; most of the noise ( which is mainly from background ) is contributed by the diffuse scattering from the sample and from air scattering of the direct beam .
large crystal - to - detector distances are especially helpful at those synchrotron beamlines where the beam has very small crossfire . in addition
, there is the problem of the series termination errors that give rise to ripples next to real density features ( see e.g. , minichino et al . and references therein ) . also , diffraction that is not isotropic , with diffraction limits that are dependent on the direction of the scattering vector ,
this situation can be helped by ellipsoidal truncation and anisotropic scaling that can , for example , be done on the ucla ( university of california , los angeles ) web server or the ccp4 ( collaborative computational project no .
the effects of radiation decay in the data sets can be alleviated by applying the so - called zero dose correction , provided that each unique reflection was measured a number of times , which may be difficult to achieve in low symmetry space groups .
the combination of the above sorts of factors will almost always lead to electron density maps that are noisy and lacking in detail . in the 4 - 5 resolution range , -helices appear as tubes and -sheets as walls of density with no indication where the individual strands might run .
indeed , for the latter , the hydrogen bonding between -sheet strands is notorious for causing confusion in tracing the path of the polypeptide chain . of course , even to see this much , some kind of phase information is needed in addition to the intensity data . unless the macromolecular assembly is mainly made up of -helical domains , in this resolution
range a complete de novo structure determination without known three - dimensional structures of its components and domains is extremely challenging and in many cases might be impossible .
an important exception is the class of cases where high - order non - crystallographic symmetry is available , such as in the case of spherical or cylindrical viruses .
it is increasingly the case , indeed now very often , that the three - dimensional structures of the components or fragments of the molecule or assembly in question are already available , and this opens up an avenue towards generating useful initial phase information .
modern automated molecular replacement ( mr ) programs such as phaser or amore can generate good solutions even when the search model is a relatively small fraction of the total scattering mass . also , programs such as phaser allow an ensemble of search models to be used , thus widening the radius of convergence of mr an important limitation when only one search model is used .
however , for any mr approach to provide meaningful phase information , a large fraction of parts of the assembly has to be known three - dimensionally and the fragment structures should not change much upon assembly formation . in favorable cases ,
a simple difference fourier calculated with the mr - based model phases can reveal interesting and previously unseen parts of the assembly .
even when mr is able to place the fragments , it remains extremely desirable to have some experimental phase information .
this may come from a selenomethionine ( se - met ) multi - wavelength anomalous diffraction ( mad ) experiment , or from heavy atom soaks with , for example , the ta6br12 cluster , which is especially suited for low resolution work on large assemblies .
the heavy atom substructure should then be solvable with phases computed from the mr solution .
optimizing the heavy atom substructure and subsequent density modification can be done with a variety of programs , such as sharp / solomon , solve / resolve , and others . beyond providing direct phase information , these approaches can also independently verify that things are proceeding well , as the substructure obtained with the mr phases must be the same ( except for a possible origin shift ) as the ones obtained independently ( e.g. , by the combined patterson - direct methods approach implemented in shelxd ) . the huge advantage of either a sad ( single - wavelength anomalous diffraction ) or a mad data set based on se - met or br - du ( bromodeoxyuridine if there is nucleic acid in the structure ) is that the heavy atom substructure could provide further positioning information for the domains or fragments in favorable cases .
a very important aspect of even modest quality experimental phases is that they are free of model bias .
model bias , which is more serious at low resolution , is perhaps the greatest caveat in crystallography because the placed model , in the absence of experimental phases , is the only source of phase information .
as phase information dominates maps , even an incorrectly placed or inappropriate model ( or both ) will inevitably show up in its own density to some extent when a map based on model phases is calculated .
in addition to the importance of experimental phases , it is not possible to emphasize how important the exploitation of real space redundancies ( non - crystallographic symmetry ) is , or if multiple crystal forms are available how important it is to attempt multi - crystal averaging .
these effectively improve the inherently poor data - to - parameter ratio but assume that the geometrical relationship between the related domains or molecules can be established . in the past , after placing known fragments into their place and perhaps some rigid body refinement , not much more optimization could be done .
however , there have recently been a number of important technical advances in this area .
one of these is b - factor sharpening , which involves the application of a negative b - factor to the diffraction data set .
this increases the highest resolution reflections in the set and can give rise to more detail - rich maps ( e.g. , visible side chains ) and it is especially useful if experimental phases are available .
care is needed in applying this as the weak highest resolution reflections also have the highest errors and it is likely that by increasing their contributions the overall noise of the map will increase as well . the optimum choice is the negative of the pseudo wilson b - factor of the diffraction data .
it is also very important to have a reliable bulk solvent model and to correct for data anisotropy .
previous procedures that have worked well when high resolution data were available displayed unstable results for low resolution sets .
new grid search - based iterative parameter optimizations of the bulk solvent model such as the ones implemented in the newer versions of cns ( crystallography and nmr [ nuclear magnetic resonance ] system ) and phenix have successfully overcome this problem .
quite clearly , any attempt to do molecular model refinement at resolutions poorer than 3.5 has to have stronger and additional restraints applied to the structure .
explicit restraints of secondary structure , typically through some kind of h - bonding potential , are very useful . an exciting recent development is the incorporation of known three - dimensional structures of homologues of the assembly investigated through incorporation of a deformable elastic network ( den ) potential into the target function used in torsion angle dynamics .
den allows restrained but still large - scale deviations from a high(er ) resolution reference structure and this , in principle , overcomes the main limitation of previous refinement protocols .
given the increasing importance of three - dimensional structures of large assemblies , one can expect further significant technical advances when dealing with low resolution single crystal x - ray diffraction data .
these may include the more robust ways to incorporate electron microscopy or small - angle x - ray or neutron scattering ( saxs or sans ) information as further restraints .
also , as one of the most difficult aspects of low resolution structure determination is the interpretation and building of models into the electron density , it will be interesting to see how far automated processes can be developed to accomplish these often frustrating and ambiguous tasks .
Output:
| despite the recent substantial technological developments in x - ray crystallography , solving and refining structures at low resolutions remain substantial challenges .
many macromolecular crystals , especially those of large molecules or multicomponent assemblies , diffract x - rays to resolutions that are worse than 3.5 .
this report summarizes several recent advances aiding low resolution crystallographic work . |
PubmedSumm118554 | ***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: clinical signs and the laboratory findings were evaluated for 17 children < 2 years of age , hospitalized in four pediatric wards in different areas of israel .
all these children had gastroenteritis attributable to eaec or enterotoxigenic e. coli ( etec ) of serotype o126:h27 ( table 1 ) .
eaec , enteroaggregative escherichia coli ; st , heat - stable toxin ; uti , urinary tract infections ; nt , not tested .
cultures were heated to 120c for 1 h , then checked for agglutination with specific o - antisera at 50c overnight . for determination of h - antigen ,
motile cultures were grown overnight in nutrient broth , treated with 0.5% formaldehyde , and investigated for agglutination with specific h - sera at 50c for 2 h. to detect eaec , we used pcr primers specific for a short sequence of the plasmid paa of eaec , which is necessary for adherence .
analysis for the presence of pcvd432 sequences was performed at the institute of hygiene and microbiology , the university of wuerzburg , and the institute of medical microbiology and hygiene , technical university of dresden , germany .
briefly , e. coli were isolates grown overnight on l - agar , and a single colony was suspended in 50 l of phosphate - buffered saline ( pbs ) .
amplification was carried out in a total volume of 50 l containing each nucleotide triphosphate at 200 m , 30 pmol of each primer , 5 l of 10-fold concentrated amplitaq dna polymerase synthesis buffer , 1.5 mm mgcl2 , 2.5 u amplitaq dna polymerase ( applied biosystems applera , weiterstadt , germany ) , and 5 l of template oligonucleotides pcvd432/start ( 5-ctg gcg aaa gac tgt atc at-3 ) and pcvd432/stop ( 5-aat gta tag aaa tcc gct gt-3 ) were purchased from sigma - ark gmbh ( darmstadt , germany ) ( 5 ) .
the pcr protocol comprises 30 rounds of amplification , each consisting of 30 s at 94c , 60 s at 52c , and 60 s at 72c .
the first cycle was preceded by a denaturation step of 10 min at 94c , and the last extension cycle was followed by a final extension step of 10 min at 72c .
enterotoxins were determined by the asialoganglioside - gm1 enzyme - linked immunosorbent assay ( gm1-elisa ) method using the direct plate cultures technique .
heat - labile toxin ( lt ) was determined by gm1-elisa using monoclonal antibodies against lt ( 11 ) .
heat - stable toxin ( st ) was determined in parallel in the same cultures by an inhibition - gm1-elisa that used monoclonal anti - st ( 12 ) .
the test was performed in two 96-well polystyrene microplates a&b ( nunc a / s roskilde , denmark ) and comprises several steps .
the plates were coated with gm1 by adding 0.1 ml of 0.3 nmol gm1 ( sigma , rehovot , israel ) in 0.1 m pbs , ph=7.2 , to each well .
after the plates incubated overnight at room temperature , they were washed three times with pbs , blocked with 0.1% bovine serum albumin ( bsa ) in pbs for 30 min at 37c , and finally washed once with pbs . to each of the gm1-coated wells in plate
a was added 0.2 ml lb broth , lennox medium , adjusted to 45 g lincomycin / ml and 2.5 mg glucose / l . from each bacterial isolate ,
plate b ( without the bacterial cultures ) was processed after step 1 in a different way to determine st .
briefly , plate b was coated with st - ctb ( consisting of the b - subunit of cholera toxin conjugated to st ) by adding 0.1 ml of st - ctb in 0.1% bsa pbs to each well and incubation of the plate at room temperature for 60 min . then the plate was washed three times with pbs . to each well in plate b , 0.05 ml of culture medium from plate a was added ( presumed to contain st ) ; immediately thereafter , 0.05 ml of the monoclonal antibody against st ( anti - st ) was added , and the plate was gently shaken .
the plate was incubated for 90 min at room temperature and then washed three times with 0.05% pbs - tween .
after the culture medium was disposed of , plate a was washed three times with pbs - tween . to each well , 0.1 ml of monoclonal antibody against lt ( anti - lt ) in pbs - bsa - tween was then added .
the plate was incubated for 90 min at room temperature and then washed three times with pbs - tween . to each well of plates a and b we added 0.1 ml of goat anti - mouse immunoglobulin g horseradish perioxidase ( jackson immuno - research laboratories , west grove , pennsylvania ) in pbs - bsa - tween .
the plates were incubated for 90 min at room temperature and then washed three times with pbs - tween .
substrate was prepared by dissolving 10 mg of ortophenylene diamine ( sigma ) in 10 ml of 0.1 m sodium citrate buffer ( ph=4.5 ) to which 4 l of 30% h2o2was added . to each well in plates a and b , 0.1 ml of this substrate solution was added .
after 20 min , the plates were read at 450 nm in a micro elisa auto reader spectrophotometer ( dynatech inc . ,
alexandria , va ) . when the optical density ( od ) decreased > 50% as compared with the od of anti - st mixed with st negative control culture , which run in parallel to the experimental wells , the result was considered st positive .
when the od value at 450 was > 0.100 above the background , the result was considered lt positive .
since serotype o126:h27 was prevalent in our eaec cultures , we tried to isolate bacteriophages specific to the eaec of this serotype from sewage water .
one milliliter of an early logarithmic broth culture of each strain was seeded in a bottle of 50-ml nutrient broth .
after incubation of 3 h at 37c , 5 ml of sewage water was added to each bottle . after a new incubation of 6 h ,
the next day the supernatant of each bottle was tested for activity on the respective strain .
the isolated phages were then diluted and purified twice by single plaque isolation ( 13 ) .
the five phages were active on eaec strains of serotype o126:h27 . from july 1999 to december 2001 , we collected and characterized 1,368 isolates of diarrheagenic e. coli .
of these isolates , 88 ( 6.4% ) belonged to one of the five most common eaec serotypes , i.e. , serotype o126:h27 ( n=48 ) , o111:h21 ( n=16 ) , o125 ( n=11 ) , o44:h18 ( n=11 ) , o?:h10 ( n=2 ) ( table 2 ) .
the percentages of eaec pcr positive strains ( table 2 ) were as follows : 73% in e. coli o126:h27 and 75% in e. coli o111:h21 .
in e. coli o125 , the percentage was approximately 50% , and in e. coli o44:h18 , unlike reported elsewhere ( 14 ) , this percentage was low . to determine
if the isolated phages were specific for the enteroaggregative strains of serotype o126:h27 , the five phages were tested by spot test at routine test dilution on our eaec and non eaec cultures of this serotype .
only phage no . 4 was active on 33 of the 34 eaec cultures and on 1 of 12 non - eaec cultures ( table 3 ) .
this phage could therefore be used as an indicator for aa in this e. coli serotype .
e. coli o126 : h27 was found in stools from 17 children in four pediatric wards in various areas in israel ( table 1 ) .
three of these 12 children had diarrhea concomitant with other diseases ( patients 11 , 13 , and 14 ) . stool cultures of these three children were taken as part of an investigation of febrile disease .
the duration of diarrhea was 140 days ( median 5 days ) starting , in some cases , before hospitalization .
five patients ( nos . 1 , 2 , 8 , 9 , 10 ) had prolonged diarrhea of > 1 week , characteristic of eaec ( 15 ) .
in our patients , eaec serotype o126:h27 appears to be a pathogenic agent of young children who require hospitalization and dehydration treatment .
this same serotype has been reported as a common cause of diarrhea in children from england ( 16 ) , japan ( 17 ) , and bangladesh ( 9 ) .
however , we were not able to associate that serotype exclusively with the enteroaggregative pathotype , since nonaggregative ec o126;h27 strains from hospitalized children ( patients 16 and 17 in table 1 ) produced st and might therefore belong to the pathotype of etec . however , st was apparently not the main diarrheagenic factor , since in the five children with prolonged diarrhea no st was produced .
some other kind of toxin was probably involved in these cases . in strains from some patients ( table 1 , numbers 1215 ) we found both traits of eaec and etec in the same organism . a simple test to identify eaec in routine laboratory work
a possible solution is to use a phage sensitivity test in addition to serotyping , such as we used here for eaec o126:h27 .
if this fact is confirmed on a large number of strains , specific phages might also be selected for eaec of other serotypes .
the obvious accumulation of pcvd432-positive e. coli of serotype o126:h27 suggests that we found a clone that spread in israel and probably has a selective advantage .
Output:
| enteroaggregative escherichia coli ( eaec ) is a newly diarrheagenic agent wherein several predominant serotypes are reported .
we studied the association between those serotypes , as clonal indicators , and the trait of enteroaggregative adherence to host cells , tested by polymerase chain reaction .
we also evaluated the clinical manifestations of infection in 17 hospitalized children by our most common eaec serotype , o126:h27 . |
PubmedSumm118555 | ***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: post - kala - azar dermal leishmaniasis ( pkdl ) is a skin disorder that often appears after treatment for visceral leishmaniasis ( vl ) patients .
it has also been reported in individuals without prior history of vl as well as those undergoing treatment for vl .
clinical manifestations of pkdl are macular , maculopapular , and nodular rash in people who are otherwise well and recovering , although more serious manifestations of facial ulcers can occur . in sudan approximately 50%
of vl patients go on to develop pkdl ; but in the indian subcontinent only 510% develop this infection .
the clinical presentation of pkdl varies , making diagnosis difficult , especially in those without a history of vl .
accurate diagnosis of pkdl is important due to the long and toxic treatment with antileishmanial drugs .
treatment can last up to 6 months , and the drugs can have serious side - effects for patients and is a waste of medical and economic resources . therefore , a testing regime with a high specificity is essential to avoid false positive results and hence to avoid waste and unnecessary treatment of patients with toxic drugs . on the other hand , diagnostics for pkdl should also have a sufficiently high sensitivity as pkdl patients may be a risk of continuing transmission of vl .
the first step in diagnosis is assessing clinical signs and symptoms , and in some areas cases are diagnosed on clinical symptoms alone .
however , there is a large geographical variation in clinical presentation , especially between east african and the indian subcontinent , and pkdl can be confused with other skin disorders . recently
, pictorial training aids have been created as a guide for health workers to distinguish pkdl patients from other skin disorders . in other areas , clinical signs and symptoms along with history of vl , living in an endemic area , and positive antibody tests
clinical signs and symptoms may not be accurate enough , and diagnosis depends on the training of an individual clinician .
in addition , around 10% of cases have no history of vl , and 10% of cases have no positive serological test .
many patients post - vl treatments have a positive antibody test as the antibodies are known to stay in the body for some years making a strict clinical definition important . this may hamper the specificity of these tests .
confirmation of diagnosis is usually done by skin slit smear ( sss ) microscopy or histopathology . however , the reported sensitivity of sss microscopy is , at best , 4060% from patients with nodular lesions [ 2 , 4 ] and even lower in patients with macular lesions .
in addition , parasite load between different clinical presentations may differ , which may mean that some diagnostic tests are more suitable for some patients than others .
the advantage of microscopy is the acknowledged high specificity , which leads to low numbers of patients unnecessarily treated with antileishmanial drugs .
however , because of the woeful sensitivity many centres do not use this test .
the aim of this overview is to systematically collect and summarize all of the published literature about the accuracy of diagnostic tests for pkdl .
this involves the assessment of the quality of these studies and extracting the diagnostic accuracy data . in the discussion section
a search was performed in medline , through pubmed to find all the literature associated with pdkl and diagnostics .
the following search terms were used : post - kala - azar , dermal leishmaniasis , pkdl , post - and visceral leishmaniasis ( see the appendix ) .
this broad search enabled the identification of all pkdl articles that might involve pkdl diagnostics .
the title and abstract of all identified papers were screened in order to exclude papers not involved in diagnosis of pkdl .
articles were included in the systematic review if they investigated the diagnostic accuracy of any test for pkdl .
this is best done in a study including a consecutive series of eligible patients who will all undergo the test under evaluation ( the index test ) .
then a reference standard , or gold standard , should be applied to all patients , enabling verification of the index test results .
the reference standard defines whether someone has the target condition or not ; studies were not included if they did not use a reference test or confirmation method .
such a design is typically a cross - sectional design , but because we suspected that there would not be many of these studies available , cohort designs and case - control type designs were also included .
case control designs select patients who have the target condition at the start of the study ( to calculate sensitivity ) , and they select a separate control group of people who do not have the target condition ( to calculate specificity ) .
if a mixture of control groups was used , then the most appropriate was chosen , that is , european controls and healthy endemic controls were omitted if possible , as these are least like the original population in which these tests will be used in practice .
studies were included if they used a reference standard ; here this consisted of clinical symptoms plus parasitological diagnosis ( e.g. , skin - slit smear or other microscopy ) or response to treatment .
studies needed to report at least an estimate of sensitivity , and preferably also specificity , or the ability to calculate these from the results .
any index test was eligible ; we expected to find information on serological , molecular diagnostics , and different types of microscopy .
articles were excluded if an index test was presented without reference to a gold standard diagnostic , if only clinical symptoms were used as the gold standard article and if a case study presented under 5 patients .
where possible , data for 2 2 tables for each index test were extracted .
geographic origin of patients , sample type , study design , control group ( if appropriate ) , and molecular target ( if appropriate ) were recorded . to assess the risk of bias in the included studies
study selection and performing data extraction were performed independently by authors iv and ea . in the case of disagreements
the quadas-2 checklist assesses the risk of bias and concerns regarding applicability over four domains : patient selection , index test , reference standard , and flow and timing .
patient selection was regarded to be at high risk of bias if a case - control design was used ; cases may have gone through confirmation methods before they were regarded real cases , making it easier for an index test to detect a case .
they are at the other end of the disease spectrum , showing no signs of leishmania and therefore more likely for any test to become negative .
the reference standard was regarded to be at high risk of bias if a nonoptimal reference standard was used , for example , any kind of microscopy , or if the assessors interpreting the reference standard were not blinded for the results of the index test .
flow and timing was regarded to be at high risk of bias when there was too much time between the index test and the reference standard , when not all patients received the ( same ) reference standard , or when not all enrolled patients ended up in the 2 2 tables .
case - control studies do not reflect the actual variation in patients , these were all scored high concern regarding applicability of the patient population .
the index test was thought to be of high concern regarding applicability if a test used in - house elisas or pcrs , due to no standardization .
any of the above items were scored unclear if the study did not report on the item , or if it was not clear whether high or low risk or concern would have been appropriate .
data were entered into revman ( version 5.2 ) to create forest and roc plots of sensitivity and specificity per study .
meta - analysis was considered if at least four studies per test were found that did not include healthy ( endemic ) controls ; however , this criterion was not met for any of the tests included in the review .
the title and abstract of 634 studies were read and taken forward to read the full text if the inclusion criteria were likely to be fulfilled ( see figure 1 ) .
eighty - five full text articles were read , and data extraction was possible from 21 articles [ 4 , 726 ] which included 43 separate 2 2 tables ( hereafter referred to as studies ) .
of three articles , the full text could not be retrieved , either from the library , online or by emailing corresponding authors .
we included 21 articles , containing a total of 635 people with pkdl and 468 people without pkdl .
patients from 17 articles came from the indian subcontinent ( india , bangladesh , or nepal ) .
most articles reported the results for only one index test or one sample type , but some reported up to 5 2 2 tables for other index tests .
twenty - seven studies concerned serological tests ( rk39 dipstick or elisa = 10 ; dat = 5 ; leishmanin skin test = 2 , and 10 other serological tests ) , six were on pcr , four on immunohistochemical staining , one on hematoxylin and eosin histochemical staining , three on microscopy of skin - slit smears , two on culture , and one on histological sections .
see figures 3 and 4 for the roc and forest plots of included studies .
we did not formally test for heterogeneity , but based on the variation in included index tests , reference standards , and study designs , we concluded that the heterogeneity in the 43 studies was large .
there are 6 types of index test of which the serological test contained several different antigens ( rk39 , dat , and unnamed antigens ) for antibody detection and several different readouts including lateral flow devices ( lfd ) , elisa , and agglutination ; the molecular tests used several different target genes , protocols ( standard versus nested ) , and different read - out systems ( realtime versus electrophoresis ) .
there were 5 different types of references standard and many types of control group for the case / control studies .
all of these parameters meant that pooling for statistical analysis was not possible in this group of studies .
the main problem in terms of risk of bias is in the patient selection ( see figure 4 ) ; this is due to the large proportion of case series and case - control studies .
only six 2 2 tables were based on a cross - sectional study , while 28 studies were based on a case - control design .
control groups ranged from healthy volunteers from europe , healthy endemic controls , and patients with diseases in the differential diagnosis of pkdl , for example , leprosy .
our dataset also contained nine cases series ( positive cases only ) , for which we could only calculate the sensitivity and not specificity .
all included studies used clinical symptoms as part of the reference standard , combined with microscopy of skin - slit smears ( 10 out of 22 articles ) , response to treatment ( 6 articles ) , microscopy with hematoxylin and eosine staining ( 2 articles ) , or histopathology or microscopy of a variety tissues or aspirates .
these tests have a low sensitivity and therefore high likelihood of false negative results by the index test .
almost all studies ( 42 studies ) scored as unclear on the timing and flow section , due to lack of reporting ; one article scored high as patients were selected from a large group of samples , but the reasons for this were not explained .
their sensitivity ranged from 91% to 100% , while the specificity ranged from 0% to 100% .
the three consecutive studies were very variable in their estimates for specificity ( 0% , 8% , and 89% resp . ) and reported 100% sensitivity .
five of them assessed the direct agglutination test ( dat ) , the sensitivity of the case - control studies ranged between 94% and 100% , while the specificity was 100% in four studies and 40% in one study .
ten case - control studies evaluated other serological tests ( figure 3 ) ; sensitivity was estimated between 67100% and specificity 81100% ; again this is likely to be an overestimation due to the study design .
six studies evaluated the diagnostic accuracy of molecular tools for pkdl on skin biopsies or skin slit smears [ 8 , 11 , 22 ] .
their sensitivities are high , ranging from 94% to 100% , but their specificities are variable , ranging from 8% to 100% .
low specificity is especially apparent in the 2 studies with a consecutive design nasreen et al .
there are 2 molecular studies which use response to treatment as a reference standard ; here the sensitivity ranges between 9496% and the specificity 90100% . leishmanin skin test , histopathology , microscopy of sss , and ihc were also assessed in several studies .
the results can be found in figure 2 . of these , only for the ihc both sensitivity and specificity were reported .
studies evaluating the diagnostic accuracy of tests for pkdl are insufficiently rigorous to draw firm conclusions with regard to their sensitivity and specificity .
the main problem is in the selection of patients , as most studies we retrieved were case - controls designs , including healthy ( endemic ) controls .
the other problem these studies face is the lack of a reference standard that is able to define beyond reasonable doubt whether a patient has pkdl or not .
there are few well - designed ( consecutive ) diagnostic accuracy studies for pkdl , those that were found use microscopy as a reference standard .
microscopy is shown to have a low sensitivity , as seen here in three studies [ 17 , 19 , 20 ] where microscopy was evaluated against response to treatment as a reference standard .
a reference standard with a low sensitivity may cause many false positive reactions in the index tests , thereby producing a low specificity ; consequently assessing the index test for accuracy becomes extremely difficult .
this is seen in most of the consecutive studies we included , where we found a wide range of variation in specificity .
some authors have managed to get round the lack of a gold standard by using the response to treatment as a reference standard .
although the use of anti - leishmanial drugs should not affect other infections , administering a toxic drug to patients who do not really have pkdl is not advisable .
it will therefore be difficult to combine the reference standard of treatment response with a neat consecutive study design . in studies using response to treatment as a gold standard , all cases ( suspected patients ) appear to respond positively to treatment .
this may suggest that ( i ) clinical suspicion alone maybe a good diagnostic tool in itself , ( ii ) that patients can also self - heal over time , or ( iii ) that the treatment has an effect on more than one pathogen . in order to test this hypothesis ,
clinical diagnosis could be treated as an index test in a cohort of pkdl suspected patients .
all other diagnostics including serological , molecular , and parasitological tools could then act as the reference test for which to compare a clinical diagnosis . in practice ,
a clinical diagnosis is frequently used for pkdl , especially in sudan ; confirmation of the efficacy of this diagnostic would be extremely beneficial .
although the serological tests seem to have reasonably high ( > 80% ) specificity , one would expect lower specificities under field circumstances , as it is known that antibodies can stay in the body for a long period of time , up to many years .
the low specificity in some of the molecular test evaluations may have a different cause ; the sensitivity of all pcr tests , regardless of target gene , was high .
due to the imperfectness of microscopy as a gold standard and the high sensitivity of the pcr tests , a ( truly ) positive test result by pcr may coincide with an infected patient in whom microscopy missed the diagnosis , thus ending in a false negative results .
several types of microscopy are reported , including light microscopy of sss , histopathology , haematoxylin and eosin histopathology stain , and immunohistochemistry . due to the lack of studies it has not been possible here to assess the differences in sensitivity between these tests .
however , it is likely that there is a wide range in diagnostic accuracy both in different microscopy tests and the type of tissue and patient ( macular versus nodular ) .
future assessment of microscopic tools should also remain a priority due to the wide use of this diagnostic . of the 21 reported articles ,
only 4 studies were done in east africa . due to known differences in performance of other diagnostics , including the rapid diagnostic tests for vl , it is important that new diagnostics are also assessed in both the isc and east africa .
several east african articles were excluded from this review as pkdl was not positively diagnosed ( i.e. , no gold standard ) ; this becomes extremely important in diagnostic evaluations where the aim is to evaluate index tests in comparison to the reference tests .
although we feel that our broad search strategy should have retrieved all relevant articles , there were a few articles to which there was no access .
another , and perhaps more relevant , limitation is the possibility of publication bias , whereby poor results of diagnostics are not published .
as most of our included studies report very high sensitivities and specificities , the likelihood of publication bias should certainly be considered , although it is however not possible to assess the impact of this , as testing for publication bias in diagnostic test accuracy studies has its own limitations and because prepublication of study protocols in this field is not encouraged .
due to poor reporting of study characteristics in the included studies it was difficult to assess the actual merit of the study results .
no additional information about the flow and timing of study methods and test reading was reported , like information on blinding and random assortment of samples .
due to the high sensitivity of molecular tests , controls must be taken along through the processes of sampling , dna extraction , and amplification with appropriate timing ( i.e. , in an assortment of positive samples ) to ensure no contamination or bias .
although there are several potentially useful diagnostic tests for pkdl , there are few studies of high quality mostly due to the poor reference standard of clinical symptoms plus microscopy .
this makes it difficult to assess new index diagnostics since microscopy is so poorly sensitive and clinical symptoms are not specific .
very few of the studies have included consecutively enrolled patients for the assessment of diagnostic tools .
this leads to an artificial increase in the diagnostic accuracy of tests as only known positives and negatives are tested ; more recently several consecutively designed studies have been published , and we encourage the move to this study design which assesses index tests against a whole range of patients and leads to less bias in results .
we recommend well - designed diagnostic accuracy trials that evaluate , side - by - side , all currently available diagnostics for pkdl .
this would include clinical symptoms and serological , antigen , molecular , and parasitological tests .
a future development may be the use of statistical modeling to evaluate diagnostics when there is no suitable gold standard to refer to as is the case with pkdl ; this would also allow clinical diagnosis to be assessed as an index test .
the aim of diagnostic evaluations should not be to find a test with a perfect sensitivity and specificity , but to get a valid estimate of its value in health practice .
therefore , as a community , we must prioritise valid evaluations of all available diagnostics in well - designed diagnostic accuracy studies .
Output:
| identification of post - kala - azar dermal leishmaniasis ( pkdl ) is important due to the long and toxic treatment and the fact that pkdl patients may serve as a reservoir for visceral leishmaniasis ( vl ) .
we summarized the published literature about the accuracy of diagnostic tests for pkdl .
we searched medline for eligible studies investigating the diagnostic accuracy of any test for pkdl .
study quality was assessed using quadas-2 .
data were extracted from 21 articles including 43 separate studies .
twenty - seven studies evaluated serological tests ( rk39 dipstick , elisa , dat , and leishmanin tests ) , six studies molecular tests , eight microscopy , and two cultures . only a few of these studies reported a valid estimate of diagnostic accuracy , as most were case - control designs or used a reference standard with low sensitivity .
the included studies were very heterogeneous , for example , due to a large variety of reference standards used .
hence , no summary estimates of sensitivity or specificity could be made .
we recommend well - designed diagnostic accuracy trials that evaluate , side - by - side , all currently available diagnostics , including clinical symptoms , serological , antigen , molecular , and parasitological tests and possible use of statistical modelling to evaluate diagnostics when there is no suitable gold standard . |
PubmedSumm118556 | ***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: successful endodontic treatment begins with an accurate diagnosis , which is the cornerstone for a successful treatment plan wherein , the clinician should go through various diagnostic modalities before diagnosis and treatment plan .
thorough clinical examination , detailed case history , radiographs , and pulp sensibility tests together aid in the diagnosis of dental pulp health and not the outcome of only one specific test . in clinical practice ,
pulp sensibility tests ( thermal and electric pulp tests [ epts ] ) assess the integrity of the nerve fibers in the dentin - pulp complex by applying the stimulus to the outer surface of the tooth , whereas pulp vitality tests should assess the blood supply of the dental pulp .
electronic root apex locators , pulp vitality tester , and early caries lesion detectors are some of such devices .
the ability of ept to indicate pulp sensibility is based on the sensitivity of neural transmission .
ept is based on stimulation of intact a nerves in the pulp - dentine complex by applying an electric current on the tooth surface , which results in an ionic shift in the dentinal fluid within the tubules causing local depolarization and subsequent generation of an action potential from the intact nerve and relies on subjective assessments and comments from the patient .
the various factors that influence ept result for false positive or false negative response include the thickness of enamel and dentine , concentration of pulpal neural elements , direction of dentinal tubules , amount of dentinal fluid , and the distance between the electrode tip and the pulp .
ept is an important aid and when properly used , is a safe clinical test that can provide useful information regarding health and disease of pulp tissue .
dental fluorosis is a developmental disturbance of dental enamel caused by excessive exposure to high concentration of fluoride during tooth development . in routine clinical scenario
they pose many challenges in diagnosis and treatment planning to the clinician right from pulp sensibility tests , shade selection , shade mimicking , etching and bonding procedures during composite restorations .
the factors that influence ept are the thickness of enamel and dentine , morphology of teeth , concentration of pulpal neural elements , direction of dentinal tubules , and the distance between the electrode tip and the pulp .
many studies were done earlier to evaluate the optimal electrode placement site and threshold levels of ept with varied opinions .
the hypermineralized enamel in fluorosed teeth may influence the fluid concentration in the dentinal tubules , which is thought to play a vital role in the conduction of electric impulses . in fluorosed enamel
, hydroxyapatite crystals are substituted by fluorapatite crystals , which may result in ionic shift in the dentinal fluid .
to best of our knowledge until date , no study has been done to evaluate threshold response and optimal electrode placement site on fluorosed teeth .
therefore , the aim of this study was to evaluate lowest threshold response and optimal electrode placement site for ept in fluorosed anterior teeth .
this clinical study was carried out in the department of conservative dentistry and endodontics , kamineni institute of dental sciences , narketpally , nalgonda ( district ) , telangana , state , india .
nalgonda district is globally recognized for the incidence of severe systemic and dental fluorosis with fluoride concentration up to 14ppm .
ethical clearance for the study was obtained from the research and ethics committee of the kamineni institute of dental sciences .
eighty volunteers of either gender , between 20 and 40 years old with intact maxillary central incisors with thylstrup and fejerskov index ( tfi ) score 1 - 4 were selected [ figure 1 ] .
clinical examination was done independently by two different investigators , after wiping dry the teeth to assess the fluorotic severity according to the tfi .
based on the incidence of fluorosis , total of 80 volunteers were divided into two groups as :
group 1- volunteers with incidence of dental fluorosis ( tfi score was between 1 and 4)group 2- volunteers without incidence of dental fluorosis ( tfi score was 0 ) .
group 1- volunteers with incidence of dental fluorosis ( tfi score was between 1 and 4 ) group 2- volunteers without incidence of dental fluorosis ( tfi score was 0 ) . the teeth with mild flourosis and intact crown ( thylstrup and fejerskov index score-2 ) selected for the study .
to standardize the study , we selected either of the maxillary central incisors with an intact crown from each volunteer [ figure 1 ] . baseline bitewing and periapical radiographs were taken for teeth which had neither history of orthodontic treatment nor trauma .
the teeth with signs of surface loss ( erosion , abrasion , attrition , abfraction ) , teeth with surface pitting , ( tfi 5 - 9 ) , cracks , inter proximal caries , metallic restorations , malformed teeth , traumatized teeth , endodontically treated teeth and teeth with periapical pathology were excluded from the study .
subjects taking narcotics , alcohol or nonsteroidal anti - inflammatory drugs and with a history of mental and emotional instability were excluded from the study .
the participants were informed fully about the procedure being carried out and informed consent was obtained . tooth to be tested was isolated with rubber dam without the clamp .
the test was conducted with a digitest ept ( parkell , farmingdale , ny , usa ) in accordance with the manufacturer 's instructions ( a monopolar ept with anodal electrode probe tip and diameter of 2 mm was used in the study ) .
the circuit was completed when the subject rested a finger on the lip clip of the ept .
the tip of the electrode was lightly coated with toothpaste as a conducting medium , a gentle pulsed stimulus was applied to the tooth until the subject felt and noted a sensation such as tingling , stinging , warmth , or heat .
they were instructed to release the clip on the first detection of a warm , tingling or painful sensation .
the digital display readout of the pulp tester at which the subject first noted the above mentioned sensation was defined as the threshold .
four sites ( incisal edge , incisal third , middle third , and cervical third ) on the labial surface of each tooth were tested .
four readings were made on the labial surface of each site in sequence , starting from the incisal edge to cervical third . to eliminate the phenomenon of nerve accommodation , at least 1 min was allowed to elapse before the tooth was revisited .
means of variables from each location were compared using one - way anova and tukey 's post - hoc test .
a total of 80 volunteers were recruited in this study and were categorized into two groups of 40 each .
three hundred and twenty electrode placement sites on 80 teeth were studied and analyzed statistically .
the mean standard deviation threshold levels in the fluorosed group were 9.32 1.35 , whereas in nonfluorosed group , it was 5.57 1.40 .
the higher threshold values were recorded in the fluorosed group when compared to that of nonfluorosed group and were statistically significant ( p < 0.05 ) . when multiple comparisons were done among the groups ,
it was observed that there was a significant difference between incisal edge , middle and cervical thirds ( p < 0.05 ) . but
no statistically significant difference between incisal edge and incisal third was noted ( p > 0.05 ) [ table 1 ] .
many studies earlier were done to evaluate the optimal electrode placement site and threshold levels of ept with varied opinions .
concluded that placing the electrode at the incisal edge of anterior teeth evoked a response with the least amount of electrical current .
conducted a study on premolar and stated that the buccal cusp tip of both maxillary and mandibular premolars were the site with the lowest threshold to ept stimulation . in this study , maxillary central incisors with intact crowns
were selected which differ from the earlier studies in relation to the sample size , population characteristics , and study design .
nalgonda district of telangana , india consists of areas with various levels of fluoride in drinking water , starting from below - optimum to optimum and above - optimum levels ( up to14ppm ) .
the earliest manifestation of dental fluorosis is an outer hypermineralized layer with a porous hypomineralized subsurface ; the pores are occupied by enamel secretory proteins that are retained due to the effect of the excessive fluoride level on ameloblasts .
clinically , the porosity in the subsurface of enamel reflects as the opacity of the enamel , ranging from fine white opaque lines running across the tooth on all parts of the enamel to entirely chalky white teeth .
high fluoride concentration on fluorosis enamel indicates the substitution of oh by f increasing the surface roughness of enamel surface . in the present study to measure dental fluorosis ,
this index allows correlation between the clinical appearance of fluorosis and pathological changes and is normally the index of choice for evaluation of fluorotic severity . in the present study ,
maxillary central incisors were selected , as these teeth are of prime aesthetic concern and are considered to be most at risk for fluorosis .
volunteers within a narrow range of age group were selected to avoid sensitivity variation caused by secondary dentine deposition which causes a reduction in the volume of pulp , dental caries and tooth wear . in the present study ,
fluorosed teeth showed high threshold response when compared to nonfluorosed teeth , possible reasons may be hypermineralized enamel , which might influence the fluid concentration in the dentinal tubules , which is thought to play a vital role in the conduction of electric impulses . in fluorosed enamel hydroxyapatite crystals
are substituted by fluorapatite crystals which may result in ionic shift in the dentinal fluid . in the present study , in both fluorosed and nonfluorosed teeth incisal edge showed lowest threshold levels for ept when compared to incisal , middle and cervical thirds because the enamel is thinnest incisally with the highest concentration of neural elements in the pulp horns while in the cervical area the number of nerve fibers decrease .
the straight course of dentinal tubules at the incisal edges of anterior teeth offers faster flow rate to the electric current .
this explains why the threshold values were lower at the incisal edge region than in the cervical third .
these results were in accordance with bender et al . who found that the lowest threshold response was at the incisal edge .
structural and morphological variations of fluorosed anterior teeth did not show any variation in the optimal electrode placement site when compared to nonfluorosed teeth but have shown higher threshold levels to ept .
the possible reasons could be because of hypermineralized enamel , which might influence the fluid concentration in the dentinal tubules , which is thought to play a vital role in the conduction of electric impulses . in fluorosed enamel hydroxyapatite crystals
are substituted by fluorapatite crystals which may result in ionic shift in the dentinal fluid . during the study
, it was observed that teeth with mild fluorosis which mimics nonfluorosed teeth reported high threshold levels for ept which could be misread as delayed response of nonfluorosed teeth . in such cases ,
this base line study was done only on the anterior teeth with mild fluorosis with intact enamel surface .
further studies are required in posterior and severe fluorosed teeth for better understanding of the threshold response of fluorosed teeth to ept .
within the limitations of the study , it was observed that fluorosed teeth responded to high threshold levels , and the appropriate electrode placement site was the incisal edge .
the authors of this manuscript declare that they have no conflicts of interest , real or perceived , financial or non - financial in this article .
the authors of this manuscript declare that they have no conflicts of interest , real or perceived , financial or non - financial in this article .
Output:
| background : accurate diagnosis is key to success . diagnosing the pulpal status in varied clinical situations poses a challenge to the clinician . electric pulp test ( ept ) is one of the valuable attempts in evaluating the sensibility of pulp tissue .
the aim of this study was to find out and compare the threshold levels and optimal electrode placement site for ept in fluorosed and nonfluorosed anterior teeth.materials and methodology : eighty volunteers recruited for this study were divided into two groups based on the incidence of dental fluorosis .
electric pulp testing was done on either of the central incisors in fluorosed and nonfluorosed group .
four sites on each crown were tested 4 times with digitest electric pulp tester , and the mean of the threshold responses was recorded .
the data were analyzed with spss , version 11 .
means of variables from each location were compared using one - way anova and tukey 's post - hoc test while the critical level of significance was set at p < 0.05.results:the mean and standard deviation of threshold levels in fluorosed teeth were greater when compared to that of nonfluorosed teeth at all sites with incisal edge showing the least mean threshold levels for both the groups ( p > 0.05).conclusion : within the limitations of this study , it can be concluded that fluorosed teeth respond to higher threshold levels than the non - fluorosed teeth , and incisal edge was the optimal electrode placement site . |
PubmedSumm118557 | ***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: acrokeratosis verruciformis of hopf ( akv ) is a rare disorder of keratinization inherited in an autosomal dominant fashion .
it usually presents with multiple small , flat , flesh - colored , warty papules on dorsa of the hands , feet , knees , elbows , and on forearms .
the eruption affects both genders and is usually present at birth or appears in early childhood .
it shares some of the features of the acral variety of darier 's disease ( dd ) .
acral dd may be indistinguishable from the akv in childhood when the other features of dd may not be apparent .
some of the lesions that may present for long time may transform into squamous cell carcinoma .
a 15-year - old female presented with complaints of multiple small , firm eruptions over neck and dorsum of hands and feet since 7 years .
initially the patient noticed few , small skin - colored papules over dorsum of hands and feet , which gradually over a period of 3 months extended over both the forearms and the neck .
the patient noticed gradual increase in size and number of the lesions , which were asymptomatic . on examination , multiple skin - colored , small ( approximately 0.5 cm ) , discrete warty papules were present mainly over forearms , feet , and neck [ figure 1a and b ] .
there were no lesions over palms , soles , nails , oral mucosa , and seborrheic areas of trunk and face .
routine blood investigations were within normal limits . with the characteristic clinical findings a probable diagnosis of akv with differential diagnosis of dd , epidermodysplasia verruciformis , and porokeratoses were made .
biopsy was taken from right forearm and histopathologic examination showed hyperkeratosis , hypergranulosis , papillomatosis with epidermis showing characteristic church spires appearance and absence of acantholysis and dyskeratosis [ figure 2a and b ] . considering the above
clinical photograph showing ( a ) multiple , small , flesh - colored papules present over dorsum of the hand ; ( b ) few similar lesions over feet ( a , b ) histopathologic features showing hyperkeratosis , hypergranulosis , and papillomatosis with epidermal upgrowths resembling church spires ( h and e , 10 ) mother of the patient ( case 1 ) had multiple , flesh - colored , discrete , warty papules since 6 years of age .
initially the lesions were limited to dorsum of the hands and feet , which then gradually over months developed over forearm and neck [ figure 3a and b ] .
the mother gave history of similar lesions in her mother , four of the five sisters , and one of the two brothers [ figure 4 ] .
clinical photograph showing ( a ) multiple , small , skin - colored , warty papules present over dorsum of the hands ; ( b ) multiple skincolored , warty papules over feet family tree showing affected individuals
a 15-year - old female presented with complaints of multiple small , firm eruptions over neck and dorsum of hands and feet since 7 years .
initially the patient noticed few , small skin - colored papules over dorsum of hands and feet , which gradually over a period of 3 months extended over both the forearms and the neck .
the patient noticed gradual increase in size and number of the lesions , which were asymptomatic . on examination , multiple skin - colored , small ( approximately 0.5 cm ) , discrete warty papules were present mainly over forearms , feet , and neck [ figure 1a and b ] .
there were no lesions over palms , soles , nails , oral mucosa , and seborrheic areas of trunk and face .
routine blood investigations were within normal limits . with the characteristic clinical findings a probable diagnosis of akv with differential diagnosis of dd , epidermodysplasia verruciformis , and porokeratoses were made .
biopsy was taken from right forearm and histopathologic examination showed hyperkeratosis , hypergranulosis , papillomatosis with epidermis showing characteristic church spires appearance and absence of acantholysis and dyskeratosis [ figure 2a and b ] . considering the above
clinical photograph showing ( a ) multiple , small , flesh - colored papules present over dorsum of the hand ; ( b ) few similar lesions over feet ( a , b ) histopathologic features showing hyperkeratosis , hypergranulosis , and papillomatosis with epidermal upgrowths resembling church spires ( h and e , 10 )
mother of the patient ( case 1 ) had multiple , flesh - colored , discrete , warty papules since 6 years of age .
initially the lesions were limited to dorsum of the hands and feet , which then gradually over months developed over forearm and neck [ figure 3a and b ] .
the mother gave history of similar lesions in her mother , four of the five sisters , and one of the two brothers [ figure 4 ] .
clinical photograph showing ( a ) multiple , small , skin - colored , warty papules present over dorsum of the hands ; ( b ) multiple skincolored , warty papules over feet family tree showing affected individuals
akv occurs due to heterozygous missense mutation in atp2a2 gene , the gene involved in dd .
the lesions typically present over acral region that increases slowly in number and persist throughout life .
akv may show involvement of palms and soles in the form of palmar hyperkeratosis and interrupted dermal ridges in the finger pads and palms .
the patient may present with the lesions that may mimic acral form of dd , epidermodysplasia verruciformis , and porokeratoses .
dd and akv are believed to be allelic to each other due to the occurrence of similar gene defect in both the diseases .
the site of predilection are the seborrheic area of the trunk and face where greasy , keratotic , foul - smelling , and skin - colored papules are seen with nail abnormalities in the form of fragility of the nail and red and white longitudinal stripes , which were absent in our cases .
although relationship between akv and dd has been discussed repeatedly , there is no doubt that akv usually occurs as an independent entity in family . in epidermodysplasia verruciformis ,
the warty lesions of viral origin are bigger in size , often present widespread all over the body and unlike akv may show mucosal involvement along with characteristic histopathologic features of hyperkeratosis , acanthosis , vacuolation , and ballooning in the keratinocytes .
disseminated porokeratoses is characterized by widely disseminated , skin - colored , flat papules with peripheral hyperkeratotic border , which usually begin in childhood with classical histopathologic features of hyperkeratosis , parakeratosis , cornoid lamella in stratum corneum and spongiosis .
akv has been reported in association with dilated cardiomyopathy as a result of inability to transport calcium in myocardial cells secondary to the mutation in serca2 .
the treatment of akv is topical retinoids , cryotherapy , and carbon dioxide laser ablation .
oral retinoids showed variable results with a few cases , which have been successfully treated with acitretin .
as the patient was economically poor only retinoic acid 0.05% was given for topical application with no response after second month of follow up .
Output:
| acrokeratosis verruciformis of hopf ( akv ) is a rare disorder of keratinization inherited in an autosomal dominant fashion . a 15-year - old female presented with numerous skin - colored papular lesions over the neck as well as dorsa of the hands and feet of 7 years duration .
similar lesions were noted in her mother .
six other members of her family showed similar lesions with similar site of involvement .
presence of characteristic warty papules and histopathology led to diagnosis of a rare condition of acrokeratosis verruciformis . |
PubmedSumm118558 | ***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: naf is a very useful imaging agent for the evaluation of bone abnormality . owing to its high bone affinity , rapid clearance , and low protein binding ,
naf is superior to tc - labeled phosphate agents in terms of bone image quality ( 1 , 2 ) .
furthermore , the fast kinetics of naf enables image acquisition as early as 30 minutes post injection , improving patient compliance ( 3 , 4 ) . in fact , naf has been introduced as a bone imaging agent for positron emission tomography ( pet ) since the 1960s ( 5 ) .
however , bone pet using naf could not be routinely used in clinical practice during those years due to the undeveloped pet imaging technology .
the advent of gamma imaging technology and the development of tc - labeled phosphate agents in the 1970s have almost replaced bone pet with the bone scan ( 6 ) .
the recent innovative advancement of the pet technique allowed naf to resurface as a promising bone imaging agent ( 3 , 7 ) .
pet integrated with ct , yielding pet / ct , further improved the lesion detection rate with the aid of anatomical information from the ct . thanks to the effective attenuation correction algorithm , pet generated a more accurate quantitative image data set than gamma camera imaging ( 7 - 9 ) .
furthermore , the supply crisis of mo , the parent radionuclide of tc , in 2010 had many physicians pay more attention to the usefulness of bone pet using naf ( 1 , 4 ) .
bone pet is able to effectively evaluate not only malignant diseases ( 8 - 10 ) , but also benign bone diseases ( 11 - 13 ) .
previously , we reported the utility of bone pet for the evaluation of bone abnormalities for the first time in korea ( 14 ) .
however , in the previous study , bone pet was not directly compared to the bone scan for the detection rate of bone metastasis ( bm ) .
thus , in the current study , we aimed to compare the diagnostic accuracies between bone pet and bone scan in cancer patients who underwent both imaging studies .
sixteen cancer patients ( m : f = 10:6 , mean age = 60 12 ) were enrolled in this study .
eleven of these patients were included in our previous report ( 14 ) , which did not involve the head - to - head comparison between the bone scan and the bone pet .
underlying diseases of the patients included breast cancer ( n = 5 ) , prostate cancer ( n = 5 ) , thyroid cancer ( n = 3 ) , gastric cancer ( n = 1 ) , colon cancer ( n = 1 ) , and larynx cancer ( n = 1 ) ( table 1 ) . the bone scan and the bone pet were performed within 1 month apart from each other .
the reasons for the bone evaluation were regular follow - up ( n = 10 ) , presence of suspicious bm ( n = 5 ) , and post - therapeutic evaluation of the known bm ( n = 1 ) .
this study was approved by the institutional review board of seoul national university bundang hospital .
a bone scan was performed using tc - hydroxymethylenediphosphonic acid ( hdp , mallinckrodt , st .
whole body bone scan images were acquired using a dual - head gamma camera ( forte , adac - philips , holt , mo , usa ) equipped with low energy high resolution collimator 3 hours post tc - hdp injection .
naf was generated from a reaction of o ( p , n)f using an in - house cyclotron ( kotron13 , kirams , seoul , korea ) .
ten minutes later , furosemide ( 10 mg , lasix ) was injected in order to flush the activity of the renal pelvis or urinary excretory system .
bone pet images were obtained from the skull base to the upper thigh or from the skull vertex to the feet , as requested by the physicians who had set the orders starting 30 minutes post naf injection .
a dedicated pet scanner ( allegro , philips medical systems , andover , ma , usa ) was used for 9 patients prior to the year 2009 ( 14 ) and a pet / ct scanner ( dvct , ge healthcare , milwaukee , wi , usa ) was used for 7 patients afterwards .
pet images from the dedicated pet scanner were attenuation - corrected using cs transmission scans and then reconstructed using an iterative algorithm ( row - action maximum - likelihood , philips medical systems , andover , ma , usa ) .
pet / ct images were attenuation - corrected using the ct scan and then reconstructed using a 3-dimensional ordered - subset iteration algorithm ( vue point , ge healthcare , milwaukee , wi , usa ) .
the resolutions of the reconstructed trans - axial images were 4.8 mm and 5.1 mm for pet and pet / ct , respectively .
a positive finding for bm was defined as the presence of an abnormally high bony uptake , which is not associated with typical degenerative , traumatic or periarticular lesions ( 8) .
diagnostic accuracies were also analyzed using the receiver operating characteristic ( roc ) curve analysis by utilizing a 4-point grading system ; definite , probable , less likely , and no evidence of bm .
consensus was reached by two nuclear medicine physicians in order to call a lesion bm .
a gold standard for bm was either the presence of typical findings compatible with bm in at least 2 imaging studies among mri , f - fdg pet / ct or i whole body scan , or the presence of a clinical progression causing a change of treatment plan during at least a one - year follow - up . those who had at least one proven bm lesion were considered bm positive patients regardless of the presence of any false positive bm findings .
mcnemar 's chi - square test or fisher 's exact test or roc analysis was used for the comparison of the diagnostic accuracy .
sixteen cancer patients ( m : f = 10:6 , mean age = 60 12 ) were enrolled in this study .
eleven of these patients were included in our previous report ( 14 ) , which did not involve the head - to - head comparison between the bone scan and the bone pet .
underlying diseases of the patients included breast cancer ( n = 5 ) , prostate cancer ( n = 5 ) , thyroid cancer ( n = 3 ) , gastric cancer ( n = 1 ) , colon cancer ( n = 1 ) , and larynx cancer ( n = 1 ) ( table 1 ) . the bone scan and the bone pet were performed within 1 month apart from each other .
the reasons for the bone evaluation were regular follow - up ( n = 10 ) , presence of suspicious bm ( n = 5 ) , and post - therapeutic evaluation of the known bm ( n = 1 ) .
this study was approved by the institutional review board of seoul national university bundang hospital .
a bone scan was performed using tc - hydroxymethylenediphosphonic acid ( hdp , mallinckrodt , st .
whole body bone scan images were acquired using a dual - head gamma camera ( forte , adac - philips , holt , mo , usa ) equipped with low energy high resolution collimator 3 hours post tc - hdp injection .
naf was generated from a reaction of o ( p , n)f using an in - house cyclotron ( kotron13 , kirams , seoul , korea ) .
ten minutes later , furosemide ( 10 mg , lasix ) was injected in order to flush the activity of the renal pelvis or urinary excretory system .
bone pet images were obtained from the skull base to the upper thigh or from the skull vertex to the feet , as requested by the physicians who had set the orders starting 30 minutes post naf injection .
a dedicated pet scanner ( allegro , philips medical systems , andover , ma , usa ) was used for 9 patients prior to the year 2009 ( 14 ) and a pet / ct scanner ( dvct , ge healthcare , milwaukee , wi , usa ) was used for 7 patients afterwards .
pet images from the dedicated pet scanner were attenuation - corrected using cs transmission scans and then reconstructed using an iterative algorithm ( row - action maximum - likelihood , philips medical systems , andover , ma , usa ) .
pet / ct images were attenuation - corrected using the ct scan and then reconstructed using a 3-dimensional ordered - subset iteration algorithm ( vue point , ge healthcare , milwaukee , wi , usa ) .
the resolutions of the reconstructed trans - axial images were 4.8 mm and 5.1 mm for pet and pet / ct , respectively .
a positive finding for bm was defined as the presence of an abnormally high bony uptake , which is not associated with typical degenerative , traumatic or periarticular lesions ( 8) .
diagnostic accuracies were also analyzed using the receiver operating characteristic ( roc ) curve analysis by utilizing a 4-point grading system ; definite , probable , less likely , and no evidence of bm .
consensus was reached by two nuclear medicine physicians in order to call a lesion bm .
a gold standard for bm was either the presence of typical findings compatible with bm in at least 2 imaging studies among mri , f - fdg pet / ct or i whole body scan , or the presence of a clinical progression causing a change of treatment plan during at least a one - year follow - up .
those who had at least one proven bm lesion were considered bm positive patients regardless of the presence of any false positive bm findings .
mcnemar 's chi - square test or fisher 's exact test or roc analysis was used for the comparison of the diagnostic accuracy .
of the 16 patients in the current study , 8 ( 50.0% ) proved to be bm positive and 8 ( 50.0% ) as bm negative .
of the 8 bm ( + ) patients , 2 had disseminated metastatic lesions , as shown in figure 1 .
all of the 8 bm ( + ) patients were categorized as having bm in the bone pet , yielding 100% sensitivity , whereas 7 of the 8 bm ( + ) patients were positive in the bone scan , yielding an 87.5% sensitivity ; the sensitivities were not statistically different between the bone pet and the bone scan ( p > 0.05 ) .
of the 8 bm ( - ) patients , 7 were correctly categorized as having no bm in the bone pet , yielding an 87.5% ( 7/8 ) specificity , whereas only 2 were correctly diagnosed in the bone scan , yielding a 25.0% ( 2/8 ) specificity . as a result ,
a bone pet had a significantly higher specificity than a bone scan in the patient - based analysis ( p < 0.05 ) .
a case showing higher specificity of a bone pet than a bone scan is demonstrated in figure 2 .
overall , the accuracy of bone pet ( 93.8% = 15/16 ) was significantly greater than that of the bone scan ( 56.3% = 9/16 , p < 0.05 ) in the patient - based analysis ( table 2 ) .
lesion - based analysis was conducted for the bone lesions identified by imaging studies , namely bone pet , bone scan , or ct .
this is because benign bone lesions without abnormal findings in the imaging studies can not be the lesions of interest in clinical practice .
table 1 ) were excluded in the lesion - based analysis because it was not sensible to identify a few more lesions in the clinical context of disseminated bm . as a result , 43 bone lesions were found in 14 patients .
of the 43 lesions , 31 were proven to be malignant and 12 were benign .
all of the 31 bm lesions were positive in the bone pet ( sensitivity 100% = 31/31 ) , whereas only 12 bm lesions were positive in the bone scan ( sensitivity 38.7% = 12/31 ) .
as a result , bone pet was found to be significantly more sensitive than the bone scan ( p < 0.01 ) ( fig .
specificity was also significantly greater for bone pet ( 75% = 9/12 ) than the bone scan ( 8.3% = 1/12 ) ( p < 0.05 ) .
overall , the accuracy of bone pet ( 93.0% = 40/43 ) was significantly greater than that of the bone scan ( 30.2% = 13/43 , p < 0.005 ) in the lesion - based analysis ( table 3 ) .
three false positive bone pet lesions were noted in 3 patients ( nos . 5 , 6 , and 9 ) .
the first two were sacrum and rib lesions from patients with spinal bone metastases proven by a spine mri .
with regard to the other proven bone metastases , the two lesions were strongly suggested to be clinical metastatic lesions . however , bone pet positive sacral lesion was negative in f - fdg pet / ct , while other bone pet positive lesions were all positive in the same patient .
in addition , bone pet positive rib lesion was clinically stable without any evidence of a disease progression for 4 years and 2 months afterward .
thus , the 2 lesions were considered to be benign . for the last bone lesion in patient no.9 ( fig .
4 ) , the rib lesion appeared to be positive in both the bone scan and the bone pet ; however , it was negative on the f - fdg pet / ct and the i whole body scan .
serum thyroglobulin ( < 0.2 ng / ml ) and anti - thyroglobulin antibody ( < 25 u / ml ) were undetectable .
the lesion was considered to be a benign lesion because other imaging studies were all negative ; moreover , there was no evidence of a disease progression thereafter for more than one year .
in the roc curve analyses , the bone pet was significantly more accurate than the bone scan for the detection of bm . in the patient - based analysis ,
the area under the curve ( auc ) of the bone pet ( auc = 0.992 , standard error [ se ] = 0.0110 , 95% confidence interval [ ci ] = 0.781 - 1.000 ) was significantly higher than that of the bone scan ( auc = 0.750 , se = 0.118 , 95% ci = 0.476 - 0.927 ) ( p = 0.0306 ) .
in addition , in the lesion - based analysis , the auc of the bone pet ( auc = 0.976 , se = 0.0155 , 95% ci = 0.876 - 0.999 ) was significantly greater than that of the bone scan ( auc = 0.691 , se = 0.0752 , 95% ci = 0.532 - 0.823 ) ( p = 0.0001 ) ( fig . 5 ) .
no difference was observed between the two studies in both patient and lesion - based analyses ( table 4 ) .
of the 16 patients in the current study , 8 ( 50.0% ) proved to be bm positive and 8 ( 50.0% ) as bm negative .
of the 8 bm ( + ) patients , 2 had disseminated metastatic lesions , as shown in figure 1 .
all of the 8 bm ( + ) patients were categorized as having bm in the bone pet , yielding 100% sensitivity , whereas 7 of the 8 bm ( + ) patients were positive in the bone scan , yielding an 87.5% sensitivity ; the sensitivities were not statistically different between the bone pet and the bone scan ( p > 0.05 ) .
of the 8 bm ( - ) patients , 7 were correctly categorized as having no bm in the bone pet , yielding an 87.5% ( 7/8 ) specificity , whereas only 2 were correctly diagnosed in the bone scan , yielding a 25.0% ( 2/8 ) specificity . as a result ,
a bone pet had a significantly higher specificity than a bone scan in the patient - based analysis ( p < 0.05 ) .
a case showing higher specificity of a bone pet than a bone scan is demonstrated in figure 2 .
overall , the accuracy of bone pet ( 93.8% = 15/16 ) was significantly greater than that of the bone scan ( 56.3% = 9/16 , p < 0.05 ) in the patient - based analysis ( table 2 ) .
lesion - based analysis was conducted for the bone lesions identified by imaging studies , namely bone pet , bone scan , or ct .
this is because benign bone lesions without abnormal findings in the imaging studies can not be the lesions of interest in clinical practice .
table 1 ) were excluded in the lesion - based analysis because it was not sensible to identify a few more lesions in the clinical context of disseminated bm . as a result , 43 bone lesions were found in 14 patients .
of the 43 lesions , 31 were proven to be malignant and 12 were benign .
all of the 31 bm lesions were positive in the bone pet ( sensitivity 100% = 31/31 ) , whereas only 12 bm lesions were positive in the bone scan ( sensitivity 38.7% = 12/31 ) .
as a result , bone pet was found to be significantly more sensitive than the bone scan ( p < 0.01 ) ( fig .
specificity was also significantly greater for bone pet ( 75% = 9/12 ) than the bone scan ( 8.3% = 1/12 ) ( p
overall , the accuracy of bone pet ( 93.0% = 40/43 ) was significantly greater than that of the bone scan ( 30.2% = 13/43 , p < 0.005 ) in the lesion - based analysis ( table 3 ) .
three false positive bone pet lesions were noted in 3 patients ( nos . 5 , 6 , and 9 ) . the first two were sacrum and rib lesions from patients with spinal bone metastases proven by a spine mri . with regard to the other proven bone metastases , the two lesions
were strongly suggested to be clinical metastatic lesions . however , bone pet positive sacral lesion was negative in f - fdg pet / ct , while other bone pet positive lesions were all positive in the same patient .
in addition , bone pet positive rib lesion was clinically stable without any evidence of a disease progression for 4 years and 2 months afterward .
thus , the 2 lesions were considered to be benign . for the last bone lesion in patient no.9 ( fig .
4 ) , the rib lesion appeared to be positive in both the bone scan and the bone pet ; however , it was negative on the f - fdg pet / ct and the i whole body scan .
serum thyroglobulin ( < 0.2 ng / ml ) and anti - thyroglobulin antibody ( < 25 u / ml ) were undetectable .
the lesion was considered to be a benign lesion because other imaging studies were all negative ; moreover , there was no evidence of a disease progression thereafter for more than one year .
in the roc curve analyses , the bone pet was significantly more accurate than the bone scan for the detection of bm . in the patient - based analysis ,
the area under the curve ( auc ) of the bone pet ( auc = 0.992 , standard error [ se ] = 0.0110 , 95% confidence interval [ ci ] = 0.781 - 1.000 ) was significantly higher than that of the bone scan ( auc = 0.750 , se = 0.118 , 95% ci = 0.476 - 0.927 ) ( p = 0.0306 ) .
in addition , in the lesion - based analysis , the auc of the bone pet ( auc = 0.976 , se = 0.0155 , 95% ci = 0.876 - 0.999 ) was significantly greater than that of the bone scan ( auc = 0.691 , se = 0.0752 , 95% ci = 0.532 - 0.823 ) ( p = 0.0001 ) ( fig .
no difference was observed between the two studies in both patient and lesion - based analyses ( table 4 ) .
bone pet has been proven to be a useful bone imaging modality worldwide ( 1 , 4 ) . the combination of excellent physico - chemical characteristics of naf and robust imaging techniques of modern pet scanner enabled the bone pet to be the most promising tool for bone imaging .
not only malignant bone diseases ( 8 - 10 ) , but benign metabolic bone diseases ( 11 - 13 ) have also been successfully investigated using the bone pet .
furthermore , pet integrated with ct , yielding pet / ct , increased the diagnostic accuracy of bone pet in a variety of bone diseases ( 16 ) .
in korea , there has been only one clinical report on naf bone pet ( 14 ) .
the study investigated only the feasibility of naf bone pet in both cancer and benign bone disease patients .
however , a critical question regarding the diagnostic accuracy of bone pet vs. bone scan for the detection of bm has not been addressed in the previous report .
thus , in the current study , we performed a direct comparison between the diagnostic accuracies of naf bone pet vs. tc - hdp bone scan in cancer patients who underwent both imaging studies .
the major finding of the current study is that the bone pet was found to be more accurate than the bone scan in the evaluation of bm and further , bone pet was shown to improve the sensitivity ( in the lesion - based analysis ) and specificity for bm .
bone pet could effectively exclude non - metastatic bone lesions , which was reflected by its high specificity , compared to the bone scan in both patient- and lesion - based analyses .
the improved specificity of the bone pet compared to the bone scan seems to be mostly due to the tomographic nature of a pet and/or supplemental information from a ct ( 1 , 4 , 15 ) . planar bone scan images often fail to give confidence to readers regarding the exact location of the bone lesions due to the lack of depth information . on the contrary ,
of course , if we had adopted a single photon emission computed tomography ( spect ) instead of the simple planar bone scan , the diagnostic accuracy of tc - hdp bone imaging would have been better ( 16 ) , although a whole body coverage by spect might have been unrealistic due to the limited axial field of view of the current gamma camera .
another reason for the high specificity of bone pet compared to a bone scan also could be explained by the way the patients were recruited to the current study .
bone scan has already been proven to be useful as an initial screening test for bm evaluation ( 6 , 15 ) , and patients without any abnormality on their bone scans are not regarded as candidates for further tests , such as bone pet .
therefore , due to the test referral bias , true negative bone scan cases are typically excluded in this kind of retrospective study , resulting in a low specificity of the bone scan .
however , bone pet and bone scan had comparable sensitivities in the patient - based analysis ( table 2 ) .
with regard to the sensitivity of bm , bone pet seems to have a physico - chemical advantage over the bone scan ( 8 , 17 ) .
the high first - pass extraction , rapid blood clearance , and low protein binding of naf provide bone pet imaging with a high image - quality and a high lesion - contrast ( 3 , 7 ) . in our cases ,
bone pet clearly showed a more prominent uptake pattern compared to the bone scan in most of the bm lesions ( figs . 1 - 3 ) , providing the readers with more confidence in the reading
nevertheless , given the comparable sensitivity in the patient level ( table 2 ) and the relatively low cost , the bone scan may continue to be the primary screening study for the evaluation of bm for the time being .
in fact , one crucial obstacle in the clinical application of bone pet is the cost - effectiveness of bone pet over the bone scan ( 10 ) .
first , pet imaging is quantitative , whereas gamma camera imaging is not ( 1 , 4 , 7 ) .
bone blood flow and bone turnover could be quantitatively measured using dynamic naf pet studies in malignant bone disease , paget disease , or renal osteodystropy ( 3 , 11 , 18 , 19 ) .
second , patient compliance for a bone pet should be better than that for a bone scan because it only takes about 0.5 - 1 hour for a bone pet acquisition in order to get started after the injection , which is shorter than the time for a bone scan , which takes at least 3 - 4 hours .
third , none - medical issues , such as the supply problem of mo and the parent radionuclide of tc may advance the clinical use of naf bone pet faster than expected . in this
regard , physicians need to increase their awareness and pay closer attention to the development of naf bone pet in the future . in conjunction with all the mentioned points above , the unique strength of the current study could be the comparison of the diagnostic accuracies between bone pet / ct and bone pet .
although the analyzed number of patients ( n = 16 ) or lesions ( n = 43 ) were quite low compared to other studies , the competency of bone pet was not inferior to that of bone pet / ct ( table 4 ) .
although bone pet / ct may be more accurate for the identification of a particular bm lesion than the bone pet ( fig .
2 ) , overall , the two studies were equivalent in terms of detection of bm in the level of patients and individual lesions ( table 4 ) .
if the results could be advocated in other larger scale studies , it might provide some chances of clinical utility to the out - dated dedicated pet scanners in a few hospitals in korea , including one in our hospital .
the characteristics of bm ( i.e. , osteoblastic , osteolytic , or mixed ) or the known predilection site of bm may also have played some roles for determining the diagnostic accuracy of the bone pet .
the heterogeneity of patient diseases also may have affected the low diagnostic accuracy of the bone scan ; particularly with single malignant disease patients , such as breast cancer , a bone scan may have a better diagnostic accuracy than other studies ( 20 , 21 ) .
furthermore , the fact that not all of the suspicious lesions were pathologically proven is another critical limitation of the study .
100% sensitivity of bone pet in the current study may overestimate the genuine diagnostic accuracy of the bone pet .
some bone metastatic lesions have been reported to be contained within the bone marrow without involving the cortical bone ( 22 ) .
if we had performed more f - fdg pet / ct studies , such bm lesions may have been missed by the bone pet , but observed by f - fdg pet / ct , generating a sensitivity of bone pet to be lower than 100% .
f - fdg pet has been reported to be more accurate than tc - mdp bone scan ( 21 ) ; however , f - fdg pet seems to have a lower accuracy for bm than naf bone pet ( 14 ) . as a matter of fact , not only f - fdg pet / ct , but also mri sometimes offers equivocal findings regarding the nature of bone lesions ( 20 ) . without a doubt
, a bone biopsy would determine the exact nature of the bone lesion ; yet , it is not always a practical approach for patient management .
furthermore , the cost - effectiveness of a bone pet was not evaluated in this study . in this
regard , further large scale studies are required to determine the role of the bone pet for the evaluation of bm in the current medical reimbursement condition of korea .
naf bone pet is more accurate than tc - hdp bone scan for the evaluation of bm .
bone pet by itself has a potential to be a gold standard test for bm .
however , without sufficient confirmatory data in korea , we claim , solely from our findings , that the accuracy of bone pet is superior to that of the bone scan .
the characteristics of bm ( i.e. , osteoblastic , osteolytic , or mixed ) or the known predilection site of bm may also have played some roles for determining the diagnostic accuracy of the bone pet .
the heterogeneity of patient diseases also may have affected the low diagnostic accuracy of the bone scan ; particularly with single malignant disease patients , such as breast cancer , a bone scan may have a better diagnostic accuracy than other studies ( 20 , 21 ) .
furthermore , the fact that not all of the suspicious lesions were pathologically proven is another critical limitation of the study .
100% sensitivity of bone pet in the current study may overestimate the genuine diagnostic accuracy of the bone pet .
some bone metastatic lesions have been reported to be contained within the bone marrow without involving the cortical bone ( 22 ) .
if we had performed more f - fdg pet / ct studies , such bm lesions may have been missed by the bone pet , but observed by f - fdg pet / ct , generating a sensitivity of bone pet to be lower than 100% .
f - fdg pet has been reported to be more accurate than tc - mdp bone scan ( 21 ) ; however , f - fdg pet seems to have a lower accuracy for bm than naf bone pet ( 14 ) . as a matter of fact , not only f - fdg pet / ct , but
also mri sometimes offers equivocal findings regarding the nature of bone lesions ( 20 ) . without a doubt , a bone biopsy would determine the exact nature of the bone lesion ; yet , it is not always a practical approach for patient management .
furthermore , the cost - effectiveness of a bone pet was not evaluated in this study . in this
regard , further large scale studies are required to determine the role of the bone pet for the evaluation of bm in the current medical reimbursement condition of korea .
naf bone pet is more accurate than tc - hdp bone scan for the evaluation of bm .
bone pet by itself has a potential to be a gold standard test for bm .
however , without sufficient confirmatory data in korea , we claim , solely from our findings , that the accuracy of bone pet is superior to that of the bone scan .
Output:
| objectivena18f bone positron emission tomography ( bone pet ) is a new imaging modality which is useful for the evaluation of bone diseases . here ,
we compared the diagnostic accuracies between bone pet and bone scan for the detection of bone metastasis ( bm).materials and methodssixteen cancer patients ( m : f = 10:6 , mean age = 60 12 years ) who underwent both bone pet and bone scan were analyzed .
bone pet was conducted 30 minutes after the injection of 370 mbq na18f , and a bone scan was performed 3 hours after the injection of 1295 mbq 99mtc - hydroxymethylene diphosphonate.resultsin the patient - based analysis ( 8 patients with bm and 8 without bm ) , the sensitivities of bone pet ( 100% = 8/8 ) and bone scan ( 87.5% = 7/8 ) were not significantly different ( p > 0.05 ) , whereas the specificity of bone pet ( 87.5% = 7/8 ) was significantly greater than that of the bone scan ( 25% = 2/8 ) ( p < 0.05 ) . in the lesion - based analysis ( 43 lesions in 14 patients ; 31 malignant and 12 benign ) , the sensitivity of bone pet ( 100% = 31/31 ) was significantly greater than that of bone scan ( 38.7% = 12/31 ) ( p < 0.01 ) , and the specificity of bone pet ( 75.0% = 9/12 ) was also significantly higher than that of bone scan ( 8.3% = 1/12 ) ( p < 0.05 ) .
the receiver operating characteristic curve analysis showed that bone pet was significantly more accurate than the bone scan in the patient ( p = 0.0306 ) and lesion ( p = 0.0001 ) based analyses.conclusionna18f bone pet is more accurate than bone scan for bm evaluation . |
PubmedSumm118559 | ***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 commonest fungal infection reported , of the central nervous system ( cns ) , is candidal meningitis.[15 ] we undertook a retrospective analysis of six cases from which the candida species were isolated from ventriculoperitoneal shunt fluids .
a retrospective analysis of six cases of candidal infection of the vp shunt was carried out in children ranging from newborns to six months . the data collected included age , sex , underlying predisposing factors , and clinical manifestations .
the vp shunt fluid was processed with the help of a microscopic examination and the cultures were performed on blood agar , macconkey 's agar , and sabouraud 's dextrose agar ( sda ) .
when a colony appeared on sda , the yeast was identified using the germ tube test , the growth pattern on cornmeal agar ( cma ) and tobacco agar , and sugar assimilation tests .
out of the 24 suspected cases of vp shunt infections , the candida species were isolated in six ( 25% ) cases .
shunt infection was defined as an isolation of the organism from the ventricular fluid , shunt tube , and reservoir , along with signs or symptoms suggestive of shunt infection or malfunction .
all the patients had undergone the shunt procedure under an antibiotic cover , with a combination of augmentin , gentamicin , ceftriaxone or ciprofloxacin .
all the six cases were premature babies with birth weight ranging from 1000 to 2000 grams , their median gestational age being 26 weeks .
the time of onset of clinical presentation ranged between seven days to one month after placement of the shunt .
the clinical manifestation was fever ( 100% ) , vomiting ( 100% ) , and altered sensorium in 50% of the cases .
gram staining of the fluid showed a presence of yeast cells in only three ( 50% ) cases .
out of the six isolated candida species , the commonest was candida albicans 66.6% ( 4/6 ) followed by candida parapsilosis and candida glabrata in one case each .
patients were given intravenous amphotericin b and all the patients responded and no mortality was noted in the study .
meningitis caused by candida species is a serious condition that may result in significant morbidity and mortality if not recognized and treated effectively .
although candida meningitis remains rare , its frequency has increased in the last few years , particularly in patients undergoing neurosurgical procedures such as vp shunts.[16 ] infection is a common complication of ventriculoperitoneal shunt ( vp ) placement .
cns shunt infection is a cause of significant morbidity , causing malfunction and chronic ill health , and a few cases may even turn fatal .
shunt associated infections are most frequently caused by coagulase negative staphylococcus ( cons ) ( 65% ) followed by gram negative bacteria .
however , this reported incidence of vp shunt infection might be underestimated , considering that some of the cultures , negative for bacterial culture , might have a fungal etiology .
chiou et al , found that fungi accounted for 17% of shunt infections ( 8/48 ) in a retrospective study performed in 1994 .
our findings , that is , 25% of shunt infections were due to fungi , is comparable with that study . even higher infection rates with candida species , that is , 59% was reported by viudes et al . and 74% by fernandez et al . in our study , all the six patients from whom candida species were isolated were premature babies with birth weight ranging from 1000 to 2000 grams and the median gestational age was 26 weeks .
viudes , while studying 15 patients with ages ranging from one year to 65 years , showed that the most common neurosurgical procedure performed was for the treatment of hydrocephalus .
chiou et al . reported that all the infections due to candida species occurred in premature babies , as noted in the present study , and the underlying factors were the neurosurgical procedures performed for the treatment of hydrocephalus .
viudes et al . also showed that hydrocephalus was the only underlying procedure performed before the development of shunt infection .
, one month after the neurosurgical procedure for hydrocephalus was performed . in one review , 77% of candida infections developed within three months of shunt manipulation , suggesting inoculation of the organism during surgery as suggested by nguyaen et al .
other risk factors for candida shunt infections and meningitis include administration of broad spectrum antibiotics , prior or concurrent meningitis , cerebrospinal fluid leakage , bowel perforation , and/or abdominal surgery , steroids , and indwelling catheters .
in this study , all the patients presented with clinical symptoms from seven days to one month after neurosurgical procedure for hydrocephalus was performed .
transient candidemia and secondary colonization of vp shunts have been suggested by other investigators as a possible source of infecting candida organisms .
distal shunt infection refers to an infection at the site of the shunt drainage , which is either a vascular site such as the right atrium , the symptoms are nonspecific and include fever and malaise .
proximal candida shunt infections are manifested by malfunction associated with high intracranial pressure , including headaches , nausea , vomiting , and altered mental status .
the most common symptoms of ventriculoperitoneal infections include fever ( 31% ) and meningoencephalitis ( 21%).[911 ] out of the six isolates of the candida species in the present study , candida albicans was the most common 66.66% ( 4/6 ) cases , while candida parapsilosis and candida glabrata were isolated in one case each .
candida albicans has been reported as the predominant isolate in all reports earlier,[16 ] followed by candida parapsilosis .
the predominant clinical manifestations in all the individuals in the present study were fever ( 100% ) , vomiting ( 100% ) , and altered sensorium in 50% of the cases .
sanchez - patocarreo et al . , in his study , showed that fever was present in 31% of the patients , signs of meningoencephalitis in 21% of the patients , while abdominal symptoms were present in 10% of the cases .
in the present study the abdominal symptom present was vomiting in 100% of the cases .
similar findings were also reported by nguyaen et al . , but lymphocytic predominance was reported by sanchez - patocarreo et al .
amphotericin b is effective against all species of candida including candida glabrata , which is inherently resistant to fluconazole .
hence , identification of the species is important , as this gives a clue to the treating clinician for choosing the proper antifungal agent .
, this study highlights the importance of early diagnosis and proper treatment of vp shunt fungal infections,,to prevent mortality .
Output:
| although ventriculoperitoneal ( vp ) shunt infection is a common complication of shunt procedures , fungal infection is considered to be rare . in the present study , we performed retrospective analysis of six cases in which candida infection occurred .
in all these six cases , vp shunt was performed in children for hydrocephalus and the onset of symptoms varied between seven days to one month after the surgical procedure was performed .
the commonest clinical signs and symptoms were fever ( 100% ) , vomiting ( 100% ) , and altered sensorium ( 50% ) .
the commonest isolate was candida albicans ( 66.66% ) followed by candida parapsilosis and candida glabrata in one case each .
all the patients were successfully treated with amphotericin b and there was no mortality recorded . |
PubmedSumm118560 | ***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: transapical transcatheter aortic valve replacement ( ta - tavr ) through mini - thoracotomy is an alternative approach to aortic valve replacement that has been used successfully in patients with symptomatic severe aortic stenosis .
patients who qualify for ta - tavr are considered to be high - risk or inappropriate candidates for traditional aortic valve replacement surgery , frequently possessing poor peripheral arterial access excluding them from trans - femoral tavr . in europe ,
importantly , ta - tavr patients have had higher rates of morbidity and mortality than tf - tavr patients .
the reason for this observation may be related to both the characteristics of the cohort selected for ta - tavr as well as the procedure itself [ 2 , 3 ] .
importantly , the rate of chronic obstructive pulmonary disease in ta - tavr patients ranges between 20 - 40% [ 2 , 4 , 5 ] .
poor respiratory function has been shown to be a predictor of mortality in ta - tavr patients .
a recent single institution review found that much of the additional morbidity in ta - tavr cases may be related to pulmonary complications such as post - operative pneumonia , and that epidural analgesia was associated with a decrease in both morbidity and mortality .
however , epidural anesthesia in patients with severe aortic stenosis can result in problematic vasodilation and is not recommended in patients on clopidogrel therapy .
paravertebral analgesia has been safely used since the initiation of the ta - tavr program at maine medical center . in this study
it was hypothesized that paravertebral blockade in this population would be associated primarily with decreased opioid requirements and more frequent extubation in the operating room .
secondarily it was hypothesized that paravertebral blockade would be associated with a decrease in new onset atrial fibrillation rates , shorter intensive care unit ( icu ) stay , and a decrease in 30 day mortality .
after institutional review board approval , demographic , procedural and post - procedural outcome data was retrospectively obtained via electronic chart review on 61 patients who underwent ta - tavr .
patients scheduled for ta - tavr were evaluated and consented for left sided thoracic paravertebral blockade .
of the 61 total patients , 48 received a left sided single shot paravertebral blockade .
all nerve blockades were performed in a designated room outside of the operating suite , prior to placement of invasive monitors .
13 patients receiving a ta - tavr did not receive a paravertebral block either because they had their surgery prior to the initiation of the block protocol , or because they had a contraindication to paravertebral blockade according to the american society of regional anesthesia guidelines related to anti - coagulation .
one patient had the blockade aborted as a result of a small subcutaneous hematoma produced with the initial infiltration of local anesthetic .
anesthesiologists primarily employed a landmark technique to access the paravertebral space rather than an ultrasound guided technique .
additional levels were added to ensure block success if a patient was found to have poor anatomic landmarks or the block was considered technically difficult .
patients were placed in a sitting position , with arms rested on a pillow , head and neck flexed , and shoulders relaxed with standard asa ( american society of anesthesiologists ) non - invasive monitors applied .
entry sites were marked 2.5 cm lateral to the spinous process marks on the left side .
skin was prepared with a 2% chlorhexidine gluconate solution and aseptic technique was maintained throughout the procedure .
a 20-gauge tuohy needle was attached to extension tubing and a syringe filled with local anesthetic mixture .
the tuohy needle was then inserted perpendicular to the skin until it came in contact with the transverse process . then the needle was redirected caudad or cephalad and advanced until a loss of resistance was detected .
the needle was aspirated , if no blood , air , or spinal fluid was encountered then 0.2% ropivicaine with clonidine was injected at each level .
single level blockades were performed using a total of 20ml 0.2% ropivicaine with 100mcg clonidine .
two level and three level blockades were performed using a total of 30ml 0.2% ropivicaine with 100mcg clonidine divided equally between levels .
transesophageal echocardiography ( tee ) was performed by cardiology . with regard to peri - operative anticoagulation management
pre - operatively , patients anticoagulation regimens varied based on their pre - existing comorbidities , however warfarin was generally withheld 5 days prior to surgery and patients were bridged on iv heparin infusions until midnight the night before surgery .
intra - operatively unfractionated heparin was bolused targeting an activated clotting time greater than 250s .
postoperatively , clopidogrel was continued for at least 6 months , and aspirin was continued indefinitely .
patient medical records were reviewed to collect preoperative demographic and comorbidity data in addition to the following information : 1 ) peri - operative fentanyl dose administered by the anesthesiologist , 2 ) timing of extubation , 3 ) new onset atrial fibrillation , 4 ) length of icu stay and 5 ) 30-day mortality rate . analyzing the incidence of new onset post - operative atrial fibrillation in our patient population , 16 patients who received a paravertebral blockade and 5 patients who did not had pre - existing atrial fibrillation and therefore were excluded from analysis . statistical analysis . due to the small sample size in this study
, group comparisons were performed using fisher s exact test for categorical variables e.g. extubation in the operating room vs. extubation in the icu .
continuous variables including fentanyl dosage and time spent in the icu were compared between groups using an unpaired t - test .
as previously mentioned , in the analysis of the incidence of new onset atrial fibrillation , 16 of 48 patients in the paravertebral group and 5 of 13 patients in the non - paravertebral group were excluded due to pre - existing atrial fibrillation .
of the patients receiving a paravertebral blockade , no adverse outcomes occurred related to block placement .
the mean peri - operative opioid administration was slightly less in patients receiving a paravertebral blockade .
patients with paravertebral blockades also appeared to be extubated more frequently in the operating room .
the incidence of new onset post - operative atrial fibrillation was significantly less in patients who received a paravertebral blockade . of patients receiving a paravertebral blockade for their ta - tavr , 40 of 48 ( 83.3% )
this is in contrast to the patients who did not receive a paravertebral blockade in which 6 of 13 ( 46.2% ) were successfully extubated in the operating room .
there was a non - statistically significant trend towards decrease length of icu stay among those ta - tavr patients with paravertebral analgesia ( 58.3 hrs vs 75.8 hrs , p value 0.35 ) .
there were no deaths in the 30-day post - operative period in either group ( table 2 ) .
to the authors knowledge , this is the first published case series of the use of paravertebral blocks in ta - tavr patients .
this preliminary experience suggests that paravertebral analgesia may have a valuable role in caring for ta - tavr patients .
importantly , this analysis demonstrates both the safety and practicality of using paravertebral blockades in this patient population . there were no complications in 48 patients related to paravertebral blockades and importantly
, these blockades were performed in a time efficient manner in a busy clinical practice .
additionally , this analysis supports that paravertebral blockades are associated with a slightly lower intra - operative opioid administration and a higher rate of extubation in the operating room . with regard to post - operative outcomes
, a lower frequency of new onset atrial fibrillation was observed in patients who received paravertebral analgesia as well . while there was a trend towards a decreased length of stay in the intensive care unit , this was not statistically significant .
thoracic surgery in general is associated with a decline in post - operative pulmonary function as a result of pain , diaphragmatic dysfunction , impaired chest wall compliance and atelectasis .
this effect is likely more pronounced in elderly patients and those patients with pre - existing pulmonary disease . in the tavr population ,
pain is a powerful stimulator of catecholamine release which may contribute to cardiac irritability , postoperative agitation , and pulmonary complications [ 11 , 12 ] .
transapical access in tavr is a risk factor for new onset atrial fibrillation , which occurs in about one - third of patients undergoing tavr .
the use of epidurals in both thoracic and cardiac surgery has been associated with improved post - operative pulmonary function and cardiovascular outcomes including atrial fibrillation [ 7 , 9 , 14,15,16,17,18 ] .
it is therefore not surprising that the use of epidurals in patients undergoing ta - tavrs has been associated with a decrease respiratory complications , new onset atrial fibrillation and mortality [ 7 , 19 , 20 ] .
paravertebral nerve blockades have been documented to be at least as effective as epidural anesthesia , and superior to parenteral opioids in relieving post - thoracotomy pain [ 9 , 21,22,23,24 ] . unlike epidural anesthesia , which impacts the sympathetic chain bilaterally ,
this theoretically reduces the risk of hypotension associated with block use and is substantiated by studies that have demonstrated lower fluid and vasopressor requirements with the use of paravertebral catheters when compared to epidurals [ 22 , 25 , 26 ] .
significant concerns also exist about the use of epidural analgesia in the setting of systemic anticoagulation and the use of anti - platelet agents [ 27 , 28 ] .
single shot paravertebral blockade with long acting local agents largely circumvents these concerns . this initial small retrospective review has unavoidable limitations .
this small control group of patients who did not receive paravertebral blockades may be too small to be representative , and lack of randomization clearly limits the wider clinical applicability of our observations .
this pilot study also does not include post - operative pain scores or post - operative opiate administration .
visual analogue scales for pain assessment were recorded by nursing staff at variable time points , were frequently confounded by the use of sedation on intubated patients and by pain at unrelated non - operative sites such as lower back pain . a formal analysis of the post - operative visual analogue scale was therefore not possible .
we acknowledge that the rate of atrial fibrillation in our control group is above published levels in recent literature .
the number of blockade levels varied between 1 and 3 and the volume of local given also varied which would quality of the blockade .
finally , plasma clonidine levels following epidural administration have been shown to approximate plasma levels after intravenous administration .
systemic absorption of clonidine may contribute to hypotension , and could influence the post - operative course of cardiac surgery patients and may have confounded our observations .
finally , the goal for every patient in this cohort was an on - table extubation in the setting of adequate oxygenation , ventilation , hemodynamic stability and neurologic function .
though some unavoidable inter - operator subjectivity may exist in regards to readiness for extubation , the observed statistical difference favoring intraoperative extubation would appear clinically relevant .
this is the first reported experience of paravertebral analgesia in ta - tavrs . despite the obvious and unavoidable limitations of this retrospective review , our initial experience and patient outcomes using paravertebral blockade in ta - tavrs
the pilot outcome data from this case series suggests that addressing peri - operative sympathetic stimulation with neuraxial anesthesia may have a measurable benefit garnered beyond what is achieved with an opioid - based approach .
the lack of complications at a minimum demonstrates the technique can be done safely in this high - risk patient cohort .
these preliminary observations should be confirmed using a more formal prospective , randomized , potentially multi - institutional investigation .
Output:
| introductiontransapical transcatheter aortic valve replacement is an option for patients who are not candidates for traditional aortic valve surgery but have severe aortic stenosis and unfavorable ileo - femoral anatomy .
epidural analgesia in these cases has been associated with improved morbidity and mortality .
the following manuscript presents the findings of an initial clinical experience employing paravertebral analgesia for patients undergoing transapical transcatheter aortic valve replacement.methodsa retrospective review was performed of 61 transapical transcatheter aortic valve replacement cases over a two - year period from november 2012 through july 2014 .
paravertebral analgesia was provided as left sided single injections covering 1 - 3 dermatome levels using 0.2% ropivicaine with supplemental clonidine to 48 patients .
the following outcome metrics were collected : 1 ) peri - operative opiate administration , 2 ) rate of extubation in the operating room , 3 ) new atrial fibrillation , 4 ) duration of intensive care stay , 5 ) 30-day mortality.resultsthe mean opiate administration was less in patients with paravertebral analgesia ( 128.65mcg vs. 163.46mcg fentanyl , p value 0.05 ) and these patients were more frequently extubated in the operating room ( 83.3% vs. 46.2% , p - value 0.0107 ) .
incidence of atrial fibrillation was less in patients who received paravertebral analgesia ( 18.8% vs. 75.0% , p - value 0.0048 ) .
there was a non - significant trend towards decreased intensive care stay in patients who received paravertebral analgesia ( 58.3 hrs vs 75.8 hrs , p value 0.35 ) .
there was no difference in 30-day mortality .
no complications resulted from paravertebral analgesia.conclusionsthis is the first reported case series of paravertebral blockade in transapical transcatheter aortic valve replacement patients .
the findings suggest that paravertebral single shot blocks are both safe and practical for use in this patient population .
a formal prospective investigation of paravertebral analgesia in these patients is warranted . |
PubmedSumm118561 | ***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 ability to maintain balance is the most basic element required for people to lead
normal daily lives and perform intended activities1 .
however , difficulty with balance and postural control in stroke
patients leads to defective movement ability , interferes with detailed performance of upper
limb functions , and disables walking and activities of daily living2 .
therefore , balance is the most basic requirement to prevent
falling , undertake the activities of daily living , and maintain an independent life in
stroke patients3 . to restore the balance
of poststroke hemiplegic patients ,
motor learning methods have been used , such as lateral
weight shifting4 , a method using
balls5 , raising the foot of the
unaffected side on a board at a certain height6 , visual feedback training7 , and auditory feedback training8 .
training on an unstable surface
rather than a stable surface can generate more external sway , thus improving postural
control ability9 , can induce more diverse
motions and muscular uses , can increase proprioceptive senses , and can potentially change
the neuromuscular mobilization pattern10 .
the training requires the subject to maintain their balance and posture or shift their
weight on unstable surfaces , such as a sling , a rocker board , a swiss ball , a balance ball ,
and a balance pad .
furthermore , as another approach to balance training , task - oriented
training repeats functional movements that are required for actual living . there are various
studies that have found better results for gait or gait - related functions of stroke patients
with the application of task - oriented training rather than simply increasing the movement of
hemiplegic limbs11 .
furthermore , focusing
on repeated functional tasks helps to improve the motor functions of stroke patients12 .
many activities of daily living require the performance of more than one task at a
time13 , and include dual tasks that
involve the simultaneous performance of two movement tasks14 .
performing one task while simultaneously performing another task
or performing two or more tasks continuously and simultaneously is referred to as dual - task
performance15 .
when put into a
situation of dual - task performance , people whose cognitive or physical functions are not
smooth , such as stroke patients and the aged , lose their physical abilities or experience
physical injuries , such as falls16 , 17 .
for this reason , studies are being
conducted on the application of dual - task performance for subjects such as stroke patients
and aged people18,19,20 .
yang et al.17 observed a reduction of actual movements
in patients with neurological injuries due to various tasks and emphasized the importance of
performing dual tasks through behavior enhancement by performing two exercise tasks
simultaneously in a complex environment .
furthermore , canning et al.21 argued that two exercise tasks must be performed
simultaneously to effectively carry out complex tasks , such as the activities of daily
living , and erickson et al.22 reported
that training in dual - task situations resulted in more positive results , such as an increase
in cerebral blood flow , than training in single - task situations .
dual - task training methods
include performing a cognitive task , such as calculating numbers or guessing an answer while
performing a functional task , or simultaneously performing two or more exercise tasks , such
as moving things or throwing and holding balls , to promote functional activities23 . in a study by yang et al.18 ,
the
application of exercises based on dual tasks to chronic stroke patients , improved their gait
ability . in a study by schwent et al.24 ,
12 weeks of dual - task training in dementia patients improved their dual - task performance
abilities compared with a control group . furthermore , canning et al.21 reported that application of multi - task training for 8
weeks to patients with parkinson s disease resulted in improved confidence in performing
multiple tasks , decreased mental and physical fatigue , reduced senses of difficulty and
anxiety , and enhanced gait speed in multiple tasks .
these results of previous studies were
brought about by formation of the ability to integrate multiple exercise tasks into complex
environment of daily living .
however , most
studies on dual - task training have focused on enhancement of task performance abilities , and
there are few studies on the effects of dual - task training on improvement of balance
ability .
therefore , in this study , the effects of dual - task training on the balance ability of
stroke patients were investigated .
the subjects of this study were 40 patients with hemiplegia resulting from stroke diagnosed
by a rehabilitation doctor practicing in n hospital located in daegu , south korea .
they were
randomly and equally assigned to a dual - task training group ( dtg ; 9 male , 11 female ) and a
single - task training group ( stg ; 12 male , 8 female ) .
the mean sd age , height , and weight
of the dtg was 55.37 20.6 years , 165.00 9.53 cm , and 64.12 14.12 kg , respectively .
the mean sd age , height , and weight of the stg was 57.10
7.83 years , 162.20 9.21 cm , and 63.20 11.26 kg , respectively .
the
inclusion criteria were as follows : no visual field defect , no abnormality in the vestibular
organs , no orthopedic disease , an unrestricted range of motion , the ability to understand
and perform the exercise as instructed by the researcher , and a score of 24 or higher on the
mini - mental state examination
this study was approved by the university
institutional review board , and all the subjects understood the purpose of the study and
provided written informed consent prior to participation , in accordance with the ethical
standards of the declaration of helsinki .
the subjects in the single - task traing group stood in a
comfortable position on the therapy room floor , faced a therapist , then threw a swiss ball
back and forth . during this training , the therapist adjusted the direction and speed of the
ball in such a way that the center of gravity of the patients would move out of the base of
support ( bos ) and then return to its original position25 .
next , the subjects performed balance training , which involved
raising and lowering two ankles while facing the forward26 or moving objects from one table to another table in a standing
position25 .
lastly , the subjects
performed balance training while facing forward in a tandem standing position . the patients
were accompanied by a support therapist or guardian , who simultaneously performed the
training near them to ensure that they did not trip or fall .
the dtg performed dual tasks ,
which involved performing a task on an unstable surface using a balance pad ( airex , sins ,
switzerland ) .
the participants ( n = 40 ) were randomly divided into the stg ( n = 20 ) and the dtg ( n = 20 ) .
both groups completed 30 minutes of exercise each day , five times a week for 8 weeks . for
measurement of balance ability , a biofeedback analysis system ( ap1153 biorescue , rm
ingenierie , rodez , france ) was used to determine weight bearing , sway length , anterior range
los ( limit of stability ) , and posterior range los on the affected side in a static standing
position .
for the measurement of dynamic balance , we used the berg balance scale ( bbs ) .
after the general characteristics of the subjects were determined , a
paired t - test was used to compare the variations in weight distribution on the affected side
when standing , sway length , anterior los , posterior los , and bbs scores .
the significance of
differences between the two groups was investigated using an independent t - test .
both the dtg and the stg showed significant differences between before and after the
interventions in the weight distribution rate , sway length , anterior los , posterior los , and
bbs scores ( p < 0.05 ) .
furthermore , when the differences between before and after interventions were compared
between the dtg and the stg , the dtg showed significant increases in weight distribution
rate , anterior los , posterior los , and bbs scores compared with the stg ( p < 0.05 ) ( table 1table 1.comparison of the change in balance ability in the training groups with values
presented as the mean standard deviationdtgstgbeforepostbeforepostaffected side wd ( % ) 43.6 3.847.2 2.0 * 43.0 6.044.5 8.3*sway length ( mm)37.0 16.829.5 9.4 * 36.1 11.333.3 10.1*anterior los ( mm)2701.8 3111.46209.9 3992.9 * 2361.6 2472.53596.9 3140.7*posterior los ( mm)1755.0 1611.42688.0 1870.0 * 1216.4 1014.91670.2 1143.2*bbs
( scale)37.5 10.545.5 6.3 * 42.3 7.745.9 7.2**significant difference compared with before therapy at < 0.05 .
dtg : dual task training group ; stg : single task training
group ; wd : weight distribution ; los : limit of stability ; bbs : berg balance scale ) . *
dtg : dual task training group ; stg : single task training
group ; wd : weight distribution ; los : limit of stability ; bbs : berg balance scale
the functional recovery of stroke patients is more effective when their therapies includ
high - intensity training and appropriate practices that allow volutary use of specific
motions and functions that are similar to actual tasks27 .
furthermore , adjusting the patient s pelvic movement is critical because dynamic balance is
controlled by the harmonious movement between the pelvis and the upper body as well as by
the muscles around the hip joint ; the weights of the head , upper limbs , and trunk is
transferred to the lower limbs through the pelvis28 . as a therapeutic method for restoration of this function ,
dual - task training is very popular , and active research is being conducted on the
performance of dual tasks that reduce postural sway and improve postural stability .
therefore , in this study , stroke patients were classified into two groups : an stg that
performed various training exercises on the floor , and a dtg that balanced on a balance pad
and performed various training exercises . as a result ,
both the dtg and the stg showed
improvements in static balance and dynamic balance .
this result agrees with the report of
sackley and baguly29 , who showed that the
amount of body sway significantly decreased in hemiplegic patients trained to shift their
weight to a target that moved within the range of the individual s stability limit .
the
reason for this is the increase in weight shifting and dynamic balance movements , which
effectively restore dynamic balance , as a result of the various training methods performed
in the stg , such as moving the center of the body out of the base of support and then
returning it to its original position .
furthermore , the results of this study suggest that the balance ability of the dtg
increased more significantly compared with the stg .
this was similar to the results of
irion30 , who reported that a balancing
exercise on an unstable surface promoted postural control and dynamic balance compared with
training on a stable surface .
smania et al.31reported that stroke patients who had performed a balancing exercise
on a stable surface for 2 weeks followed by a balance exercise on an unstable surface ,
showed significant differences in balance and gait speed after their experiment .
furthermore , a study that compared a group that performed a balance exercises on an unstable
surface with a control group reported that there were significant differences in bbs scores
and activities - specific balance .
soo - chan bae et
al.32 reported that significant
improvements in postural sway and left and right weight support rates appeared after balance
exercise on an unstable surface in stroke patients .
balance exercises on an unstable surface
sensitizes muscle spindles through the gamma motor neurons , resulting in the improvement of
motor output , which influences the stiffness of joints33 .
the result of improved balance ability after training on an
unstable surface is similar to the results of previous studies , but the objective of this
study was to investigate whether the dual- task training on an unstable surface improves
dynamic balance as well as static balance in stroke patients .
the results of this study are
supported by the previous study of dennis et al.34 , who reported that the test results for standing up and walking ( of
the experimental group ) improved compared with the control group as a result of circulation
and gait tasks ( including dual tasks performed by chronic stroke patients ) .
a study by
kramer et al.35 reported that when
different balance control training programs were applied to three groups , the balance of the
group that performed dual tasks improved , which also supports the findings of this study .
these previous studies results were brought about by formation of the ability to integrate
multiple exercise tasks in the complex environment of daily living by performing an exercise
task while already performing anothe task18 .
the most fundamental goal of treatment in stroke patients is to return the patients to
society .
for this reason , the recovery of balance ability in stroke patients has been a very
important goal of physical therapy and has been regarded as having a high research value .
furthermore , enhancement of the balance ability of patients through dual tasks has clinical
significance in several areas .
as patients show diverse reactions to the level of dual
tasks , assessment of dual tasks can be very important for stroke patients and can contribute
to the individual therapy plans of patients .
furthermore , compared with the traditional single - task exercise task , dual tasks are
performed in activities of daily living and , therefore , they can be a better indicator of
functional daily living in the stroke patient .
Output:
| [ purpose ] the purpose of this study was to determine the effects of training using dual
tasks on balance ability in stroke patients . [ subjects ]
forty stroke patients were divided
into a dual - task training group ( n = 20 ) and a single task training group ( n = 20 )
randomly . [ methods ]
the subjects in the single - task traing group stood in a comfortable
position , faced a therapist , then threw a swiss ball back and forth .
they then performed
balance training in which they raised and lowered their ankles while facing forward or
moved objects from one table to another .
the dtg performed dual tasks , which involved
performing a task on an unstable surface using a balance pad .
both groups received
training 30 min per day , five times per week , for eight weeks .
[ results ] the dtg showed
significant increases in weight distribution rate , anterior limit of stability , posterior
limit of stability , and bbs scores compared with the stg .
[ conclusion ] according to the
results of this study , dual - task training and single - task training were effective in
improving balance in stroke patients , dual task training is more effective for increasing
balance ability . |
PubmedSumm118562 | ***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 right to health services in equal conditions is a priority in the developed world and particularly in the countries of the european union , of which spain is a member state .
access to health services should be regardless of wealth , education , age or ethnic group , among other social markers . yet
, this is often not the case , at least as far as immigrant populations are concerned [ 13 ] .
spain has attracted a large number of economic migrants in recent years . as of 1 january 2010
, immigrants in spain accounted for 12.15 % of the total population and 12.79 % of that of the autonomous region of aragon . to date , the use of health services by immigrant populations has been studied by means of surveys or samples [ 3 , 59 ] .
these studies serve an important purpose but have clear methodological limitations , such as biases in sample selection , low response rates and different forms of biases in responses . these limitations
may be overcome if health system utilization is studied by accessing national health insurance scheme databases and those containing electronic medical records available in primary care .
this may even allow us to discover the part of the population that has not made use of health services in a given period .
three recent reviews have pointed out the need for this type of studies [ 5 , 6 , 10 ] .
this approach is quite important because it will give us real evidence of possible inequities in access to health services and health outcomes in the immigrant population , particularly when legal access is acknowledged and encouraged by spanish law .
additionally , the same law reminds public administrations that they are to direct their actions towards preventing discrimination against any collective that may have particular difficulty in accessing the spanish national health system services for cultural , linguistic , religious or social reasons .
the spanish national health system has two important features that make it particularly relevant for this type of study .
it is a universal and practically free system ( there is only a reduced co - payment for outpatient prescription drugs ) .
the health system operates in the same way for the immigrant population , including those whose status in the country is irregular , which should improve real access to it [ 12 , 13 ] .
there is only one condition : to be registered on the census this does not involve any risks to individuals who are in an irregular administrative situation .
universal health care is provided to all immigrants under the age of 18 , to pregnant women and in any emergency situation .
the present study aims to overcome the previously - mentioned methodological difficulties , and has the purpose of gaining insight into the real use of primary care services made by both spanish nationals and immigrants
its aims are : to analyse the use of primary care services by immigrants compared to spanish nationals , adjusted by age and sex;to analyse the differences in frequency of visits to primary care in relation to geographic origin . to analyse the use of primary care services by immigrants compared to spanish nationals , adjusted by age and sex ; to analyse the differences in frequency of visits to primary care in relation to geographic origin .
this is a retrospective observational study of all primary care visits made during 2007 to 26 health centres of a large spanish city , zaragoza , with a population of 700,000 inhabitants .
the main variable is defined as the total number of health centre visits / year .
the dependent variables were type of clinician with whom an appointment was requested ( general practitioner , paediatrician , midwife , physiotherapist , dentist , social worker or for diagnostic tests ) ; type of care requested : on demand ( requested by patient ) , scheduled ( by clinician ) , urgent ( requested by patient ) , scheduled house call and urgent house call ; and origin of immigrants .
for the purpose of this study , an immigrant was defined as a person whose nationality was not spanish ( foreign national ) , regardless of his / her economic situation .
statistics on patients with health care entitlements were obtained from the electronic medical records register ( omi : computerized medical office ) .
regardless of their use of primary care services during 2007was extracted from the central medical database of the regional health service .
patient anonymity was guaranteed at all times . in order to match data from both registers ,
frequency rates of primary care visits were calculated adjusting for age and sex both for the immigrant and spanish national populations .
rates were also standardized by the direct method , taking the spanish population as a benchmark , according to data from the spanish national institute of statistics ( www.ine.es ) on 1 january 2008 , in order to prevent differences caused by population distribution .
the 4,933,521 appointments made in 2007 were analysed for a reference population of 594,145 individuals , of which 66,264 were immigrants ( 11.15 % ) .
547,524 were paediatric appointments ( 015 years ) for a population of 71,114 children ( 10.87 % were immigrants ) .
the distribution of the studied population is given in table 1.table 1distribution of the studied population by sex and originmales%females%total%spain251,92187.93275,96089.70527,88188.85foreign nationals34,58012.0731,68410.3066,26411.15latin america10,7753.7614,1964.6124,9714.20eastern europe10,0723.5210,3093.3520,3813.43sub - saharan africa5,9072.062,4310.798,3381.40north africa4,7091.642,2820.746,9911.18eu and usa / canada1,6870.591,1960.392,8830.49asia / oceania1,4300.501,2700.412,7000.45 distribution of the studied population by sex and origin table 2 shows the adjusted frequency of visits ( no .
the adjusted annual frequency of visits for the nationals was 833 , whereas this was 458 for immigrants .
the asia / oceania population had the lowest frequency ( 308 ) , followed by the eastern european ( 329 ) , sub - saharan african ( 479 ) , north african ( 479 ) , the european union ( pre-2007)-usa / canada ( 516 ) and latin american ( 518 ) populations.table 2number of visits per 100 persons / year to health centres by type of clinician and attention typespanish nationalsimmigrantssub - saharan africanasia / oceaniaeastern europeanlatin americannorth africaneuropean union ( pre-2007)-usa / canadapopulation527,88166,2648,3382,70020,38124,9716,9912,883clinicianprimary care team appointments833458479308329518479516gp appointments506305324207203359327323paediatric appointments631408414279390431444348nurse appointments227838947588781117midwife appointments18149918191314physiotherapy appointments20000111dental appointments56656583social worker appointments32301223diagnostic tests6541413433433759attention typeon demand529306317212222353311332scheduled2131051086873117101123urgent6642512729446442scheduled house call61100004urgent house call1953143214general practitioner ( gp ) number of visits per 100 persons / year to health centres by type of clinician and attention type general practitioner ( gp ) figure 1 shows the frequency rate of visits to doctors by age.fig .
1frequency rates of visits to doctors by age frequency rates of visits to doctors by age the rate with which women visit doctors is higher than for men in both national and immigrant populations .
figure 2 shows the same values in relation to age in total visits to primary care teams.fig .
2frequency rate of primary care visits by age and sex frequency rate of primary care visits by age and sex
the results of this study are conclusive : the immigrant population makes less use of primary care services than the population of spanish nationals .
the city of zaragoza is the capital of the autonomous region of aragon , which , as all spanish autonomous regions , is responsible for health care provision to its population . in recent years , aragon has become home for a large number of immigrants who now have access to the health system in the conditions established by the law .
our results are in agreement with other similar , recently - published studies focused on hospital utilization [ 1517 ] , prescription drug utilization [ 18 , 19 ] and the utilization of primary care services in spain . in the systematic review by uiters et al . , lower frequencies of primary care use were also found in the immigrant population , but with significant variance in the studies it covers .
esteva surveyed a sample of 159 spanish general practitioners , of whom 81 % agreed that immigrants visit hospital accident and emergency departments and primary care practices with greater frequency than other registered patients .
these stereotypes , which also exist in other countries such as the us , have recently been refuted by other authors . however , despite coinciding findings , we have also observed a number of differences with regard to other studies .
other authors using surveys have found that the use of primary care services by immigrants is only slightly lower than the use made by spanish nationals [ 8 , 9 , 23 , 24 ] or even higher .
it is interesting to observe that when working with population data , the use of services by immigrants is found to be much lower .
however , these differences tend to disappear or are inverted when the data is gathered from survey - based studies
. this may be due to possible biases in sample selection or in responses .
underuse of health services by immigrants in our study can be explained by different factors .
first , there is an a priori unexpected difficulty to real access to the health system . although rivera and carrasco - garrido [ 3 , 25 ] defend the notion that there are no major barriers to access
, other authors assert that there are barriers caused by cultural differences , language , legal status , lack of familiarity with health care provision services , employment situation and timetable incompatibility [ 26 , 27 ] that hinder access . as a denominator ,
our study used the population recognized as holding the public health insurance card ; therefore , a possible legal barrier to access does not seem to be an explanation .
another possible explanatory factor would be incompatibility with practice hours , which may be caused by lower levels of stable employment conditions , where it becomes more difficult for people in this situation to take time off work to go to the doctor .
a qualitative analysis would be required to confirm this hypothesis in order to explore these aspects . however , if we assume that the immigrant population has a lower socio - economic level than that of the spanish population , it would seem that immigrants should have lower levels of health , and therefore greater needs for health care [ 9 , 12 , 28 ] .
the low visit frequency rate in the immigrant population compared to spanish nationals found in our study could respond to the classic inverse care law described by hart : the availability of good medical care tends to vary inversely with the need of the population served .
another possibility could be that , despite the social determinants to which immigrants are subjected , their health may be better that expected . in other words , it could be thought that immigrants make fewer visits to the doctor because they are healthier .
this contradicts the theory that associates lower socio - economic level with worse general health .
there are numerous studies pointing out that immigrants generally have a better level of health than host populations because the healthiest are more likely to migrate [ 3137 ] ( healthy migration effect ) and this population group has better lifestyles [ 3 , 23 , 32 ] . the lower use of health services could be also based on the different concepts of and attitudes towards health and illness in both groups .
this idea is supported by the different rates found according to region of origin and culture .
for example , immigrants of asian origin have much lower visit frequencies than latin americans .
this could also be due to a greater use of traditional medicines by some of these groups .
health and illness are socially - construed concepts , and therefore vary greatly according to the cultural environment .
preventive activities , whether for children or adults , may not be seen to be priorities as they are not acknowledged as needs , at least in their first years in the host country .
this would derive in lower rates of scheduled visits and fewer on - demand visits , particularly those monitoring the evolution of chronic processes . following this premise ,
the health culture of the countries of origin should be considered in public health programs for prevention and care .
health care in the immigrants countries of origin is generally characterized by major deficiencies , which make them relegate medical attention to processes they consider to be more serious , while treating
habit may endure once these people arrive in spain , particularly during the first years . with time
studies with individuals follow - up over time will be necessary to confirm this trend .
very different rates of visit frequency have been observed depending on the immigrants region of origin . among the foreign national population ,
the groups with highest frequency rates are those from rich countries ( with a similar socio - economic level and concept of health - illness to the spanish population ) and latin americans ( with significant cultural and linguisitc similarities ) . at the opposite end of the scale
are asian immigrants ( with great linguistic and cultural differences ) and the population from eastern europe ( mainly romanians , who learn spanish very quickly ) .
although included with asians , immigrants from oceania form a very small minority and their behaviour is not reflected in this discussion . for cultural reasons ,
the main methodological strength of this study is that it analyses real visits for the entire reference population ( whether or not they have made use of the health system during the year ) and measures the impact on the real utilization of the public health system by immigrants and spanish nationals .
likewise , as the demographic information relative to patients is available , the statistics could be adjusted for age and sex .
studies based on surveys may have significant bias in sample selection or in the quality of the collected information [ 3 , 6 , 9 , 23 , 38 ] .
another strength is the very high volume of statistics taken from the studied population , both national and immigrant , making up for 5 million appointments at the region level .
although the number of immigrants from latin america , eastern europe and north africa form the bulk , information is available on all immigrant populations , regardless of their origin . as limitations to the study , we would point out that bias could occur as the result of one health insurance card being used by several immigrants , who visit a health centre using a card belonging to a family member or acquaintance .
this would cause an overestimation of the frequency of visits by immigrants compared to nationals , leading to a widening of the differences found .
however , this phenomenon has been reduced after spanish law 4/2000 was passed governing the rights and freedoms of foreign nationals in spain and their social integration .
this has made their access to the public health system easier , given that the only requisite is that they should be registered on the census .
another limitation is that we are unable to adjust the figures for morbidity , making it difficult to speak of the adaptation of either group in this regard .
further studies regarding this aspect are being developed at present . in summary , in a universal , free health care system , immigrants show a lower frequency of visits than that of spanish nationals for any age group , regardless of sex and geographic origin .
there is an important variance depending on geographic background that could be studied in more detail . in this
regard , cultural factors , varying access or the concepts of health and illness may play an important role .
such studies should be assessed when planning health policies dealing with access to health services .
Output:
| knowing what real use is made of health services by immigrant population is of great interest .
the objectives are to analyze the use of primary care services by immigrants compared to spanish nationals and to analyze these differences in relation to geographic origin .
retrospective observational study of all primary care visits made in 26 urban health centers .
main variable : total number of health centre visits / year .
dependent variables : type of clinician requested ; type of attention , and origin of immigrants .
the independent variable was nationality .
statistics were obtained from the electronic medical records .
the 4,933,521 appointments made in 2007 were analyzed for a reference population of 594,145 people ( 11.15 % immigrants ) .
the adjusted annual frequency for nationals was 8.3 , versus whereas 4.6 for immigrants .
the immigrant population makes less use of primary care services than national population .
this is evident for all age groups and regardless of the immigrants countries of origin .
this result is important when planning health care resources for immigrant population . |
PubmedSumm118563 | ***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: twenty - eight healthy participants were recruited from employees and patients of mayo clinic , or local area residents as part of a multicenter clinical trial ( nct01677507 ) .
each participant underwent a general health interview and comprehensive ophthalmologic examination including visual acuity , iop with pneumatonometry , gonioscopy , slit - lamp biomicroscopy , and fundoscopy .
subjects were excluded if they had a history or evidence of ocular pathology , intraocular surgery or trauma , laser treatment , narrow angles , or glaucoma .
each subject gave informed consent to participate after discussion of the nature and possible risks of the study .
this study was approved by the institutional review board at mayo clinic and followed the tenets of the declaration of helsinki .
baseline iop was measured in both eyes in the sitting position by using a pneumatonometer ( model 30 classic ; medtronic solan , jacksonville , fl , usa ) .
the subject was placed in a supine position and after 5 minutes , iop was remeasured ( p0 ) .
calibration of the tonometer was verified according to the manufacturer 's instruction and the tip was cleaned before each set of measurement .
subjects were then asked to breathe normally and fixate on a target on the ceiling approximately 2 m from their eyes during the procedure .
the eyelids were gently retracted by the examiner 's fingers without applying additional pressure on the globe .
the corneas were anesthetized by instilling proparacaine 0.5% topically . the pneumatonometer probe ( tip diameter of 5.3 mm ) with an added 10-g weight ( fig .
1 ) was placed on the center of the cornea and held perpendicularly to the corneal surface .
intraocular pressure was recorded for 2 minutes and the probe was removed from the eye .
pneumatonometer and its probe , which has a flat tip with an external diameter of 5.3 mm . the weight on the probe is used only for tonography .
2 ) , scanned , and digitized by using curvesnap 1.1 ( fig . 3 ; http://xoofee.com/2012/12/curvesnap/ ) .
a second - order polynomial line was fitted to the pressure curve by least - squares regression and the iop at the beginning ( p1 ) and end of the interval ( p2 ) , while the eye was exposed to the weighted probe , was determined from the value of the line at 0 and 2 minutes .
the outflow facility coefficient , c , was determined by using grant 's formula :
where vs is the intraocular volume change from relaxation of tension in the sclera and corresponding to the pressure change during tonography , vc is the change in intraocular volume by corneal indentation , p0 is pressure in the supine position , pc is a correction of the steady - state pressure , and t is the duration of the contact , typically 2 or 4 minutes .
have estimated that pc is equal to 4 mm hg because of an assumed indentation effect by the pneumatonometer , while friedenwald has estimated a value of 1.25 mm hg to account for episcleral venous pressure change during schitz tonography , based on the measurement made by linner .
a second - order polynomial was fitted to iop , and outflow facility was calculated by using iop determined from the fitted curve at 0 and 2 minutes .
the relationship between pressure and indentation volume is based on the value of ocular rigidity for each instrument .
a constant value for ocular rigidity is implicit in the tables by langham et al . for pneumatonography ( 0.0126 l ) and friedenwald for the schitz tonometer ( 0.0215 l ) .
in addition , we calculated the ocular rigidity coefficient ( k ) from measurements of pressure without and with the weight added to the pneumatonometer probe and by using the equation of friedenwald :
where v1 and v0 are the volumes indented in the eye by the tonometer when the pressure was p1 and p0 , respectively . for pneumatonography , these volumes were extracted from data tabulated by langham et al .
outflow facility was also measured 45 minutes after pneumatonography by using a digital schitz tonographer designed by the mayo clinic division of engineering .
this tonographer probe had a plunger with a concave tip and an external diameter of 10 mm ( fig .
the subjects were placed in the supine position for 5 minutes and fixated on a target on the ceiling , approximately 2 m in front of their eyes .
the corneas were anesthetized by instilling proparacaine 0.5% topically , and the probe with a 5.5-g weight was placed on the center of cornea and held perpendicularly for 4 minutes .
a second - order polynomial was fitted to pressures recorded by the tonographer ( fig .
5 ) and outflow facility was determined from pressure on the fitted curve at 0 and 4 minutes by using equation 2 . the change in corneal indentation volume ( vc ) was estimated from the 1955 tables by friedenwald , and pc was set to 1.25 mm hg on the basis of the measurements made by linner .
the change in scleral distension volume ( vs ) was determined by using the standard tables introduced by friedenwald , which assumes a normal ocular rigidity coefficient ( 0.0215 l ) , and by using the ocular rigidity coefficient estimated by our measurements with pneumatonometry .
custom digital schitz tonographer and its probe , which has a plunger with a concave tip and an external diameter of 10 mm .
a second - order polynomial was fitted to iop , and outflow facility was calculated by using iop determined from the fitted curve at 0 and 4 minutes .
the difference in outflow facility between instruments and significance of correlations between instruments were examined by using generalized estimating equation models to account for possible correlation between fellow eyes .
limits of agreement between measurements were defined as the mean difference 2 standard deviations ( sds ) of the difference ( bland and altman ) .
all statistical tests were two sided and were calculated by using spss statistical software ( version 21.0 ; spss , inc . ,
twenty - eight healthy participants were recruited from employees and patients of mayo clinic , or local area residents as part of a multicenter clinical trial ( nct01677507 ) .
each participant underwent a general health interview and comprehensive ophthalmologic examination including visual acuity , iop with pneumatonometry , gonioscopy , slit - lamp biomicroscopy , and fundoscopy .
subjects were excluded if they had a history or evidence of ocular pathology , intraocular surgery or trauma , laser treatment , narrow angles , or glaucoma .
each subject gave informed consent to participate after discussion of the nature and possible risks of the study .
this study was approved by the institutional review board at mayo clinic and followed the tenets of the declaration of helsinki .
baseline iop was measured in both eyes in the sitting position by using a pneumatonometer ( model 30 classic ; medtronic solan , jacksonville , fl , usa ) .
the subject was placed in a supine position and after 5 minutes , iop was remeasured ( p0 ) .
calibration of the tonometer was verified according to the manufacturer 's instruction and the tip was cleaned before each set of measurement .
subjects were then asked to breathe normally and fixate on a target on the ceiling approximately 2 m from their eyes during the procedure .
the eyelids were gently retracted by the examiner 's fingers without applying additional pressure on the globe .
the corneas were anesthetized by instilling proparacaine 0.5% topically . the pneumatonometer probe ( tip diameter of 5.3 mm ) with an added 10-g weight ( fig .
1 ) was placed on the center of the cornea and held perpendicularly to the corneal surface .
intraocular pressure was recorded for 2 minutes and the probe was removed from the eye .
pneumatonometer and its probe , which has a flat tip with an external diameter of 5.3 mm . the weight on the probe is used only for tonography .
2 ) , scanned , and digitized by using curvesnap 1.1 ( fig . 3 ; http://xoofee.com/2012/12/curvesnap/ ) .
a second - order polynomial line was fitted to the pressure curve by least - squares regression and the iop at the beginning ( p1 ) and end of the interval ( p2 ) , while the eye was exposed to the weighted probe , was determined from the value of the line at 0 and 2 minutes .
the outflow facility coefficient , c , was determined by using grant 's formula :
where vs is the intraocular volume change from relaxation of tension in the sclera and corresponding to the pressure change during tonography , vc is the change in intraocular volume by corneal indentation , p0 is pressure in the supine position , pc is a correction of the steady - state pressure , and t is the duration of the contact , typically 2 or 4 minutes .
have estimated that pc is equal to 4 mm hg because of an assumed indentation effect by the pneumatonometer , while friedenwald has estimated a value of 1.25 mm hg to account for episcleral venous pressure change during schitz tonography , based on the measurement made by linner .
a second - order polynomial was fitted to iop , and outflow facility was calculated by using iop determined from the fitted curve at 0 and 2 minutes .
the relationship between pressure and indentation volume is based on the value of ocular rigidity for each instrument .
a constant value for ocular rigidity is implicit in the tables by langham et al . for pneumatonography ( 0.0126 l ) and friedenwald for the schitz tonometer ( 0.0215 l ) .
in addition , we calculated the ocular rigidity coefficient ( k ) from measurements of pressure without and with the weight added to the pneumatonometer probe and by using the equation of friedenwald :
where v1 and v0 are the volumes indented in the eye by the tonometer when the pressure was p1 and p0 , respectively . for pneumatonography , these volumes were extracted from data tabulated by langham et al .
outflow facility was also measured 45 minutes after pneumatonography by using a digital schitz tonographer designed by the mayo clinic division of engineering .
this tonographer probe had a plunger with a concave tip and an external diameter of 10 mm ( fig .
the subjects were placed in the supine position for 5 minutes and fixated on a target on the ceiling , approximately 2 m in front of their eyes .
the corneas were anesthetized by instilling proparacaine 0.5% topically , and the probe with a 5.5-g weight was placed on the center of cornea and held perpendicularly for 4 minutes . the right eye was always tested first followed by the left eye .
a second - order polynomial was fitted to pressures recorded by the tonographer ( fig . 5 ) and
outflow facility was determined from pressure on the fitted curve at 0 and 4 minutes by using equation 2 .
the change in corneal indentation volume ( vc ) was estimated from the 1955 tables by friedenwald , and pc was set to 1.25 mm hg on the basis of the measurements made by linner .
the change in scleral distension volume ( vs ) was determined by using the standard tables introduced by friedenwald , which assumes a normal ocular rigidity coefficient ( 0.0215 l ) , and by using the ocular rigidity coefficient estimated by our measurements with pneumatonometry .
custom digital schitz tonographer and its probe , which has a plunger with a concave tip and an external diameter of 10 mm .
a second - order polynomial was fitted to iop , and outflow facility was calculated by using iop determined from the fitted curve at 0 and 4 minutes . a , b , c : constants of second - order polynomial .
baseline iop was measured in both eyes in the sitting position by using a pneumatonometer ( model 30 classic ; medtronic solan , jacksonville , fl , usa ) .
the subject was placed in a supine position and after 5 minutes , iop was remeasured ( p0 ) .
calibration of the tonometer was verified according to the manufacturer 's instruction and the tip was cleaned before each set of measurement .
subjects were then asked to breathe normally and fixate on a target on the ceiling approximately 2 m from their eyes during the procedure .
the eyelids were gently retracted by the examiner 's fingers without applying additional pressure on the globe .
the corneas were anesthetized by instilling proparacaine 0.5% topically . the pneumatonometer probe ( tip diameter of 5.3 mm ) with an added 10-g weight ( fig .
1 ) was placed on the center of the cornea and held perpendicularly to the corneal surface .
intraocular pressure was recorded for 2 minutes and the probe was removed from the eye .
pneumatonometer and its probe , which has a flat tip with an external diameter of 5.3 mm . the weight on the probe is used only for tonography .
2 ) , scanned , and digitized by using curvesnap 1.1 ( fig . 3 ; http://xoofee.com/2012/12/curvesnap/ ) .
a second - order polynomial line was fitted to the pressure curve by least - squares regression and the iop at the beginning ( p1 ) and end of the interval ( p2 ) , while the eye was exposed to the weighted probe , was determined from the value of the line at 0 and 2 minutes .
the outflow facility coefficient , c , was determined by using grant 's formula :
where vs is the intraocular volume change from relaxation of tension in the sclera and corresponding to the pressure change during tonography , vc is the change in intraocular volume by corneal indentation , p0 is pressure in the supine position , pc is a correction of the steady - state pressure , and t is the duration of the contact , typically 2 or 4 minutes .
have estimated that pc is equal to 4 mm hg because of an assumed indentation effect by the pneumatonometer , while friedenwald has estimated a value of 1.25 mm hg to account for episcleral venous pressure change during schitz tonography , based on the measurement made by linner .
a second - order polynomial was fitted to iop , and outflow facility was calculated by using iop determined from the fitted curve at 0 and 2 minutes .
the relationship between pressure and indentation volume is based on the value of ocular rigidity for each instrument .
a constant value for ocular rigidity is implicit in the tables by langham et al . for pneumatonography ( 0.0126 l ) and friedenwald for the schitz tonometer ( 0.0215 l ) .
in addition , we calculated the ocular rigidity coefficient ( k ) from measurements of pressure without and with the weight added to the pneumatonometer probe and by using the equation of friedenwald :
where v1 and v0 are the volumes indented in the eye by the tonometer when the pressure was p1 and p0 , respectively . for pneumatonography , these volumes were extracted from data tabulated by langham et al .
outflow facility was also measured 45 minutes after pneumatonography by using a digital schitz tonographer designed by the mayo clinic division of engineering .
this tonographer probe had a plunger with a concave tip and an external diameter of 10 mm ( fig .
the subjects were placed in the supine position for 5 minutes and fixated on a target on the ceiling , approximately 2 m in front of their eyes .
the corneas were anesthetized by instilling proparacaine 0.5% topically , and the probe with a 5.5-g weight was placed on the center of cornea and held perpendicularly for 4 minutes .
a second - order polynomial was fitted to pressures recorded by the tonographer ( fig .
5 ) and outflow facility was determined from pressure on the fitted curve at 0 and 4 minutes by using equation 2 . the change in corneal indentation volume ( vc ) was estimated from the 1955 tables by friedenwald , and pc was set to 1.25 mm hg on the basis of the measurements made by linner .
the change in scleral distension volume ( vs ) was determined by using the standard tables introduced by friedenwald , which assumes a normal ocular rigidity coefficient ( 0.0215 l ) , and by using the ocular rigidity coefficient estimated by our measurements with pneumatonometry .
custom digital schitz tonographer and its probe , which has a plunger with a concave tip and an external diameter of 10 mm .
a second - order polynomial was fitted to iop , and outflow facility was calculated by using iop determined from the fitted curve at 0 and 4 minutes .
the difference in outflow facility between instruments and significance of correlations between instruments were examined by using generalized estimating equation models to account for possible correlation between fellow eyes .
limits of agreement between measurements were defined as the mean difference 2 standard deviations ( sds ) of the difference ( bland and altman ) .
all statistical tests were two sided and were calculated by using spss statistical software ( version 21.0 ; spss , inc . , chicago , il , usa ) .
fifty - six eyes from 28 healthy participants ( 6 males and 22 females ; 27 caucasians and 1 african american ) , ages 41 to 68 years ( 51 8 years , mean sd ) were included in the study .
the mean outflow facility was 0.29 0.09 l / min / mm hg ( sd ) by schitz tonography and 0.24 0.08 l / min / mm hg by pneumatonography ( p < 0.001 ) when using the assumed ocular rigidity coefficient for each device ( table ) .
outflow facilities by the two devices were correlated ( r = 0.6 , p < 0.001 ) ( fig .
the mean difference between instruments was 0.05 0.08 l / min / mm hg and limits of agreement ranged from 0.1 to 0.21 l / min / mm hg ( fig .
correlation of outflow facility measured by pneumatonography and schitz tonography with assumed ocular rigidity coefficient .
limits of agreement , outflow facility measured by pneumatonography and schitz tonography with assumed ocular rigidity coefficient .
the mean calculated ocular rigidity coefficient was 0.028 0.01 l ( sd , n = 56 eyes ) . when the same calculated ocular rigidity coefficient was used to calculate outflow facility for both schitz tonography and pneumatonography ,
the mean outflow facility was 0.23 0.08 l / min / mm hg by schitz tonography and 0.21 0.07 l / min / mm hg by pneumatonography ( p = 0.003 ) .
there was a strong correlation between outflow facility calculated by the two devices ( r = 0.7 , p < 0.001 ) ( fig .
the mean difference between instruments was 0.02 0.06 l / min / mm hg and limits of agreement ranged from 0.09 to 0.14 l / min / mm hg ( fig . 9 ) .
correlation of outflow facility measured by pneumatonography and schitz tonography with calculated ocular rigidity coefficient .
limits of agreement , outflow facility measured by pneumatonography and schitz tonography with calculated ocular rigidity coefficient .
with tonography , we calculate the outflow facility of aqueous humor from the volume of aqueous humor forced out of the eye by a transiently elevated pressure . the pressure is increased by placing a weighted tonometer probe on the cornea , and the volume of fluid loss is estimated from the change in pressure from the beginning to the end of application of the weighted probe .
the pressure change is recorded through the tonometer , but the volume change must be estimated from the indentation volume of the tonometer during contact with the eye and the change in ocular volume associated with the reduced pressure during tonography .
however , differences in the way that indentation volume is calculated , along with the subsequent calculation of ocular rigidity , may result in slightly different values for outflow facility from the two devices .
the two tonographers used here both measure iop but the approach to deriving the change in volume from pressure is somewhat different between instruments .
the indentation volume from the schitz tonometer has been tabulated and is based on geometric considerations of the probe plunger as it indents the cornea .
the indentation volume is directly related to the height of the plunger below the probe contact position on the cornea , and this is directly related to the measured pressure .
these relationships are unique for each weight added to the plunger and have been tabulated for direct conversion to outflow facility .
the pneumatonometer does not have a plunger and the indentation volume is associated with the indentation of the entire probe , and because there is not a way to measure the indentation of the probe directly , this relationship has been determined empirically and published by langham et al .
however , the derivation of this relationship for the pneumatonometer has not been explicitly described .
the relationship between volume and pressure for both instruments is dependent on the ocular rigidity coefficient , a parameter determined by the resistance that the eye exerts against distending forces and described by equation 3 .
this relationship is implicit in the calculation of outflow facility , and the most commonly used pressure volume relationship for the calculation of ocular rigidity has been the equation of friedenwald .
friedenwald found a mean value of 0.0215 l as derived from measurements on cadaveric human eyes and this has been used in the calibration data for conversion of schitz tonometer scale readings to iop measurements in millimeters of hg , as well as tables for estimation of ocular volume change ( microliters ) .
since the schitz scale is based on the assumption that the eye has an average normal rigidity , large deviations in rigidity from the average normal eye will result in erroneous estimates of iop or outflow facility .
clearly , accuracy of the outflow facility estimates from each device is dependent on the accuracy of the calibration data , but it is unclear if either the schitz or pneumatonography calibration data are superior to the other in accuracy .
another potential difference between the two devices is the reported difference in the pressure volume relationship of living eyes compared with enucleated eyes .
several studies have concluded that the ocular rigidity of enucleated eyes is higher than that in living human eyes .
the difference may be related to lack of active choroidal blood flow that leads to smaller volume of displaced fluid and postmortem changes in enucleated eyes .
while the ocular rigidity coefficient in friedenwald 's tables for schitz tonography was calculated based on enucleated eyes , the assumed ocular rigidity coefficient for pneumatonography in langham 's tables was developed based on living eyes .
measurement of ocular rigidity in living human eyes has been reported previously , based on injection of small volumes of saline solution into the anterior chamber and measurement of the resulting pressure change with a transducer .
this method has been reported by prijot and weekers , prijot , ytteborg , and eisenlohr et al .
more recently , pallikaris et al . calculated the ocular rigidity coefficient as the slope of the line fitted by linear regression , to the pressure
used the same manometric method and fitted an exponential curve to the pressure - volume relationship over a range of iop from 15 to 40 mm hg .
this variability in directly measured ocular rigidity coefficient in different study populations suggests that assumption of a constant value may not be ideal for calculation of outflow facility .
because the friedenwald and langham tables assume a constant ( normal ) ocular rigidity coefficient , calculation of outflow facility can be different on eyes with high or low ocular rigidity .
we accounted for these differences by calculating the ocular rigidity coefficient for each eye from iop measured by using a pneumatonometer without and with a 10-g weight added to the tonometer probe , based on the friedenwald 's equation ( equation 3 ) , and by using langham 's tables for determining ocular volume change .
notably , our mean ocular rigidity coefficient , 0.028 0.01 l , was higher than both assumed values .
one possible reason is that we assumed that the ocular displacement volume was zero when the probe was not weighted on the initial supine measurement ( p0 ) .
however , the inherent weight of the tonometer probe would have indented the cornea slightly , and this would have somewhat reduced the volume change used to determine the ocular rigidity coefficient . this coefficient therefore may have been slightly overestimated .
although our estimate was somewhat higher than that reported for living eyes by friedenwald ( 0.021 l ) and dastiridou et al .
( 0.028 l ) , who used a manometric technique to determine the ocular rigidity coefficient .
the effect of the ocular rigidity coefficient on outflow facility was apparent from the results of our study .
when we used the traditional assumed constant ocular rigidity coefficients , the outflow facilities calculated by pneumatonometry were significantly lower than those by schitz tonography .
however , when we calculated k , based on friedenwald 's equation and the estimated indentation volumes from langham et al .
, our estimate of outflow facility by pneumatonography was much closer to that by schitz tonography .
another potential error in the outflow facility calculation is in the measurement of the initial unweighted supine iop ( p0 ) .
the ocular volume parameters vary with pressure , and an error of a few millimeters of hg in p0 can cause large errors in the outflow facility coefficient
. this may be particularly important for the schitz tonometer , since it can not measure p0 directly ( because a weight is a necessary component of the device ) and consequently , values of p0 are determined by using an average value of the ocular rigidity coefficient .
several studies have reported that current schitz readings based on friedenwald 's 1955 calibration scale are in error .
friedenwald used applanation tonometry on seated patients as a means of checking the indentation calibration scale , based on the assumption that the mean iop of normal eyes increased by 1 mm hg upon lying down , owing to an identical pressure increment in the episcleral vein .
however , subsequent studies report that this postural effect exceeds 1 mm hg and is between 1.8 and 5 mm hg .
these studies suggest that the schitz values may be significantly low , with the schitz calibration in error by as much as 3 to 5 mm hg .
in contrast to schitz tonometry , pneumatonometry can measure initial unweighted supine iop ( p0 ) directly without the need to use the ocular rigidity relationship .
report that pneumatonometry measurements are 2.6 0.26 mm hg greater than goldmann applanation tonometry measurements from normal and glaucomatous eyes in the sitting position .
they state that this difference is caused by a slight corneal indentation by the pneumatonometer .
measurements in the supine position increases an additional 1 mm hg owing to the weight of the piston when the tonometer is held vertically .
hence , for pneumatonography , langham et al . suggest the addition of a correction factor of 4 mm hg to the p0 in equation 2 . the outflow facility estimated by pneumatonometry with default ocular rigidity in our study subjects ( 0.24 0.08 l / min / mm hg ) was close to that estimated by others .
report an outflow facility of 0.28 0.01 l / min / mm hg by 4-minute pneumatonography , which is not significantly different from 0.29 0.01 l / min / mm hg by 2-minute pneumatonography .
liu et al . report 0.23 0.05 l / min / mm hg for normal subjects aged 37 to 74 years and in another study toris et al .
obtained 0.25 0.11 l / min / mm hg for subjects aged 21 to 30 years and 0.20 0.09 l / min / mm hg for subjects aged 60 to 79 years . the difference between age groups is not significant .
our outflow facility measured by digital schitz tonography ( 0.29 0.09 l / min / mm hg ) with assumed constant ocular rigidity was also similar to measurements of others by the same method .
grant reports values of 0.23 l / min / mm hg and 0.24 l / min / mm hg for outflow facility by tonography in normal human living eyes , and becker reports a mean value of 0.28 0.05 l / min / mm hg in his study on 909 normal eyes .
they report an outflow facility of 0.28 0.09 l / min / mm hg in one study , and in two separate studies report 0.28 0.09 l / min / mm hg in younger group ( age 3045 years ) and 0.23 0.06 l / min / mm hg in older subjects ( age 4776 years ) .
other investigators compared schitz tonography to pneumatonography in the same subjects and found that the two methods produce similar mean outflow facilities , although outflow facility measured by pneumatonography shows more variability .
feghali et al . found no significant difference in outflow facility between methods on 13 normal subjects and 3 glaucoma patients ( 0.24 0.11 l / min / mm hg with pneumatonography and 0.22 0.07 l / min / mm hg with schitz tonography ) .
estimate a mean outflow facility of 0.22 0.09 l / min / mm hg and 0.23 0.07 l / min / mm hg with pneumatonography and schitz tonography , respectively , in eight normal subjects .
although these mean outflow facilities are not significantly different , pneumatonography had high standard deviation and poor reproducibility .
studied 30 subjects and found a mean of tonographic outflow facility of 0.23 0.09 l / min / mm hg and 0.22 0.08 l / min / mm hg with schitz and 2-minute pneumatonography , respectively , for right eye and 0.26 0.07 l / min / mm hg and 0.20 0.08 l / min / mm hg with schitz and 2-minute pneumatonography , respectively , for left eye .
the higher variability of outflow facilities by pneumatonography may be associated with a greater mobility of the smaller probe tip , which is flat and can slide across the cornea .
this tip design could allow more transmission of eye and hand movements to the transducer and cause variable indentation and transient changes in iop .
in contrast , the tip of the schiotz tonometer is concave , has larger diameter , and rests more steadily on the cornea
. the greater mechanical stability of this design may result in less variability of iop than with pneumatonography .
it is not completely clear why our study found a difference between schitz tonography and pneumatonography , while previous investigators did not .
one significant difference in the analysis methods was the use of data extraction by fitting of a second - order polynomial to the data in our study .
it is possible that this technique accentuates differences by eliminating the temptation to manually smooth a paper tonography tracing .
further research is required to determine if the differences in outflow facility between the two devices persist in other populations , such as glaucoma patients .
outflow facilities measured by using the pneumatonography are correlated with those measured by schitz tonography , but schitz tonography reports approximately 10% to 20% higher facilities .
consequently , the measurements from these devices can not be directly compared to determine differences in outflow facility , and the devices can not be used interchangeably .
differences in shape , size , and weight of the two tonographer tips , method of iop measurement , and using different calibration tables may be responsible for the differences in outflow facility measurement . when the ocular rigidity coefficient for each eye was calculated and the same value used for both instruments , outflow facilities were much closer between methods .
each method has several advantages and disadvantages , and which method is more accurate can not be determined from our noninvasive study .
each of the methods appears to provide reasonable estimates of outflow facility , and while the indicated values are not identical , they are tightly correlated .
therefore , the instruments can not be used interchangeably , but either is a reasonable choice for assessing differences in outflow facilities in human subjects .
Output:
| purposeit is not known if outflow facilities measured by pneumatonography and schitz tonography are interchangeable . in this study
we compared outflow facility measured by pneumatonography to outflow facility measured by digital schitz tonography.methodsfifty-six eyes from 28 healthy participants , ages 41 to 68 years , were included . intraocular pressure ( iop ) was measured in the sitting and supine positions with a pneumatonometer . with the subject in the supine position ,
iop was recorded for 2 minutes by using a pneumatonometer with a 10-g weight and for 4 minutes by using a custom digital schitz tonometer .
outflow facility was determined from the changes in pressure and intraocular volume and a standard assumed ocular rigidity coefficient for each instrument , respectively , and by using an ocular rigidity coefficient calculated by measuring pressure without and with a weight added to the pneumatonometer tip.resultsthe outflow facility was 0.29 0.09 l / min / mm hg by schitz tonography and 0.24 0.08 l / min / mm hg by pneumatonography ( p < 0.001 ) when using the standard assumed constant ocular rigidity coefficient . mean calculated ocular rigidity coefficient was 0.028 0.01 l1 , and outflow facility determined by using this coefficient was 0.23 0.08 l / min / mm hg by schitz tonography and 0.21 0.07 l / min / mm hg by pneumatonography ( p = 0.003 ) .
outflow facilities measured by the two devices were correlated when the ocular rigidity was assumed ( r = 0.60 , p < 0.001 ) or calculated ( r = 0.70 , p < 0.001).conclusionsoutflow facilities measured by pneumatonography were correlated with those measured by schitz tonography , but schitz tonography reported approximately 10% to 20% higher facilities when using the standard method .
when ocular rigidity was determined for each eye , differences were smaller .
measurements from these devices can not be compared directly . |
PubmedSumm118564 | ***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: sample
preparation . gold nanorods ( 50 nm 60 nm 160
nm )
were fabricated on a glass coverslip with a 50 nm au layer and
a 1 nm titanium adhesion layer by negative - tone electron - beam lithography
in combination with reactive - ion etching .
lh2 was purified from rhodopseudomonas acidophila ( strain 10 050 ) , as described
previously .
this cylindrical complex
coordinates 9 bacteriochlorophylls that absorb at = 800 nm
and 18 bacteriochlorophylls that absorb at = 860 nm ; the latter
shows an emission band at around = 870 nm .
lh2 was diluted in an aqueous pva solution ( 10 mm tricine ph 8.0 ,
0.03% -dodecyl - n - maltoside , 0.45% pva : mowiol
20 - 98 , mw 125 kda , sigma - aldrich ) and spin - casted over a glass coverslip
with or without a nanoantenna array at 3000 rpm for 30 s. confocal microscopy .
microscopy was performed using a commercial
time - resolved confocal microscope ( micro time 200 , picoquant , germany ) .
the excitation was with linearly polarized pulsed light at
= 800 nm ( titanium sapphire pulsed laser , coherent - mira ) , with
a repetition rate of 76 mhz . a high numerical aperture ( 1.46 , 100 ,
zeiss )
oil immersion objective mounted on an inverted microscope ( olympus )
was used for both excitation and collection .
the fluorescence light
was separated from the excitation light using a dichroic mirror and
long - pass filters ( = 835 nm + 850 nm ) and detected by an avalanche
photodiode ( mpd , micro photon devices ) .
Output:
| nanoantennas
are well - known for their effective role in fluorescence enhancement ,
both in excitation and emission
. enhancements of 34 orders
of magnitude have been reported . yet in practice , the photon emission
is limited by saturation due to the time that a molecule spends in
singlet and especially triplet excited states . the maximal photon
stream restricts the attainable enhancement .
furthermore , the total
number of photons emitted is limited by photobleaching .
the limited
brightness and observation time are a drawback for applications , especially
in biology . here
we challenge this photon limit , showing that nanoantennas
can actually increase both saturation intensity and photostability .
so far , this limit - shifting role of nanoantennas has hardly been explored .
specifically , we demonstrate that single light - harvesting complexes ,
under saturating excitation conditions , show over a 50-fold antenna - enhanced
photon emission stream , with 10-fold more total photons , up to 108 detected photons , before photobleaching .
this work shows
yet another facet of the great potential of nanoantennas in the world
of single - molecule biology . |
PubmedSumm118565 | ***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: leiomyomatosis peritonealis disseminata ( lpd ) is a benign condition , and a very rare disease .
it is suspected that this disease originates from a metaplasia of submesothelial multipotent mesenchymal cells .
since female gonadal steroids play an important role in the pathogenesis of lpd , it is generally associated with high levels of exogenous and endogenous female gonadal steroids .
the definite treatment of lpd is transabdominal hysterectomy and bilateral salpingo oophorectomy ( tah - bso ) .
however we here describe a case that in spite of tah - bso and removal of all peritoneal myomatous nodules , developed retroperitoneal fibroma six years later .
the patient was a 29-year - old woman who complained of the presence of a mass in her lower abdomen , and a right flank pain for the preceding six months .
the pain increased gradually , and the patient referred to hospital . at clinical examination , the patient did nt present abdominal distention .
she , however , had a diffuse pain , which was most intensely observed in the right lower quadrant .
ultrasonography revealed a large ( 7945 mm ) solid oval shape and well - defined hypoechoic mass in the right adnexal site , which most likely was a residue or recurrence of a previously resected pelvis mass .
six years earlier , due to diffuse and progressive abdominal pain she had undergone abdominal ultrasonography , which revealed a semi - solid mass ( 5427 mm ) in the left side of adnexa attached to uterus .
the laparotomy revealed a very fragile , largely vascular and multi nodular solid mass , which had originated in posterior part of uterus and extended to peritoneum and retroperitonem .
tah - bso were performed because of intractable bleeding following the resection of a retroperitoneal mass .
the microscopic pathology findings confirmed the mass as leiomyoma . for more than 5.5 years after the surgery , the patient was doing well with no recurrence of the tumor .
however , flank pain and mass sensation started and persisted during hormone replacement therapy since six months ago .
she underwent the second operation six months ago , and a retroperitoneal solid mass ( 68 mm ) with an irregular border and a pseudo - capsule was found just adjacent to the external iliac artery .
histopathogical examination of the pelvic mass exhibited interlacing bundles of smooth muscle cells without cytological atypia , and a few mitoses ( figure 1 ) .
immunohistochemical evaluation was strongly positive for the smooth muscle antigen ( figure 2 ) , progesterone receptors ( figure 3 ) , and estrogen receptors ( figure 4 ) , but was negative for cytokeratin .
considering the patient s history , the mass was suggested to be a retroperitoneal fibroma , a remenant of previous disseminated peritoneal leiomyomatosis .
the patient was , therefore , scheduled for a long - term follow - up .
histological examination of the retroperitoneal mass show bundles of spindle cells with eosinophilic cytoplasm ( h&e ) the immunohistochemical evaluation is strongly positive for smooth muscle actin ( cytoplasmic staining ) .
the immunohistochemical evaluation is strongly positive for progesterone receptors(nuclear staining ) the immunohistochemical evaluation is strongly positive for estrogen receptors(nuclear staining ) .
lpd is a very rare and benign disease , of which less than 140 cases have been reported .
it is characterized by the presence of multiple smooth muscle nodules in the peritoneal surface .
some authors believe that female gonadal steroids play an important and primary role in the pathogenesis of leiomyomatosis peritonealis .
similar to a number of situations such as pregnancy , extended exposure to oral contraceptives and/or combined hormonal replacement therapy , oestrogen - secreting ovarian fibrothecoma , the disease is generally associated with high levels of exogenous and endogenous female gonadal steroids . since
, the disease is seen in post menopausal women and in males , the possible causes of it could be divided into hormonal , subperitoneal mesenchymal stem cells metaplasia , genetic , or iatrogenic after morcellation of myoma during laparoscopic surgery .
surgeans and pathologisis face a challenge when dealing with lpd because its macroscopic appearances resembles peritoneal carcinomatosis . while this condition is not common , it has to be taken into account in dealing with a patient with abdominal masses , and especially after a previous myomectomy or hysterectomy .
the diagnosis of lpd is made on biopsy specimen , which generally demonstrates a benign smooth muscle abnormal growth originating from the multicentric metaplasia of the peritoneal surface .
therefore surgical casteration or gonadotropin releasing hormone agonist seems the appropriate treatment of such conditions .
leiomyomas should be considered in the differential diagnoses of intraperitoneal or retropevitoneal masses distinct from the uterus .
Output:
| leiomyomatosis peritonealis disseminata is a very rare condition characterized by the development of multiple smooth muscle - like nodules in the peritoneal cavity .
it is associated with increased serum levels of gonadal steroids .
the present report describes a 29-year - old patient underwent transabdominal hysterectomy and bilateral salpingo oophorectomy six years ago because of leiomyomatosis peritonealis disseminata .
after six years she referred to us again because of retroperitoneal fibroma , another rare entity , during hormone replacement therapy inspite of lack of uterus and previous castration . |
PubmedSumm118566 | ***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
enantioselective , intermolecular hydroallylation of vinylarenes
employing allylic phosphate electrophiles has been achieved through
a copper hydride catalyzed process .
the protocol described herein
can be applied to a diverse set of vinylarene substrates and allows
for the installation of the parent allyl group as well as a range
of 2-substituted allylic fragments . |
PubmedSumm118567 | ***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: monocytes have been demonstrated to be precursors of professional antigen - presenting cells , such as macrophages and dendritic cells ( dcs ) [ 13 ] . in response to danger stimuli ,
circulating blood monocytes migrate into damaged or infected tissues and differentiate into mature macrophages or dcs . after taking up antigens ,
the activated macrophages and dcs migrate to the draining lymph nodes to present the antigens to t and b cells .
chemokine receptors confer upon cells the ability to detect and move directionally toward a chemotactic stimulus .
c - c chemokine receptor type 7 ( ccr7 ) plays a leading role in the mechanism controlling the entry of lymphocytes and mature dcs into lymph nodes . within lymph nodes ,
these cells encounter other immune cells for activation , determining the success of cellular immunity after infection . for immature dcs ,
( tissue damage , inflammatory cytokines , or pathogens ) ; this process occurs concomitantly with their migration from peripheral tissues to the draining lymph nodes . during maturation ,
ccr7 expression is upregulated , which guides the migratory dcs to the lymph nodes [ 68 ] .
the chemokines ccl19 and ccl21 are the natural ligands of ccr7 , and they are expressed by lymphatic endothelium and/or within lymph nodes by stromal cells , endothelial cells , and dcs [ 913 ] . mice deficient in ccl19 , ccl21 , or ccr7 demonstrate defective dc trafficking and altered immune responses [ 6 , 14 , 15 ] . recently , ccr7 expression was discovered on human monocytes . as observed with dc migration , prostaglandin e2 ( pge2 ) , a pleiotropic immunomodulatory molecule , appears to have a dual role in monocyte migration by regulating the expression and activity of ccr7 through the involvement of ep2 and ep4 receptors .
moreover , in dcs , pge2 has been reported to synergize with tumor necrosis factor - alpha ( tnf- ) to promote ccr7 expression and the chemotactic responsiveness of dcs to ccl19 and ccl21 [ 1719 ] .
recent results indicate that ccl19 binding to ccr7 promotes the activation of p38 , extracellular signal - regulated kinase 1/2 , and c - jun n - terminal kinase and leads to monocyte migration . moreover , the rhoa / rock pathway is essential for pge2-mediated ccr7-dependent monocyte migration .
the physiological importance of ccr7 for the immune response has been demonstrated by several studies , and although ccr7 expression and functionality have been extensively characterized in dcs , much less is known about the fate of its expression in macrophages .
as it has been demonstrated that monocytes express the chemokine receptor ccr7 and differentiate upon immune activation , we asked whether monocyte maturation in the presence of pge2 has a direct effect on ccr7 expression and functionality . in a unpolarized environment ,
our results demonstrate that monocyte maturation downregulates ccr7 expression in macrophages derived from mono mac-1 cells ( mdmm-1 cells ) and monocyte - derived macrophages ( mdms ) from healthy donors . in parallel
, chemotaxis assays were performed to establish the influence of differentiation on ccr7 signaling function .
our results clearly indicate that mdmm-1 cells and mdms lose functional ccr7 expression , which inhibits their migration toward the ccr7 ligands ccl19 and ccl21 .
thus , these data reveal that unlike dcs , macrophages lose ccr7 expression and functional activity upon differentiation , even in the presence of pge2 .
the chemokines ccl19 and ccl21 and antibodies anti - ccr7-apc and anti - igg2a - apc were purchased from r&d systems ( minneapolis , mn , usa ) .
anti - cd14-fitc , anti - cd64-fitc ( bd biosciences , mississauga , on , canada ) , and anti - igg2a - fitc were purchased from santa cruz biotechnology ( santa cruz , ca , usa ) .
the monocytoid cell line mono mac-1 was purchased from the german collection of microorganisms and cell culture ( braunschweig , germany ) .
cells were maintained in rpmi 1640 medium ( wisent , saint - bruno , qc , canada ) supplemented with 10% heat - inactivated fetal bovine serum ( fbs ; wisent ) , 1 mm sodium pyruvate ( wisent ) , 0.1 mm nonessential amino acids , 100 u / ml penicillin g , and 100 g / ml streptomycin ( wisent ) .
mono mac-1 cells were induced to differentiate into macrophage - like ( mdmm-1 ) cells with pma .
briefly , cells were plated in 100 mm dishes ( 7 10 cells ) in fresh medium and incubated with 20 ng / ml pma for 72 h .
mono mac-1 and mdmm-1 cells were stimulated for the indicated times using 1 m pge2 .
total blood mononuclear cells were isolated from the blood of healthy donors using lymphocyte separation medium 1077 ( sigma ) and washed twice in hank 's balanced salt solution ( wisent ) .
cells were cultured in rpmi 1640 medium , 20% heat - inactivated fbs , and 10% heat - inactivated human serum for 2 h before use .
monocytes were then enriched from peripheral blood mononuclear cells using the macs monocyte isolation kit ii and macs ls columns ( miltenyi biotec , auburn , ca , usa ) , yielding an average purity of 98% .
the purity was assessed by flow cytometric analyses as recommend by the manufacturer , and isolated monocytes were fluorescently stained with cd14-fitc and anti - biotin - pe that labeled nonmonocytes . to differentiate monocytes into mdms
, cells ( 2 10/ml ) were plated in rpmi 1640 medium with 2
mmol / l l - glutamine ( wisent ) containing 20% human ab serum ( wisent ) in 24-well plates ( millipore , nepean , on , canada ) .
after 24 h , nonadherent cells were removed , and adherent cells were cultured in rpmi with 20% fbs ( wisent ) in 5% co2 at 37c for 12 days .
macrophages were detached using cell dissociation buffer ( wisent ) , washed with 1 pbs , and used in experiments .
blood monocytes and mdms were stimulated for the indicated times using 1 m pge2 .
images of whole - cell morphology were acquired by interferential contrast using a olympus ix70 microscope ( olympus canada inc . , richmond hill , on , canada ) and processed by image pro plus software ( media cybernetics inc . ,
fc receptors were blocked using 1 g of purified igg ( santa cruz biotechnology ) for 15 min at room temperature and washed in pbs containing 3% bovine serum albumin ( bsa ) .
cells were labeled with an anti - ccr7 antibody conjugated with allophycocyanin or the corresponding antibody isotype for 45 min on ice and protected from light .
samples were analyzed in a bd facscalibur flow cytometer ( bd biosciences ) using cellquest software ( bd biosciences ) .
chemotaxis was measured by migration through a polycarbonate filter with 5 and 8 m pores for blood cells and mono mac-1 cells , respectively , in 96-well transwell chambers ( millipore ) .
rpmi with 0.25% bsa ( 100 l ) containing the indicated concentrations of ccl19 or ccl21 or medium alone as a control for spontaneous migration was added to the lower chamber . to the upper chamber , 1 10 cells ( 150 l )
a 150 l aliquot of the cells that migrated to the bottom chamber was counted by flow cytometry in a facscan that acquired events for a fixed period of 60 s using cellquest software .
the percentage of migrated cells was calculated as follows : the number of migrated cells in response to medium only was subtracted from the number of migrated cells in medium supplemented with ccl19 or ccl21 , and this number was reported according to the total input of cells .
each experiment was performed in triplicate , and migration assays were repeated at least three times .
mdmm-1 cells were incubated with or without 1 m pge2 for the indicated times , and total rna was extracted with the total rna kit e.z.n.a .
( omega bio - tek , mississauga , on , canada ) according to the manufacturer 's instructions .
rna was reverse - transcribed into cdna in the presence of 200 u of m - mlv rt ( promega , madison , wi , usa ) , 0.5 g of oligonucleotide d(t)15 , and 500 m deoxyribonucleotide triphosphates at 42c for 1 h. one microliter of cdna was used and analyzed using the platinum sybr green qpcr supermix system from invitrogen ( burlington , on , canada ) .
the pcr mixture consisted of 0.25 m forward and reverse primers for ccr7 as described previously , 0.4 mm deoxyribonucleotide triphosphate , 2 mm mgcl2 , and 1.25 u of taq dna polymerase ( roche , indianapolis , in , usa ) .
the pcr cycling conditions consisted of initial denaturation at 95c for 10 min and 40 cycles of 95c for 30 s , 55c for 45 s , and 72c for 45 s. samples were run in an applied biosystems 7500 gel electrophoresis apparatus ( applied biosystems , foster city , ca , usa ) , and the results were analyzed using v1.4 software .
mono mac-1 is a cell line assigned to the monocytic lineage according to morphological , cytochemical , and immunological criteria .
recently , mono mac-1 cells and blood - isolated monocytes were shown to express functional ccr7 chemokine receptors that are upregulated by treatment with pge2 . in this study , we investigated the impact of the maturation of monocytes into macrophages on ccr7 expression and functionality .
first , the differentiation of mono mac-1 cells into a more mature , macrophage - like phenotype was induced by treatment with 20 ng / ml pma for 72 h as previously described .
differentiation was assessed by morphological changes such as cell clustering , cellular adhesion to the bottom surface of the culture dish , and a reduction in the nucleocytoplasmic ratio due to an increase in cytoplasmic volume [ 23 , 24 ] . as anticipated and shown in figures 1(a ) and 1(b ) ,
another feature of macrophage differentiation is enhanced granularity , as demonstrated by increased side scatter ( ssc ) on flow cytometry .
compared to mono mac-1 cells , mdmm-1 cells have increased ssc as shown in figure 1(c ) . as cd14 expression is a phenotypic marker for monocyte differentiation , cd14 expression on mono mac-1 cells was determined after differentiation using pma .
the percentage of cd14 cells increased from 2.1% to 12.6% during maturation , whereas the mean fluorescence intensity ( mfi ) was 4.3 and 9.9 in mono mac-1 and mdmm-1 cells , respectively ( figure 1(d ) ) .
in addition , it has been revealed that the expression of the cell surface antigen cd64 is downregulated in macrophages .
thus , we next investigated whether macrophages exhibit a significant decrease in cd64 expression , and the results indicated that cd64 expression was significantly decreased in mdmm-1 cells ( 34.6% compared to 68.9% in mono mac-1 ) ( figure 1(d ) ) .
we also investigated whether monocytes from the blood of healthy donors that were differentiated into mdms exhibited the morphological and immunological characteristics of macrophages .
as observed with mono mac-1 and mdmm-1 cells , morphological differences were noted between monocytes and mdms ( figures 2(a ) and 2(b ) ) , and ssc also increased in macrophages ( figure 2(c ) ) . in human blood cells ,
we found that macrophage differentiation decreased cd14 expression ( mfi of 25.6 in mdms ; mfi of 138.9 in blood monocytes ) .
conversely , mdms exhibited a significant diminution in cd64 expression as expected ( mdms : 4.9% with a mfi of 32.7 ; blood monocytes : 31.0% with a mfi of 61.1 ) ( figure 2(d ) ) .
altogether , our results demonstrate that mdmm-1 cells and mdms exhibit characteristics attributed to macrophages in the literature . to evaluate whether monocyte maturation in the absence of m1/m2 polarizing conditions affects the cell surface expression of ccr7 on mono mac-1 and mdmm-1 cells , the cells were incubated in the presence or absence of pge2 for 24 h , and the expression of ccr7 was analyzed by flow cytometry ( figure 3 ) .
increased cell surface expression of ccr7 has been previously demonstrated on mono mac-1 cells by ct et al .
however , an important diminution of ccr7 expression is detected on cell surface of mdmm-1 cells ( mono mac-1 : a mfi of 94.95 ; mdmm-1 : a mfi of 52.23 ) . as it has been demonstrated that pge2 increases ccr7 expression on mono mac-1 cells , we next determined whether pge2 stimulation also affected ccr7 expression on mdmm-1 cells .
after 24 h of treatment , ccr7 expression was significantly increased on mdmm-1 cells ( mfi of 52.23 ) .
we asked whether ccr7 upregulation was also observed at the mrna level by using real - time rt - pcr to verify the presence of ccr7 mrna after mono mac-1 differentiation and treatment with pge2 over a 24 h time course ( figure 4 ) .
as observed in undifferentiated mono mac-1 cells , ccr7 mrna levels were highest when mdmm-1 cells were stimulated with 1 m pge2 for 12 h. altogether ,
our results indicate that pma - induced mono mac-1 differentiation decreased the cell surface expression of ccr7 , but treatment with the immunomodulatory molecule pge2 slightly increased the transcription and expression of ccr7 in mdmm-1 cells . to further investigate the effects of monocyte maturation on ccr7 expression , we repeated this series of experiments with freshly isolated human blood monocytes .
monocytes were cultured up to 8 days to induce differentiation , and ccr7 mrna level ( figure 5 ) as well as ccr7 cell surface expression was analyzed by flow cytometry ( figure 6 ) . as observed in mdmm-1 cells , ccr7 expression was higher on human blood monocytes , and it was downregulated upon the maturation of mdms ( human blood monocytes : 14.0% with a mfi of 31.0 ; mdms : 4.9% with a mfi of 16.7 ) . interestingly , and unlike the effect observed in the differentiated mdmm-1 cell line , no significant change in ccr7 mrna level and ccr7 expression was detected after pge2 treatment ,
thus , overall the differentiation of cultured monocytes or freshly isolated monocytes from human blood resulted in a decrease in ccr7 surface expression , and pge2 slightly restored ccr7 expression in mdmm-1 cells but not mdms . to confirm the impact of ccr7 functionality on monocyte maturation into macrophages and the effect of pge2 treatment on this process , we performed chemotaxis assays using these cells and ccr7 ligands ( figure 7 ) .
first , mono mac-1 and mdmm-1 cells were incubated for 24 h in the presence or absence of pge2 and evaluated for chemotaxis in response to 300 ng / ml ccl19 or ccl21 .
the differentiation of mono mac-1 cells significantly decreased their cellular responsiveness to both ccr7 ligands ( figure 7(a ) ) ; however , the chemotaxis of mdmm-1 cells increased upon treatment with pge2 , which supports the flow cytometry and rt - pcr results . in the case of mdms ,
no specific migration was observed compared to that in freshly isolated blood monocytes ( figure 7(b ) ) , confirming the absence of functional ccr7 receptors on the mdms cell surface .
moreover , pge2 failed to induce specific migration in mdms , as was suggested by the flow cytometry results . to confirm the specificity of the observed migration
, we incubated cells with a blocking antibody against human ccr7 for 10 min at room temperature prior to the migration assays .
this treatment completely abolished cell - specific migration in response to the ccl19 and ccl21 ( data not shown ) .
in response to injury or infection , blood monocytes migrate to tissues to neutralize and eliminate potentially injurious stimuli . depending on the inflammatory milieu and pathogen - associated pattern recognition receptors
monocytes can first differentiate into immature dcs and then mature upon exposure to antigens while changing their surface expression of chemokine receptors .
indeed , maturing dcs are known to downregulate ccr1 , ccr5 , and ccr6 expression and upregulate ccr7 expression ( see review ) . as ccr7 expression
is not sufficient to ensure the migration of mature dcs in response to ccl19 and ccl21 [ 19 , 32 ] , ccr7 function is dependent on the presence of costimulatory signals such as pge2 [ 17 , 19 ] .
alternatively , monocytes can also differentiate into macrophages , long - lived cells that develop specialized functions such as phagocytosis .
after phagocytosis , it has been postulated that macrophages will either migrate to the lymphoid organs or die by apoptosis at the inflammatory focus [ 33 , 34 ] .
however , it has recently been demonstrated that inflammatory macrophages , in addition to neutrophils , die via apoptosis during the late stages of resolving a proinflammatory insult . in b cells , ccr9 and ccr10
expression permits the homing of immunoglobulin a plasma cells to mucosal tissues [ 36 , 37 ] , whereas cxcr3 and cxcr4 mediate the migration of igg+ plasma cells toward inflamed tissues and bone marrow [ 3840 ] .
however , in bone marrow myeloid cells , cxcr4 downregulation is essential to promote their mobilization from bone marrow to the peripheral blood .
in addition , in dcs , pge2 has been reported to synergize with tnf- to promote ccr7 expression and the chemotactic responsiveness of dcs to ccl19 and ccl21 in lymph nodes [ 1719 ] .
these selected examples illustrate that chemokine receptor expression , together with their natural ligands , is involved and essential in the regulation of cellular migration .
recently , monocytes were shown to express ccr7 in the presence of the proinflammatory molecule pge2 , which is required to ensure migration in response to ccr7 ligands . in the current study , we determined whether monocyte differentiation and the presence of the immunomodulatory molecule pge2 had an effect on ccr7 expression and ccr7-dependent migration .
our results provide evidence that unpolarized blood macrophages do not express functional ccr7 , even in the presence of pge2 while polarized m1 macrophages have been shown to upregulate ccr7 expression .
we used the mono mac-1 cell line and freshly isolated blood monocytes that were differentiated into a macrophage - like cell phenotype ( figures 1 and 2 ) . in both cases , we observed downregulation of ccr7 expression ( figures 3 and 6 ) and ccr7-specific migration ( figure 7 ) .
further , we observed that the addition of pge2 did not modulate ccr7 mrna transcription , expression , and functionality in mdms ( figures 5 , 6 , and 7 ) .
the results obtained using the cell line were different from those obtained using freshly isolated human blood monocytes / macrophages . in mdmm-1 cells ,
similar results were found using thp1 cells , a human monocytic cell line . in that study ,
the phenotypic differences between cell lines and human blood monocytes / macrophages could be explained by the tumor origins of both mono mac-1 and thp1 cells .
our results suggest that human blood macrophages even in the presence of pge2 do not migrate in response to the ccr7 natural ligands ccl19/ccl21 .
this reflects in vivo migration patterns because the collection of lymph through cannulation reveals that the major myeloid cell type to enter lymphatic vessels is antigen - presenting dcs rather than classical macrophages [ 7 , 46 ] .
accordingly , monocyte - derived cells that leave acute inflammatory sites have a dc phenotype , and these cells migrate to the t - cell zone of the lymph node , which is rich in dcs but not in macrophages . by contrast , little is known regarding macrophage migration .
migration of activated macrophages from the peritoneum to the lymphatics is accelerated by mac-1 , whereas early monocyte accumulation or subsequent redistribution within the peritoneum appears unaffected by this integrin .
our findings are relevant to plaque formation in atherosclerosis because in this chronic inflammatory disease , the migratory process associated with resolution is impaired and macrophages accumulate in plaques , contributing to the build - up of necrotic pools .
indeed , it has been demonstrated that mouse circulating monocyte subsets labeled with fluorescent latex beads did not emigrate out of plaques during disease progression [ 50 , 51 ] .
restoration of monocyte - derived cell migration out of plaques could be an effective means to stimulate atherosclerosis disease regression .
moreover , some authors postulate that lipid - derived signals such as prostaglandins are strong candidates for impairing migration , and oxidized phospholipids along with lipoprotein a are disease - relevant mediators that may shift the fate of monocyte - derived cells to a more sessile phenotype [ 50 , 52 , 53 ] .
restoration of monocyte - derived cell migration out of plaques could be an effective means to stimulate atherosclerosis disease regression . in summary
, we demonstrated that monocyte differentiation into macrophages directly modifies migratory behavior via ccr7 ( figure 8) .
thus , our results suggest that human monocytes express ccr7 as shown with dcs , and t cells can , whereas unpolarized macrophages do not express ccr7 even in the presence of pge2 .
both mdmm-1 and mdm cells lost the functional capacity to migrate in response to the ccr7 ligands ccl19 and ccl21 .
however , we can not state conclusively that the migratory behavior of monocytes and macrophages is due solely to ccr7 expression .
the implication of other chemokine receptors and their regulation by prostaglandins should be investigated further .
Output:
| previously , we demonstrated that prostaglandin e2 ( pge2 ) induces c - c chemokine receptor type 7 ( ccr7 ) expression on human monocytes , which stimulates their subsequent migration in response to the ccr7 natural ligands ccl19 and ccl21 . in this study , we determined whether pge2 affects ccr7 expression on macrophages .
flow cytometric analysis and chemotaxis assays were performed on mono mac-1-derived macrophage ( mdmm-1 ) as well as unpolarized monocyte - derived macrophages ( mdms ) to determine the ccr7 expression and functionality in the presence of pge2 .
data revealed that a mdmm-1 exhibited markedly downregulated ccr7 expression and functionality that were partially restored by treatment with pge2 . in mdms
, we observed a drastic downregulation of ccr7 expression and functionality that were unaffected following pge2 treatment .
our data indicate that monocyte differentiation induces the loss of ccr7 expression and that pge2 is unable to modulate ccr7 expression and functionality as shown previously in monocytes . |
PubmedSumm118568 | ***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: transesterification and acylation reactions are important transformations in organic chemistry , and esters are widely found in many naturally occurring compounds.1 although a number of methods have been reported for the acylation of alcohols , some of these use bases , elevated temperatures , or lengthy workup procedures . in some instances ,
the methods are incompatible with particular functional groups.2
we have recently developed new methods for the cyclopropanation of allylic alcohols3 and for the tetrahydrofuranylation and tetrahydropyranylation of alcohols,4 catalysed by lowvalent titanium species .
we obtained either the cyclopropanated product or the thf / thp ether , depending on the alkyl halide used .
furthermore , we observed that when the cyclopropanation reaction of geraniol mediated by a ti species was quenched by the addition of ethyl acetate , transesterification occurred , giving the acetates of geraniol ( 3b ) and its cyclopropyl derivative [ ( )3a ] rather than compounds [ e.g. , ( )2 ] retaining the free hydroxy group .
this result shows that activated species derived from geraniol and cyclopropylgeraniol were present in the solution .
this unexpected observation has led to a mild and efficient method for the esterification of a wide variety of primary and secondary alcohols mediated by a ti species . in this paper
, we report our recent results on the first transesterification and oacylation of alcohols mediated by cp2ticl in the presence of ch2i2 and an ester or an acyl chloride .
this method gives esters from primary , secondary , and tertiary alcohols , and from phenol , under mild conditions at room temperature .
bis(cyclopentadienyl)titanium(iii ) chloride , cp2ticl,5 has become a very popular reagent in radical reactions because of its soft oneelectronreductive character.6 this complex is tolerated by a variety of functional groups.7 in our previous work , we prepared cp2ticl in situ by stirring a red solution of commercially available cp2ticl2 ( 0.5 equiv . ) with manganese dust ( 12.8 equiv . ) in dry and degassed tetrahydrofuran to give a green solution of the ti complex.8 a solution of the allylic alcohol geraniol ( 1 ; 1 equiv . ) together with ch2i2 ( 5 equiv . )
was then added , and the mixture was stirred for 2.5 h. the reaction was quenched under an inert gas with ethyl acetate ( 2 equiv . ) to give acetates ( )3a and 3b quantitatively ( scheme 1).3
preparation of compounds ( )2 , ( )3a , and 3b . as part of our work on exploring the reactivity of ti species and developing new titaniumcatalysed reactions , we examined the role of each reagent and the scope of the esterification reaction .
we evaluated the roles of titanium , manganese , and diiodomethane in the reaction ( see table 1 ) .
we observed that the transesterification did not proceed in the absence of ch2i2 ( entry 2 , table 1 ) .
furthermore , the initial generation of a ti species from ti and mn was required .
no reaction was observed in the absence of either ti or manganese dust , indicating that both titanium and manganese participated in the reaction ( entries 36 , table 1 ) .
acetylation of geraniol ( 1 ) using different reaction conditions under basefree conditions determined by gc analysis of the crude mixture .
we went on to study the reaction conditions and the nature of the alkyl halide ( table 2 ) .
the reaction of a thf solution of geraniol ( 1 ) in the presence of cp2ticl was examined with a series of alkyl bromides and iodides at room temperature .
we observed that the transesterification reaction did not proceed when alkyl bromides such as ch2br2 and chbr3 were used ( entries 1 , 2 , and 4 , table 2 ) .
acetylation of geraniol ( 1 ) using different alkyl halides under basefree conditions determined by gc analysis of the crude mixture .
the results showed not only that the use of ch2i2 was essential for a successful reaction , but also that the number of equivalents of both the titanium complex and manganese ( compare entries 3 and 5 , table 2 ) was crucial .
the use of different iodide sources such as chi3 or i2 resulted in the formation of ( )4 or a complex mixture ( entries 6 and 7 , table 2 ) . to examine the generality of the procedure ,
the acetylation conditions were applied to a variety of primary , secondary , and tertiary alcohols , and to phenol , at room temperature .
the reaction proceeded quantitatively with aliphatic , benzylic , and allylic primary and secondary alcohols ( 1 and 511 ; entries 18 , table 3 ) .
it is worth noting that each of the allylic alcohols reacted to give a mixture of the corresponding acetate and the acetate of the corresponding cyclopropyl derivative ( entries 1 , 2 , and 8 , table 3 ) .
furthermore , when the reaction was quenched with ethyl acetate under an inert gas after a longer overnight reaction , the acetylated cyclopropyl derivatives [ ( )3a , ( )16a , 22a ] were formed in good yields in a simple onepot reaction ( see supporting information , s3 ) .
phenol ( 15 ) and aliphatic tertiary alcohols did not react ( entries 1012 , table 3 ) , and benzylic tertiary alcohol 12 was converted into the corresponding acetylated product ( i.e. , 23a ) in low yield , together with its corresponding thf ether ( )23b ( 15 % ; entry 9 , table 3 ) .
cp2ticlcatalysed acetylation of alcohols by ethyl acetate under basefree conditions determined by gc analysis of the crude mixture .
having made this observation , we examined the scope of the transesterification reaction with other ethyl esters . for this purpose , we chose as model substrates a group of primary , secondary , and tertiary alcohols , and phenol [ 6 , ( )9 , 14 , and 15 ] .
these were subjected to our reaction conditions using ethyl propionate , ethyl butyrate , and ethyl benzoate .
our results showed that 2phenylethanol ( 6 ) was converted into the corresponding propionate ( 24 ; 99 % yield ) and butyrate ( 25 ; 64 % yield ) derivatives in good yields ( entries 1 and 2 , table 4 ) , whereas ( )1phenylethanol [ ( )9 ] gave the propionate [ ( )27 ; 56 % yield ] and butyrate [ ( )28 ; 45 % yield ] in moderate yields ( entries 4 and 5 , table 4 ) .
ethyl benzoate only reacted with the primary alcohol ( i.e. , 6 ) , giving 26 in low yield ( 2 % ; entry 3 , table 4 ) .
the tertiary alcohol ( i.e. , 14 ) and phenol ( 15 ) did not react with any of the ethyl esters that were tested ( entries 7 and 8 , table 4 ) . in order to improve the oacylation of tertiary alcohols and phenol , and to extend the reaction to other acyl chains , we then decided to quench the reaction with acyl chlorides .
cp2ticlcatalysed transesterification of alcohols under basefree conditions determined by gc analysis of the crude mixture .
alcohols and amines react with acyl chlorides to give esters and amides , respectively , in a reaction known as the schotten
baumann reaction.9 this reaction requires a nonnucleophilic base , such as pyridine , to be present to obtain high yields .
( )1phenylethanol [ ( )9 ] was chosen as a model substrate , and subjected to our reaction conditions .
then , the reaction was quenched under an inert gas with valeroyl chloride to give ester ( )29 in 99 % yield , together with 1,4iodohydrin 30 ( 96 % yield based on the acyl chloride ; entry 1 , table 5 ) . in order to explore the oacylation reaction using an acyl chloride , the role of each reagent
firstly , we carried out a control reaction between compound ( )9 and valeroyl chloride in thf in the absence of any other reagent ( entry 2 , table 5 ) .
ester ( )29 was only obtained in 50 % yield , in contrast to the 99 % yield obtained when the reaction was carried out under our reaction conditions ( entry 1 , table 5 ) .
similar lower yields were also obtained in the absence of ch2i2 , ti , or mn ( entries 35 , table 5 ) . finally , compound ( )29 was obtained in 64 % yield together with 1,4halohydrin 30 when the reaction was carried out with mn ( 12.8 equiv . ) and ch2i2 ( 5 equiv . ; entry 6 , table 5 ) .
oacylation of ( )9 with valeroyl chloride under different reaction conditions determined by gc analysis of the crude mixture .
compounds 6 , ( )9 , 12 , 14 , and 15 were again chosen as model substrates .
these compounds were subjected to our reaction conditions , and the reactions were quenched under an inert gas with valeroyl , pivaloyl , and benzoyl chlorides .
valeroyl chloride reacted with all the tested substrates in excellent yields ( 8499 % ; entries 1 , 4 , 7 , and 11 , table 6 ) .
benzoyl chloride reacted with 2phenylethanol ( 6 ) , ( )1phenylethanol [ ( )9 ] , tertiary alcohol 14 , and phenol ( 15 ) to give esters 26 , ( )34 , 38 , and 41 , respectively , in good yields ( 7899 % ) ; ester 37 was obtained from 2phenylpropan2ol ( 12 ) in moderate yield ( entries 3 , 6 , 9 , 10 , and 13 , table 6 ) .
similar results were achieved with pivaloyl chloride , which gave esters 32 and 40 in excellent yields ( 99 and 91 % ) from 6 and 15 , respectively ; ester ( )33 was obtained in moderate yield ( 61 % ) from ( )1phenylethanol [ ( )9 ] ( entries 2 , 5 , and 12 , table 6 ) .
reaction of pivaloyl chloride with 2phenylpropan2ol ( 12 ) gave hindered ester 36 in only 20 % yield , together with thf ether ( )23b .
cp2ticlcatalysed oacylation of alcohols and phenol by acyl chlorides under basefree conditions determined by gc analysis of the crude mixture .
when the acyl chlorides used in tables 5 and 6 were present in excess , the corresponding 1,4iodohydrins ( i.e. , 30 , 42 , 43 ; figure 1 ) were obtained in high yields ( > 90 % ) , 10 together with the oacylation products of the relevant alcohols .
this shows that the excess acyl chloride was reacting with a product from the opening of the tetrahydrofuran ring.11
1,4halohydrins as byproducts in the oacylation reaction . in the context of our interest in the study of ticatalysed reactions
, we then explored the role of the solvent with the aim of avoiding the formation of the 1,4halohydrin or cyclopropyl products in the oacylation reaction .
thus , the cp2ticl reagent was generated in dry degassed 1,4dioxane and tested against a number of alcohols , quenching the reaction under an inert gas with ethyl acetate or acyl chlorides .
a solution of 1 together with ch2i2 ( 5 equiv . ) was added to the ti reagent generated under our reaction conditions in 1,4dioxane , and the mixture was stirred for 2.5 h. surprisingly , when the reaction was quenched with ethyl acetate , geranyl acetate ( 3b ) was obtained in a poor 8 % yield . the same experiment was carried out using cinnamyl alcohol ( 5 ) , and cinnamyl acetate ( 16b ) was formed in only 9 % yield .
however , when the reaction of 1 was quenched with pivaloyl , valeroyl , and benzoyl chlorides , the corresponding oacylation products 4446 ( entries 13 , table 7 ) were obtained quantitatively , and again the corresponding cyclopropyl derivatives were not detected .
these results confirm the key role of the solvent in the timediated cyclopropanation.3
cp2ticlcatalysed oacylation using 1,4dioxane as solvent determined by gc analysis of the crude mixture . in order to extend the scope of the oacylation in 1,4dioxane , model substrates 6 , ( )9 , 12 , and 15 were tested under our reaction conditions .
benzoyl , valeroyl , and pivaloyl derivatives 26 , 31 , and 32 , were obtained quantitatively from primary alcohol 6 ( entries 46 , table 7 ) when 1,4dioxane was used as a solvent .
a comparable yield was also obtained when secondary alcohol ( )9 was quenched with pivaloyl chloride ( entry 8 , table 7 ) .
in contrast , valeroyl and benzoyl derivatives ( )29 and ( )34 were obtained in lower yields than when thf was used as solvent ( entries 7 and 9 , table 7 ) .
lower yields were also observed for the formation of valeroyl , pivaloyl , and benzoyl derivatives from tertiary alcohol 12 and phenol ( 15 ) ( entries 1015 , table 7 ) . a plausible reaction mechanism is shown in scheme 2 , in which the ti species is regenerated at various stages by the excess mn .
the mechanism is similar to that described by us for the cyclopropanation reaction of allylic alcohols.3 in the light of our results , a related mechanism for the transesterification and oacylation reactions is proposed , in which an activated alkyl / aryloxytitanium species is formed prior to the reaction with esters or acyl chlorides .
coordination of the alcohol to a ti species generates complex a. a methylene iodide radical generated from methylene diiodide then reacts with complex a to give complex b. this complex is then reduced by the mn to give a ticarbenoid species c. a direct hydrogenatom transfer ( hat ) from alcohol ti complex c to the iodomethylene radical generates an activated alkyl / aryloxytitanium species.12 quenching of the reaction under an inert gas with either an ester or an acyl chloride then gives the product of transesterification or oacylation , together with species d. coordination of a new alcohol molecule to species d then regenerates complex c ( scheme 2 ) . proposed mechanism for the formation of the products of transesterification and oacylation .
the method uses substoichiometric amounts of cp2ticl with manganese(0 ) as a reductant together with methylene diiodide in thf , and uses an ethyl ester or acyl chloride as the source of the ester group .
each of these components has been shown to play a key role in the success of the reaction .
esters of primary , secondary , and benzylic alcohols have been obtained under mild conditions in good to excellent yields , both with ethyl esters and with acyl chlorides .
esters were not obtained from phenol using ethyl esters , due to the delocalization of the phenoxy radical .
however , they could be obtained in good yields using acyl chlorides , due to the higher reactivity of the carbonyl carbon atom in these reagents .
general methods : unless otherwise noted , materials and reagents were obtained from commercial suppliers and used without further purification . tetrahydrofuran and
1,4dioxane were freshly distilled from na and strictly deoxygenated under argon for 30 min before use .
purification by semipreparative and analytical hplc was carried out with a hitachi / merck l6270 apparatus equipped with a differential refractometer detector ( ri7490 ) .
a lichrospher si 60 ( 5 m ) lichrocart ( 250 mm 4 mm ) column and a lichrospher si 60 ( 10 m ) lichrocart ( 250 mm 10 mm ) were used in isolation experiments .
tlc was carried out on merck kiesegel 60 f254 ( 0.25 mm thick plates ) .
infrared spectra were recorded with an ftir spectrophotometer and are reported as wavenumbers ( cm ) .
h and c nmr spectroscopic measurements were recorded with varian unity 400 mhz and agilent 500 mhz spectrometers using sime4 as the internal reference .
chemical shifts were referenced to cdcl3 (
h = 7.25 ppm ;
c = 77.0 ppm ) .
multiplicities are described using the following abbreviations : s = singlet , d = doublet , t = triplet , q = quadruplet ; quint = quintuplet ; sext = sextuplet ; m = multiplet , br .
highresolution mass spectrometry ( hrms ) was carried out with a doublefocussing magnetic sector mass spectrometer in positiveion mode , or with a qtof mass spectrometer in positiveion apci mode or in positiveion electrospray mode at a 20 v cone voltage .
general procedure for the preparation of esters mediated by ti : a mixture of bis(cyclopentadienyl)titanium dichloride ( 81.5 mg , 0.32 mmol ) and mn dust ( 434 mg , 8.19 mmol ) in strictly deoxygenated thf or 1,4dioxane ( 12.7 ml ) under ar was stirred at room temperature for 15 min .
then , a solution of the corresponding alcohol ( 0.64 mmol ) and ch2i2 ( 3.2 mmol ) in strictly deoxygenated thf or 1,4dioxane ( 1.3 ml ) was added , and the mixture was stirred for 2.5 h. then , the corresponding ester or acyl chloride ( 1.28 mmol ) was added under an inert gas , and the reaction mixture was stirred for 1.5 h. the reaction mixture was then filtered through a celite pad , and the solvent was evaporated under reduced pressure .
the resulting crude product was purified by column chromatography on silica gel using mixtures of hexanes and ethyl acetate as eluent to give the corresponding esters .
( )(1r*,2r*)2methyl2(4methylpent3enyl)cyclopropylmethyl acetate [ ( )3a ] : spectroscopic data for compound ( )3a are identical to those described in the literature.3
( e)3,7dimethylocta2,6dienyl acetate ( 3b ) : spectroscopic data for compound 3b are identical to those described in the literature.13
( )(e)2[(3,7dimethylocta2,6dien1yl)oxy]tetrahydrofuran [ ( )4 ] : spectroscopic data for compound ( )4 are identical to those described in the literature.4
( )(1r*,2r*)(2phenylcyclopropyl)methyl acetate [ ( )16a ] : spectroscopic data for compound ( )16a are identical to those described in the literature.14
cinnamyl acetate ( 16b ) : spectroscopic data for compound 16b are identical to those described in the literature.15
phenethyl acetate ( 17 ) : spectroscopic data for compound 17 are identical to those described in the literature.16
benzyl acetate ( 18 ) : yellow amorphous solid .
ir ( film ) : = 3034 , 2940 , 1740 , 1722 , 1454 , 1374 , 1230 , 714 , 698 cm .
h nmr ( 400 mhz , cdcl3 ) : = 7.377.25 ( m , 5 h ) , 5.10 ( s , 2 h ) , 2.10 ( s , 3 h ) ppm .
c nmr ( 100 mhz , cdcl3 ) : = 170.9 , 135.9 , 128.5 ( 2 c ) , 128.24 ( 2 c ) , 128.22 , 66.3 , 21.0 ppm . hrms ( apci ) : calcd . for c9h11o2 [ m + h ] 151.0759 ; found 151.0767 .
4fluorobenzyl acetate ( 19 ) : yellow oil .
ir ( film ) : = 2953 , 1742 , 1606 , 1513 , 1231 cm .
h nmr ( 400 mhz , cdcl3 ) : = 7.33 ( dd , j = 8.7 , 5.4 hz , 2 h ) , 7.03 ( t , j = 8.7 hz , 2 h ) , 5.06 ( s , 2 h ) , 2.08 ( s , 3 h ) ppm .
c nmr ( 100 mhz , cdcl3 ) : = 170.8 , 162.6 ( d , j
c , f = 248 hz ) , 131.8 ( d , j
c , f = 3.2 hz ) , 130.2 ( d , j
c , f = 8.3 hz , 2 c ) , 115.5 ( d , j
c , f = 21.6 hz , 2 c ) , 65.6 , 21.0 ppm . hrms ( apci ) : calcd . for c9h10o2f [ m + h ] 169.0665 ; found 169.0653 .
( )1phenethyl acetate [ ( )20 ] : spectroscopic data for compound ( )20 are identical to those described in the literature.16 , 17
( r)octan2yl acetate ( 21 ) : spectroscopic data for compound 21 are identical to those described in the literature.18
( 1s,2r,4r,6r)1methyl4(prop1en2yl)bicyclo[4.1.0]heptan2yl acetate ( 22a ) : colourless amorphous solid .
t
r = 24.6 min , petroleum ether / ethyl acetate ( 99:1 ) , flow = 1.0 ml / min .
ir ( film ) : = 2943 , 1731 , 1372 , 1242 , 1025 , 966 , 890 cm .
h nmr ( 400 mhz , cdcl3 ) : = 5.21 ( dd , j = 11.0 , 5.8 hz , 1 h ) , 4.62 ( m , 2 h ) , 2.112.03 ( m , 1 h ) , 2.07 ( s , 3 h ) , 1.991.91 ( m , 1 h ) , 1.83 ( ddt , j = 12.2 , 5.8 , 2.0 hz , 1 h ) , 1.64 ( s , 3 h ) , 1.241.16 ( m , 1 h ) , 1.07 ( s , 3 h ) , 0.980.87 ( m , 2 h ) , 0.540.48 ( m , 2 h ) ppm .
c nmr ( 100 mhz , cdcl3 ) : = 171.3 , 148.4 , 109.1 , 77.2 , 41.7 , 31.3 , 29.9 , 24.0 , 21.4 , 21.2 , 20.6 , 19.4 , 17.9 ppm .
hrms ( apci ) : calcd . for c13h21o2 [ m + h ] 209.1542 ; found 209.1541 .
t
r = 19.6 min , petroleum ether / ethyl acetate ( 99:1 ) , flow = 1.0 ml / min .
ir ( film ) : = 2943 , 1731 , 1372 , 1242 , 1025 , 966 , 890 cm .
h nmr ( 400 mhz , cdcl3 ) : = 5.59 ( m , 1 h ) , 5.44 ( m , 1 h ) , 4.71 ( m , 2 h ) , 2.342.26 ( m , 1 h ) , 2.212.15 ( m , 1 h ) , 2.122.04 ( m , 1 h ) , 2.07 ( s , 3 h ) , 2.001.90 ( m , 2 h ) , 1.71 ( m , 3 h ) , 1.63 ( m , 3 h ) ppm .
c nmr ( 100 mhz , cdcl3 ) : = 171.0 , 148.3 , 132.8 , 125.9 , 109.3 , 73.2 , 40.3 , 34.0 , 30.8 , 21.2 , 20.5 , 18.8 ppm . hrms ( apci ) : calcd . for c12h19o2 [ m + h ] 195.1385 ; found 195.1377 .
2phenylpropan2yl acetate ( 23a ) : spectroscopic data for compound 23a were identical to those described in the literature.19
( )2[(2phenylpropan2yl)oxy]tetrahydrofuran [ ( )23b ] : spectroscopic data for compound ( )23b are identical to those described in the literature.4
phenethyl propionate ( 24 ) : spectroscopic data for compound 24 weare identical to those described in the literature.20
phenethyl butyrate ( 25 ) : spectroscopic data for compound 25 are identical to those described in the literature.21
phenethyl benzoate ( 26 ) : spectroscopic data for compound 26 are identical to those described in the literature.16
( )1phenethyl propionate [ ( )27 ] : spectroscopic data for compound ( )27 are identical to those described in the literature.22
( )1phenethyl butyrate [ ( )28 ] : colourless amorphous solid .
ir ( film ) : = 2966 , 2931 , 1736 , 1453 , 1179 , 760 , 699 cm .
h nmr ( 400 mhz , cdcl3 ) : = 7.357.26 ( m , 5 h ) , 5.89 ( q , j = 6.6 hz , 2 h ) , 2.31 ( t , j = 7.4 hz , 2 h ) , 1.65 ( sext , j = 7.4 hz , 2 h ) , 1.52 ( d , j = 6.6 hz , 3 h ) , 0.93 ( t , j = 7.4 hz , 3 h ) ppm .
c nmr ( 100 mhz , cdcl3 ) : = 172.9 , 141.8 , 128.4 ( 2 c ) , 127.8 , 126.0 ( 2 c ) , 72.0 , 36.5 , 22.3 , 18.4 , 13.7 ppm . hrms ( esi ) : calcd . for c12h16o2na
( )1phenethyl pentanoate [ ( )29 ] : spectroscopic data for compound ( )29 are identical to those described in the literature.23
4iodobutyl pentanoate ( 30 ) : spectroscopic data for compound 30 are identical to those described in the literature.24
phenethyl pentanoate ( 31 ) : colourless amorphous solid .
t
r = 12.3 min , petroleum ether / ethyl acetate ( 95:5 ) , flow = 3.0 ml / min .
ir ( film ) : = 2959 , 2934 , 2873 , 1737 , 1455 , 1251 , 1172 , 749 , 699 cm .
h nmr ( 400 mhz , cdcl3 ) : = 7.317.20 ( m , 5 h ) , 4.28 ( t , j = 7.1 hz , 2 h ) , 2.93 ( t , j = 7.1 hz , 2 h ) , 2.28 ( t , j = 7.6 hz , 2 h ) , 1.601.53 ( m , 2 h ) , 1.351.26 ( m , 2 h ) , 0.88 ( t , j = 7.1 hz , 3 h ) ppm .
c nmr ( 100 mhz , cdcl3 ) : = 173.8 , 137.9 , 128.9 ( 2 c ) , 128.4 ( 2 c ) , 126.5 , 64.7 , 35.1 , 34.0 , 27.0 , 22.2 , 13.7 ppm .
hrms ( esi ) : calcd . for c13h18o2na [ m + na ] 229.1204 ; found 229.1193 .
phenethyl pivalate ( 32 ) : spectroscopic data for compound 32 are identical to those described in the literature.25
( )1phenethyl pivalate [ ( )33 ] : spectroscopic data for compound ( )33 are identical to those described in the literature.26
( )1phenethyl benzoate [ ( )34 ] : spectroscopic data for compound ( )34 are identical to those described in the literature.27
2phenylpropan2yl pentanoate ( 35 ) : colourless oil .
t
r = 9 min , petroleum ether / ethyl acetate ( 95:5 ) , flow = 3.0 ml / min .
ir ( film ) : = 2959 , 2934 , 2873 , 1737 , 1455 , 1251 , 1172 , 749 , 699 cm .
h nmr ( 400 mhz , cdcl3 ) : = 7.367.20 ( m , 5 h ) , 2.28 ( t , j = 7.5 hz , 2 h ) , 1.75 ( s , 6 h ) , 1.621.53 ( m , 2 h ) , 1.371.28 ( m , 2 h ) , 0.90 ( t , j = 7.5 hz , 3 h ) ppm .
c nmr ( 100 mhz , cdcl3 ) : = 172.5 , 146.0 , 128.2 ( 2 c ) , 126.9 , 124.2 ( 2 c ) , 81.2 , 35.1 , 28.6 ( 2 c ) , 27.1 , 22.2 , 13.7 ppm . hrms ( apci ) : calcd .
t
r = 7.7 min , petroleum ether / ethyl acetate ( 95:5 ) , flow = 3.0 ml / min .
ir ( film ) : = 2958 , 2870 , 1726 , 1273 , 1134 cm .
h nmr ( 500 mhz , cdcl3 ) : = 7.367.23 ( m , 5 h ) , 1.75 ( s , 6 h ) , 1.19 ( s , 9 h ) ppm .
c nmr ( 125 mhz , cdcl3 ) : = 176.9 , 146.2 , 128.2 ( 2 c ) , 126.8 , 124.1 ( 2 c ) , 80.8 , 32.9 , 28.4 ( 2 c ) , 27.1 ( 3 c ) ppm . hrms ( apci ) : calcd . for c14h21o2
t
r = 11.2 min , petroleum ether / ethyl acetate ( 95:5 ) , flow = 3.0 ml / min .
ir ( film ) : = 2981 , 1720 , 1450 , 1314 , 1282 , 1112 , 1098 , 712 , 699 cm .
h nmr ( 500 mhz , cdcl3 ) : = 8.04 ( m , 2 h ) , 7.54 ( m , 1 h ) , 7.43 ( m , 4 h ) , 7.33 ( m , 2 h ) , 7.26 ( m , 1 h ) , 1.92 ( s , 6 h ) ppm .
c nmr ( 125 mhz , cdcl3 ) : = 165.1 , 145.8 , 132.7 , 131.5 , 129.5 ( 2 c ) , 128.33 ( 2 c ) , 128.26 ( 2 c ) , 127.0 , 124.3 ( 2 c ) , 82.2 , 28.8 ( 2 c ) ppm .
hrms ( apci ) : calcd . for c16h15o2 [ m h ] 239.1072 ; found 239.1069 .
t
r = 6.5 min , petroleum ether / ethyl acetate ( 97:3 ) , flow = 3.0 ml / min .
ir ( film ) : = 2969 , 2946 , 1714 , 1644 , 1450 , 1375 , 1314 , 1278 , 1244 , 1115 , 1082 , 710 cm .
h nmr ( 500 mhz , cdcl3 ) : = 7.997.97 ( dd , j = 8.0 , 1.0 hz , 2 h ) , 7.547.51 ( t , j = 8.0 hz , 1 h ) , 7.41 ( t , j = 8.0 hz , 2 h ) , 4.88 ( s , 2 h ) , 4.76 ( s , 2 h ) , 2.84 ( d , j = 14.5 hz , 2 h ) , 2.61 ( d , j = 14.5 hz , 2 h ) , 1.78 ( s , 6 h ) , 1.57 ( s , 3 h ) ppm .
c nmr ( 125 mhz , cdcl3 ) : = 165.9 , 141.8 ( 2 c ) , 132.5 , 131.9 , 129.4 ( 2 c ) , 128.3 ( 2 c ) , 115.5 ( 2 c ) , 84.7 , 46.7 ( 2 c ) , 24.2 ( 3 c ) ppm .
hrms ( apci ) : calcd . for c17h21o2 [ m h ] 257.1542 ; found 257.1534 .
phenyl pentanoate ( 39 ) : spectroscopic data for compound 39 are identical to those described in the literature.28
phenyl pivalate ( 40 ) : spectroscopic data for compound 40 are identical to those described in the literature.28
phenyl benzoate ( 41 ) : spectroscopic data for compound 41 are identical to those described in the literature.28 , 29
4iodobutyl pivalate ( 42 ) : spectroscopic data for compound 42 are identical to those described in the literature.24
4iodobutyl benzoate ( 43 ) : spectroscopic data for compound 43 are identical to those described in the literature.30
( e)3,7dimethylocta2,6dienyl pentanoate ( 44 ) : yellow oil .
t
r = 6 min , petroleum ether / ethyl acetate ( 95:5 ) , flow = 3.0 ml / min .
ir ( film ) : = 2962 , 2931 , 2874 , 1736 , 1450 , 1380 , 1171 cm .
h nmr ( 500 mhz , cdcl3 ) : = 5.34 ( t , j = 7.0 hz , 1 h ) , 5.08 ( t , j = 7.0 hz , 1 h ) , 4.58 ( d , j = 7.0 hz , 2 h ) , 2.30 ( t , j = 7.0 hz , 2 h ) , 2.112.02 ( m , 4 h ) , 1.70 ( s , 3 h ) , 1.68 ( s , 3 h ) , 1.641.58 ( m , 2 h ) , 1.60 ( s , 3 h ) , 1.35 ( sept , j = 7.5 hz , 2 h ) , 0.91 ( t , j = 7.5 hz , 3 h ) ppm .
c nmr ( 125 mhz , cdcl3 ) : = 173.9 , 142.1 , 131.8 , 123.8 , 118.4 , 61.2 , 39.5 , 34.1 , 27.1 , 26.3 , 25.7 , 22.3 , 17.7 , 16.4 , 13.7 ppm .
( e)3,7dimethylocta2,6dienyl pivalate ( 45 ) : spectroscopic data for compound 45 are identical to those described in the literature.31
( e)3,7dimethylocta2,6dienyl benzoate ( 46 ) : spectroscopic data for compound 46 are identical to those described in the literature.32
Output:
| a method has been developed for the conversion of primary , secondary , and tertiary alcohols , and phenol , into the corresponding esters at room temperature .
the method uses a titanium(iii ) species generated from a substoichiometric amount of titanocene dichloride together with manganese(0 ) as a reductant , as well as methylene diiodide .
it involves a transesterification from an ethyl ester , or a reaction with an acyl chloride .
a radical mechanism is proposed for these transformations . |
PubmedSumm118569 | ***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: various organs can be affected resulting in skin burn , musculoskeletal injury , myoglobinuria and ventricular fibrillation .
the electrical surge may also damage the heart conduction system resulting in various types of heart block . in this case
, the survivor of electrocution developed persistent low rate sinus bradycardia , a phenomenon not yet described in the literature .
he was holding a wire cable when the main electrical switch box suddenly exploded , throwing him a few feet away .
there was second degree burn on both hands and his head hair was completely singed with no loss of consciousness or palpitation .
he was brought to the nearest district hospital with normal blood pressure but heart rate of about 35 beats per min ( bpm ) . during the hospitalization
, there was no other complication of the electrocution and the burn wound was treated with the appropriate dressing .
hence , he was transferred to our center after one week of the index event for further assessment and consideration of pacemaker device implantation . at our center
the baseline heart rate was 35 bpm and it rose to 60 bpm during stage 3 of the est , achieving 7.10 mets and 32% of maximal age - predicted heart rate .
he could only proceed till stage 3 , limited by physical endurance fatigue . when he tried to ambulate to go to the toilet , he experienced a few episodes of near fainting .
after waiting for 3 weeks for his burn wound on the hand to heal , we proceeded to implant a dual chamber rate responsive pacemaker sensia sedr01 ( model sesr01 , medtronic , inc .
he had been coming back to our pacemaker clinic for yearly interrogation and we found him to be totally pacing dependent .
electrical or electrocution injuries are synonymous with excessive , unintended electrical current exposure and subsequent complications .
it can be broadly divided into workplace related or environmental related electrical injuries such as caused by lightning .
children and adult blue collar males are prone for accidental electrical injuries as a result of careless and inquisitive nature , and exposure to electrical hazards in the workplace , respectively .
the factors influencing electrical injury are the type of current [ direct current ( dc ) or alternating current ( ac ) ] , voltage , resistance and total exposure time .
the electrical injury can be direct immediate effect on the body , thermal injury or consequent mechanical injury .
any organ or body tissue can be affected , either singly or involving multi - organ .
it was unfortunate that this electrician was electrocuted while doing some cable wiring work . as he was exposed to ac , this
could have stimulated skeletal muscle tetany , persistently prolonging his grip on the culprit cable wire and further damaging electrical exposure , but he was fortuitously aided by simultaneous switch box explosion which generated enough shock wave to propel the patient away from the electrocution source and break his body from being continuously forming part of the harmful electrical circuit .
the short contact time may have explained his limited second degree burn on his exposed hands only and other organs mostly unscathed .
not surprisingly , skin burn is a common electrocution complication ranging from 57 - 96% of a postmortem study of 220 fatal cases .
skin burn may range from superficial first degree burn to full thickness third degree burn in association with the extent of the skin area involved . for any bystander or first medical staff contact , the first important step is assessment of the airway , breathing and circulation before more detail examination .
prompt cardiopulmonary resuscitation ( cpr ) should be initiated if there is any hemodynamic instability and cardiac arrhythmias .
the most immediate life threatening arrhythmias are asystole and ventricular fibrillation at the time of electrocution .
the patient ought to be hospitalized for further observation as some injuries may only manifest later such as rhabdomyolysis , acute kidney failure , head injury and subtle orthopedic fractures .
he should be cared in an acute setting to monitor for recurrence of the malignant arrhythmias and evidence of myocardial injury with cardiac enzymes , electrocardiogram ( ecg ) and telemetry .
if there is any occurrence of st elevation myocardial infarction ( stemi ) , the aetiology is most probably coronary vasospasm rather than acute thrombotic occlusion .
the electrical conduction system of the heart maybe damaged as well , resulting in other dysrhythmias such as first degree heart block , second degree heart block and bundle branch block . from the autopsy report , focal necrosis was found in the myocardium , as well as the sinus and atrioventricular node ( av ) , thus explaining for the heart blocks phenomenon . this patient had sinus bradycardia with every p wave conducted through the av node , resulting in ventricular response rate of 35 bpm most of the time .
no doubt the sinus node was damaged from the electrical injury . however , the constant steady heart rate at 35 bpm invariably suggested some form of autonomic system resetting with higher vagal predominance . surely with this new low baseline heart rate , his daily lifestyle would be severely curtailed .
he was still young and his work involved active field work . in this instance , a pacemaker device would definitely benefit him . as he was recovering from his burn injury ,
the timing of pacemaker implantation was of paramount importance as unhealed or active skin infection may lead to pacemaker infection and its complications .
this afforded us the luxury of time to wait for the skin to heal . a dual chamber rate responsive pacemaker was chosen with the dysfunctional sinus node in mind , as well as for optimal av synchrony .
it was of no surprise that he was now totally pacing dependent with satisfying achievable activities , demonstrating the fact that the damage on the heart conducting system was permanent .
Output:
| electrical or electrocution injury is a common accidental occurrence and mostly workplace related .
fatal arrhythmias , skin injury and sudden death may ensue . however , it is rare for electrocution to result in permanent low rate sinus bradycardia , incompatible with an active lifestyle .
the probable mechanisms for this pathological sinus bradycardia are sinus node dysfunction and autonomic dysfunction with vagal predominance .
we describe a young patient who suffered a non fatal electrocution with resultant low rate sinus bradycardia and its successful treatment with a dual chamber rate responsive pacemaker . |
PubmedSumm118570 | ***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: constant fatigue is documented as one of the most frequent , ongoing symptom description by the patients following cancer treatment . cancer - related fatigue ( crf )
is a distressing , continual , and the personal sense of physical , emotional , and/or cognitive fatigue or tiredness related to cancer or cancer therapy that is hindered with normal performance .
fatigue linked with cancer or its treatment is dissimilar from the characteristic fatigue that most people experience as a result of usual daily life .
distinct to classic fatigue in normal persons , crf is inconsistent with physical exertion level and is not releived by rest or sleep . as crf is a subjective sense of distressing , persistent emotional , and/or a cognitive tiredness ; majority of cancer patients will acknowledge some level of fatigue during their treatment and about one - third will have constant fatigue several years posttreatment .
conversely , before presuming that fatigue is related to cancer , treatable causes of this symptom should to be ruled out , such as anemia , thyroid dysfunction , pain , depression , and lack of sleep . since this is a known fact that a large proportion of cancer patients experience cancer treatment - related fatigue that includes physical and mental symptoms and it is a one of the most recurrently reported symptoms among cancer patients
. the prevalence of crf may vary with an estimate of 60%96% in cancer patients who are undergoing treatment experiencing fatigue .
the consequence of crf on a patient 's capability to function is significant ; therefore , this symptom is very hurtful as reported by patients .
crf can carry on for months or even years after the termination of cancer treatment . as the life expectancy of people with cancer increases with the evolution of new drugs and new therapeutic modalities at the same time
crf also has an effect on cancer treatment as it may compromise the timing or finishing point of treatment regimens either because fatigue is a dose - limiting adverse effect or because it reduces the patient 's willingness to adhere to treatment .
some pathophysiologic theories have been projected for crf such as disrupted circadian rhythms , chronic stress response mediated through the hypothalamic - pituitary axis , systemic inflammatory response , and pro - inflammatory cytokines .
the role of inflammatory cytokines may be based on several lines of evidence such as nononcologic patients with chronic fatigue syndrome have increased levels of pro - inflammatory cytokines such as il1 beta , il 1 receptor antagonist , and tumor necrosis factor - alpha ( tnf- ) , and fatigue is a major side effect of cancer patients receiving interleukins , tnf- , and interferon .
it is reported that 65%100% of patients undergoing radiotherapy , and up to 82%96% of those receiving chemotherapy suffer from fatigue during their treatment and nearly all patients experience crf those receiving the biologic modifiers interferon or interleukin . only in recent times , as the clinical picture of fatigue has been integrated into the field of oncology , regardless of its high occurrence and latent negative effect on patients activities and emotional comfort , research in crf is still underdeveloped and there are scarcely very few studies reporting crf among the indian population . without a doubt , its estimation is still often not included among the parameters usually used to demonstrate the toxicity of chemotherapy .
different methods of evaluating and measuring the crf have been projected or launched and the brief fatigue inventory ( bfi ) is one of the methods developed to study crf .
this instrument assesses fatigue over 24 h using a scale from 1 to 10 ( 1 indicates the absence of and 10 the worst imaginable fatigue ) .
studies have shown that values of 7 or over are robustly connected with a clinically applicable level of crf . with the above - said concern ,
we have designed a study with following objective :
the estimation prevalence of crf in cancer patient populationsto study the correlation crf with different treatment modalities , i.e. , chemotherapy , radiation , biologic modifiers , or combination of anycorrelation of crf severity with personal and demographic parametersmapping of predictors of crf and determination of various factors that are barrier to pain management in cancer patients .
the estimation prevalence of crf in cancer patient populations to study the correlation crf with different treatment modalities , i.e. , chemotherapy , radiation , biologic modifiers , or combination of any correlation of crf severity with personal and demographic parameters mapping of predictors of crf and determination of various factors that are barrier to pain management in cancer patients .
with the above - said concern , we have designed a study with following objective :
the estimation prevalence of crf in cancer patient populationsto study the correlation crf with different treatment modalities , i.e. , chemotherapy , radiation , biologic modifiers , or combination of anycorrelation of crf severity with personal and demographic parametersmapping of predictors of crf and determination of various factors that are barrier to pain management in cancer patients .
the estimation prevalence of crf in cancer patient populations to study the correlation crf with different treatment modalities , i.e. , chemotherapy , radiation , biologic modifiers , or combination of any correlation of crf severity with personal and demographic parameters mapping of predictors of crf and determination of various factors that are barrier to pain management in cancer patients .
this is a cross - sectional , noninterventional , study that has been carried out in hospitalized and outpatient department cancer patients from the oncology department at guru gobind singh medical college , faridkot .
diagnosed with cancer and receiving , i.e. , chemotherapy , radiation , or a combination of bothno history of other chronic disease such as diabetes or heart diseaseno known history of psychiatric illness or being treated with psychotropic drugs .
diagnosed with cancer and receiving , i.e. ,
chemotherapy , radiation , or a combination of both no history of other chronic disease such as diabetes or heart disease no known history of psychiatric illness or being treated with psychotropic drugs . a questionnaire containing demographics , disease description / stage / extent of treatment ( chemotherapy / radiotherapy / surgery or any combination , etc . )
were completed from the patient interview and case records . the bfi scale questionnaire for estimation of crf
data collection was done in two parts , part one contained demographic information such as age , gender , education , occupation , marital status , monthly income , and cancer specific information such as type of cancer , stage of cancer , treatment history , duration of cancer , remission , and failure .
the bfi is a screening tool which measures the severity of fatigue over the previous 24 h. the bfi has only nine items , with the items measured at 010 numeric rating scales .
three items ask patients to rate the severity of their fatigue at its worst , usual , and now during normal waking hours , with 0 being no fatigue and 10 being fatigue as bad as you can imagine .
six items assess the amount that fatigue has interfered with different aspects of the patient 's life during the past 24 h. the interference items include general activity , mood , walking ability , normal work ( includes both work outside the home and housework ) , relations with other people , and enjoyment of life .
the interference items are measured on a 010 scale , with 0 being does not interfere and 10 being completely interferes .
fatigue was categorized using the bfi as either severe ( score 710 ) or no severe ( score 06 ) , with the latter further subcategorized into moderate ( score 46 ) and mild ( score 03 ) .
baseline distinctiveness ( demographic , cancer - specific parameter , and bfi scoring ) was summarized by descriptive statistics .
bfi scoring and its relation to different parameter and demographic characteristics were compared with the chi - square statistical test .
diagnosed with cancer and receiving , i.e. , chemotherapy , radiation , or a combination of bothno history of other chronic disease such as diabetes or heart diseaseno known history of psychiatric illness or being treated with psychotropic drugs .
diagnosed with cancer and receiving , i.e. , chemotherapy , radiation , or a combination of both no history of other chronic disease such as diabetes or heart
a questionnaire containing demographics , disease description / stage / extent of treatment ( chemotherapy / radiotherapy / surgery or any combination , etc . ) were completed from the patient interview and case records . the bfi scale questionnaire for estimation of crf
data collection was done in two parts , part one contained demographic information such as age , gender , education , occupation , marital status , monthly income , and cancer specific information such as type of cancer , stage of cancer , treatment history , duration of cancer , remission , and failure .
the bfi is a screening tool which measures the severity of fatigue over the previous 24 h. the bfi has only nine items , with the items measured at 010 numeric rating scales .
three items ask patients to rate the severity of their fatigue at its worst , usual , and now during normal waking hours , with 0 being no fatigue and 10 being fatigue as bad as you can imagine .
six items assess the amount that fatigue has interfered with different aspects of the patient 's life during the past 24 h. the interference items include general activity , mood , walking ability , normal work ( includes both work outside the home and housework ) , relations with other people , and enjoyment of life .
the interference items are measured on a 010 scale , with 0 being does not interfere and 10 being completely interferes .
fatigue was categorized using the bfi as either severe ( score 710 ) or no severe ( score 06 ) , with the latter further subcategorized into moderate ( score 46 ) and mild ( score 03 ) .
baseline distinctiveness ( demographic , cancer - specific parameter , and bfi scoring ) was summarized by descriptive statistics .
bfi scoring and its relation to different parameter and demographic characteristics were compared with the chi - square statistical test .
a total of 126 patients diagnosed with cancer , including 46 males and 80 females , which consist of 36.5% and 63.5% , respectively , who participated in this observation study .
the mean age was 49.13 years with the leading age group ( 57.1% ) , being 4060 years . among 126 patients ,
the most prevalent malignancy was genitourinary cancer 36 ( 28.6% ) , followed by breast cancer 27 ( 21.4% ) and head and neck cancer 23 ( 18.3% ) as shown in table 1 .
demographic profile of cancer patients the figure 1 , described the crf , which interferes with the daily routine activities of the patient . among them , normal activities affected worst and relation with others was least hindered .
there is a statistical correlation between fatigue and chemotherapy cycle and fatigue with specific drugs such as vinblastine , dacarbazine , and cyclophosphamide described in table 2 .
crf is the most widespread observable fact , in individuals with cancer who receive radiation therapy , cytotoxic chemotherapy , or biological response modifiers .
it is a multifactorial , multidimensional phenomenon , which consists of physical , psychological , social , cognitive , and behavioral characteristic .
fatigue is more common during chemotherapy , usually persist for more than 2 weeks ; furthermore , it has been shown to have the maximum and most long - lasting impact after chemotherapy .
almost every patient go through some kind of fatigue during cancer treatment and in the scientific literature , it is about 99% reported during the treatment course . in spite of mounting confirmation , concerning the fatigue occurring due to a range of anticancer treatments and how crf influence patient 's quality of life , determining its severity is undervalued among the cancer patients suffering from this stressful symptom .
the current study focuses on measuring the prevalence rate of fatigue ( severity of fatigue ) among the cancer patients receiving the various anticancer treatments .
the findings of this study revealed that as many as 80% of the participants experienced fatigue during their course of treatment , irrespective of the diagnosis .
these scores appear to be in line with the prevalence rates of fatigue cited in other literature studies , i.e. , 30%90% during the course of treatment .
patients who received vinblastine , dacarbazine , and cyclophosphamide - based chemotherapy had statistically higher scores of fatigue .
a study by donovan et al . provides the first evidence that among women with early stage breast cancer , chemotherapy is related to more severe fatigue than radiotherapy , which is similar to our results .
no significant correlation was found between the tumor site and amount of fatigue both during and after treatment in the current study .
the results were contrary to the findings by hickok et al . , who studied the pattern of fatigue longitudinally in a sample consisting of breast , prostate , lymphoma and ovarian cancer , and prostate cancer patients experienced more fatigue .
this study had certain other limitations in terms of sample size as it was relatively small and unequal between the groups .
nevertheless , the fact we did not examine potentially correctable etiologies for patients fatigue is a limitation of this study .
we observed that crf is a symptom that is experienced by majority of cancer patients , irrespective of the diagnosis , or type of treatment received .
the study showed high prevalence of fatigue in cancer patients , and in addition , results confirmed by our observation were similar to those cited in literature .
assessment of crf should begin once the patient is diagnosed with cancer before patient receives anticancer treatment .
Output:
| objective : the objective of this cross - sectional , noninterventional 3-month observational study was to analyze the prevalence of the cancer - related fatigue ( crf ) in cancer patient populations with correlation of crf with different treatment modalities.materials and methods : a descriptive study was carried out jointly by the pharmacology and oncology departments of a tertiary care center in the malwa region of punjab .
the data collection was performed by administering the validated brief fatigue inventory ( bfi ) after obtaining the informed consent.results:one hundred and twenty - six cancer patients were recruited with the mean age of 49.13 years 14.35 ( standard deviation ) .
there are statistical correlations found between fatigue and chemotherapy agents such as vinblastine , dacarbazine , and cyclophosphamide.conclusion:we observed that crf is a symptom that is experienced by majority of cancer patients , irrespective of the diagnosis , or type of treatment received .
in addition , assessing crf before and after treatment will facilitate health - care practitioner to treat this symptom . |
PubmedSumm118571 | ***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: of the 35 patients with cutaneous or mucocutaneous / mucosal leishmaniasis , 30 were german tourists ( table 1 ) .
ten had contracted cutaneous or mucocutaneous / mucosal leishmaniasis in europe , 11 in central and south america , 6 in asia , and 3 in africa .
two persons had been infected during work stays of 1 to 4 months in french guyana , one each in peru and libya , and one patient had immigrated from afghanistan .
the median duration of lesions until the diagnosis of leishmaniasis was made was 4 months ( range 3 weeks to 2 years ) .
sixteen patients had more than one lesion ( median 2 , range 16 lesions ) .
seventeen lesions were located in the face , including mouth and nose , 28 on the upper extremities and 21 on the lower extremities .
lesions were ulcerated in 39 cases , papular - nodular in 24 , and plaque - like in 3 .
parasites were detected in 13 of 20 smears , in 9 of 10 cultures , and in 14 of 16 histologic sections ; by using pcr , leishmania - specific dna was detected in 16 of 16 biopsy specimens .
patient 2 had received methotrexate and steroids for treatment of systemic collagenosis for several weeks .
both patients were tested for leishmanial infection in the blood ; in both patients , the leishmania - specific pcr of the buffy coat of the blood was positive .
she had been treated for a skin lesion caused by l. braziliensis 3 years earlier .
a total of 18 of the 23 visceral leishmaniasis patients were german tourists ; 3 were immigrants from angola , iran , and togo ; and 2 were visitors from italy and portugal ( table 2 ) .
the median time between symptom onset and the correct diagnosis was 4 months ( range 116 months ) .
all case - patients had fever , 17 ( 74% ) had splenomegaly , 11 ( 48% ) hepatomegaly , 20 ( 87% ) anemia , 17 ( 74% ) leukopenia , and 8 ( 35% ) thrombocytopenia .
bone marrow smears indicated leishmania in 18 of 20 , bone marrow culture in 6 of 7 , bone marrow histologic sections in 7 of 8 , pcr of the bone marrow in 8 of 9 , and pcr of the buffy coat of the blood in 7 of 7 cases .
additionally , antibodies were detected in medium to high concentration by an immunofluorescence test , enzyme - linked immunosorbent assay ( elisa ) , or both , in 14 of 15 cases .
species was identified in 7 of 18 visceral cases contracted in southern europe and indicated leishmania belonging to the l. donovani complex , which implicated infection with l. infantum .
six cases of visceral leishmaniasis occurred in children 2 months of age to 11 years of age .
four german tourists and two immigrants had long - known hiv infection ( median duration 3 years , range 8 months6 years ) .
all hiv co - infected patients had cd4-cell counts below 200/l ( median 108 , range 23185 cd4 cells/l ) when the diagnosis of visceral leishmaniasis was made .
of the remaining 11 patients , 1 had a thymoma with impaired t - helper-1 cell function , 2 had received intermittent immunosuppressive therapy ( methotrexate and steroids ) for rheumatologic disease , and 2 patients had their spleens removed .
three patients were in an impaired general condition because of combinations of diabetes , hypertonus , hypercholesterolemia , and emphysema . in the remaining three patients ( 5368 years of age ) ,
information on single cases and a small case series of imported leishmaniases in germany is available , but systematic reporting on frequency , type , and origin of leishmanial infections in germany did not exist until 2000 ( 57 ) .
our recent surveillance is dependent on passive consultation and reporting and therefore may have selection bias because if visceral leishmaniasis , a potentially fatal disease that requires hospitalization , is suspected , advice on diagnosis and treatment is sought more often than for the skin infection .
we assume that our system captures approximately half of the visceral leishmaniasis cases and approximately one third of the classical cutaneous cases imported to germany .
a total of 47% of all cases , but 78% of the visceral cases were contracted in the european mediterranean area and portugal , and most of the infections indicated a species of the l. donovani complex , most probably l. infantum , as the probable causative agent .
thirteen infections ( 22% ) were acquired on the mediterranean islands of ibiza , ischia , majorca , malta , korfu , or sicily .
this distribution reflects the fact , that the mediterranean countries , spain , italy , and the mediterranean islands , in particular , are the favorite vacation areas for germans .
annually , germans take 18 million vacations to the european mediterranean area ( including 8 million to spain and 6 million to italy ) with a median duration of 2 weeks .
sixty percent of travel to italy and 90% of travel to spain are to leishmania - endemic areas .
while leishmaniasis has always been endemic in the mediterranean countries , the maximum northern latitude for sandfly survival is speculated to move further to the north , beyond germany ( 1 ) because of global warming .
if this scenario is correct , the imported cases may serve as a potential substrate for the sandfly vector .
dogs that are imported as pets from the disease - endemic areas of southwestern europe or that contract the infection when accompanying their owners for vacation are another potential substrate ( 8) . infections with l. infantum in a child , as well as in a horse who had never left germany , have recently been described and have led to speculations about an autochthonous focus ( 9,10 ) . also recently
, the first sandfly species , phlebotomus mascittii grassi , 1908 , was detected in southern germany , although its potential as a vector of leishmania remains to be demonstrated ( 11 ) .
as expected , visceral leishmaniasis is often manifested in persons with impaired immunocompetence because of young age , hiv infection , immunosuppressive therapy and , in our analysis , in older persons with concomitant diseases .
notably , 12 ( 67% ) of 18 of the visceral cases contracted in the european mediterranean area were in adults , thus confirming a change in age groups affected .
formerly , visceral leishmaniasis was known mainly as a disease of children ( 1,2 ) .
this change may partly be explained by the increased proportion of leishmania and hiv co - infected persons and partly by increased travel activities of otherwise immunocompromised persons , including elderly persons .
furthermore , even in patients with cutaneous leishmaniasis , dissemination of parasites has to be excluded in case of impaired immunocompetence ( e.g. , immunosuppressive treatment ) . in these cases ,
leishmania - specific pcr of the buffy coat of the peripheral blood is a sensitive method for detecting parasite spread beyond the skin .
parents of small children and persons with reduced immunocompetence should be informed about their increased susceptibility to infection with leishmania when traveling to disease - endemic areas .
measures to reduce the exposure to sandflies , such as clothes , repellents , and mosquito nets as well as collars impregnated with repellents for accompanying dogs , should be recommended .
Output:
| in 2000 , a reference center was created to systematically record leishmaniases in germany .
we analyzed 58 cases of leishmaniases imported during a 2-year period .
these findings will serve as a baseline for the sandfly vector s anticipated northward move because of global warming and as an advisory for immunocompromised persons traveling to leishmaniasis - endemic areas . |
PubmedSumm118572 | ***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 patient was a previously healthy 60-year - old housewife of mandarin chinese descent with well - controlled essential hypertension .
her regular medications consisted of once - daily doses of bisoprolol , irbesartan - chlorothiazide , and lercanidipine .
she lived in a bungalow in new taipei city , taiwan , with her daughter and husband , who both remained asymptomatic .
sore throat , epiphora , and otalgia developed 3 days before hospital admission to far eastern memorial hospital , new taipei city .
high sustained fever ( up to 40c ) and abrupt left lower face paresthesias prompted a clinic visit the following day .
nevertheless , she received empirical oseltamivir , according to the taiwan department of health s emergent initiatives for the peak pandemic ( h1n1 ) 2009 season .
after 3 doses of oseltamivir , she remained febrile , with progressive anorexia , malaise , and dizziness , and sought care at the emergency department of a medical center . at the emergency department ( day 4 of symptoms ) , acute urinary retention developed in the patient without anal sphincter involvement or saddle paresthesias . despite sensing urgency of her full bladder , she was unable to void spontaneously , necessitating catheterization .
her blood pressure , pulse , and respiratory rate were 125/64 mm hg , 89 beats per minute , and 20 breaths per minute , respectively .
results of her physical examination were unremarkable except for the relative bradycardia ( which may have been attributable to -blocker use ) and an above average body mass index of 28 kg / m .
a neurologic examination found diminished sensation to light touch over the distribution of her left trigeminal mandibular nerve .
ear , nose , and throat examination revealed the normal appearance of bilateral eardrums and pharynx .
initial hemogram showed borderline leukocytosis ( 10,340 cells/l ) with relative lymphopenia ( 17% lymphocytes ) and a platelet count within reference range ( 210 10/l ) .
biochemical testing revealed renal function , electrolytes , serum alkaline phosphatase , and transaminase levels within reference ranges .
magnetic resonance imaging ( mri ) of the brain on day 9 of symptoms showed multifocal scattered t2 high - signal lesions over bilateral hemispheres , occipital horn , basal ganglion , and brainstem , involving both gray and white matter , with diffusion restriction ( figure , panel a ) .
magnetic resonance imaging with fluid - attenuated inversion recovery sequence of brain for adult patient with pandemic ( h1n1 ) 2009 encephalitis , taiwan .
a ) on day 9 after symptom onset , scattered asymmetric focal hyper signal intensities over bilateral putamen and right thalamus ( arrow on the left image ) and ventriculitis over bilateral occipital horns ( arrow head over right image ) are seen .
cerebrospinal fluid ( csf ) analysis was performed on days 8 and 11 ( table ) .
csf cryptococcal antigen test ; gram , india ink , and acid - fast stains ; and subsequent bacterial , mycobacterial , and fungal cultures all yielded negative results . by real - time pcr screening of a wide panel of possible infectious etiologic agents ,
influenza a ( nonsubtyped ) was simultaneously identified in csf , nasopharyngeal swab specimen , and blood on day 11 .
a regimen of oseltamivir ( 75 mg 2/d ) , initiated at onset of fever , was completed after 5 days .
urodynamic study revealed detrusor spasticity , which was successfully treated with a combination of diazepam and phenazopyridine .
repeat brain mri on day 24 showed near total resolution of the t2-hyperintense lesions ( figure , panel b ) .
according to the centers for disease control in taiwan , the circulating influenza a strain for the winter - spring season of 2011 was pandemic ( h1n1 ) 2009 with few exceptions ( 5 ) .
the pandemic signature of novel subtype h1n1 has been its predilection for infecting healthy adults and its high transmissibility ; hence , we were unable to trace contact history in the case described here .
the patient did not have known comorbid risk factors ; hence , her clinical course was mild .
epidemiologic clues to her diagnosis included residence in an area with the highest incidence of pandemic ( h1n1 ) 2009 in taiwan in 2011 and her naive immunity ( lacking vaccination or exposure to the pandemic 1918 strain ) .
clinical clues supporting pandemic ( h1n1 ) 2009 infection include initial leukocytosis as opposed to leukopenia , relative lymphopenia , and initial false - negative rapid influenza diagnostic test ( 6 ) .
only a few cases of pandemic ( h1n1 ) 2009 encephalitis in adults have ever been reported ( table a1 ) .
the onset of neurologic symptoms usually occurs within a few days of influenza - like illness . unlike children , for whom the mortality rate can be as high as 30% ( 4 ) ,
initial neurologic severity parallels the severity of pulmonary disease and is predictive of neurologic outcomes .
this case highlights the possibility that subtle neurologic deficits may lead to underrecognition of the milder spectrum of central nervous system ( cns ) complications associated with influenza .
the patient s report of focal paresthesias and micturition difficulties ( in the absence of global neurocognitive defects ) understates the substantial , albeit transient , cns inflammation captured on serial csf and mri studies .
mri patterns of cns inflammation in adults appear nonspecific , with t2 lesions distributed across both white and gray matter , with or without symmetry , brain necrosis , infarct , hemorrhage , edema , or ventriculitis .
this patient may be the eldest and only female adult reported with pandemic ( h1n1 ) 2009 encephalitis .
as observed , other adults were men from 20 to 40 years of age ( table a1 ) .
there may be a yet unidentified genetic predisposition for influenza - related encephalopathy to develop among asians , as noted previously in children ( 4 ) ( and possibly among male adults ) .
a remarkable feature of our case was the simultaneous cns detection of virus and pleocytosis , which suggests that the pathogenesis of subtype h1n1 encephalitis may not be simply due to immune activation or cytokine storm as current favored hypotheses propose but also may be caused by direct viral invasion .
although we can not confirm the entry portal of the virus , we note that when the patient sought care , she had a peripheral cranial nerve deficit .
influenza a virus has been detected in the csf of a small minority of japanese children ( especially in those with severe brain pathology ) ( 13 ) and in 1 teenager in south korea ( 14 ) . in children ,
pleocytosis has rarely been described , whereas in this adult series , mild pleocytosis appears not infrequently ( table a1 ) . despite the 2008 recommendation of the infectious diseases society of america regarding routine lumbar puncture in the management of encephalitis for survey of possible etiologic agents ( 15 ) , csf reverse transcription pcr for influenza is infrequently performed in adults ( table a1 ) . therefore , the role of viral cns invasion may be underestimated . in conclusion
, physicians ( not just pediatricians ) should be alert to the possibility of neurologic disease due to pandemic ( h1n1 ) 2009 , especially in persons whose symptoms are subtle .
further studies are warranted to clarify and confirm the neurotropism , particularly for persons of asian heritage , of pandemic ( h1n1 ) 2009 .
Output:
| we report an unusual case of pandemic ( h1n1 ) 2009related encephalitis in an immunocompetent woman .
although rare cases of pandemic ( h1n1 ) 2009 associated with encephalitis have been reported previously , in this patient , direct viral invasion of the central nervous system was shown by simultaneous detection of viral rna and pleocytosis . |
PubmedSumm118573 | ***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: plasma cell neoplasms result from expansion of a single clone of immunoglobulin secreting plasma cells .
plasma cell myeloma is characterized by presence of a monoclonal protein in the serum or urine or both , with anemia , osteolytic lesions , bone pain , hypercalcemia , and renal failure .
osteolytic lesions in the jaw are seen in more than 30% of patients with multiple myeloma .
the oral manifestations of multiple myeloma can be the first sign of the disease in 14% of the patients .
we present the case of a 75-year - old man diagnosed with anaplastic myeloma whose initial presentation was a mandible swelling .
the present case is about a 75-year - old male patient who presented with a firm swelling on the left side of the cheek measuring 10 cm 8 cm 5 cm since 1 month with a gradual increase in size and associated with pain .
computed tomography scan displayed a soft tissue mass involving the ramus of mandible destroying the bone . after obtaining informed consent fine - needle aspiration
was done from the swelling and slides were stained with may - grnwald - giemsa .
smears showed plasma cells arranged in diffuse sheets and singly scattered [ figure 1 ] .
many cells were highly pleomorphic and showed nuclear and cytoplasmic budding [ figure 1-inset ] .
some cells had high nucleocytoplasmic ratio with prominent nucleoli suggesting a plasmablastic nature . with this picture a possibility of an anaplastic / plasmablastic myeloma was suggested .
inset plasma cells with anaplastic morphology ( mgg , 1000 ) investigations showed a raised erythrocyte sedimentation rate ( 65 mm/1 hr ) and evidence of renal failure .
bone marrow aspirate evinced 75% plasmacytosis with sheets of plasma cells and some cells showing dysplastic features and plasmablastic nature similar to that seen in the cytology smears .
the patient was subjected to multiple cycles of dialysis because of the impending renal failure .
chemotherapy could not be started and the patient died 2 months after diagnosis of myeloma .
b - cell lymphoid tissue neoplasms with plasma cell differentiation can broadly be classified into three types - multiple myeloma , solitary plasmacytoma and extramedullary plasmacytoma .
solitary plasmacytoma differs from multiple myeloma by being a solitary soft tissue or bone lesion with no systemic symptoms of multiple myeloma and less than 10% plasma cells in the bone marrow .
the most common bones affected by multiple myeloma are the vertebrae , ribs , skull , mandible , clavicles , scapula and the pelvis .
the involvement of mandible is infrequent but is even rarer to be involved as the first bone affected .
incidental discovery of lesions in the jaw may be the first evidence of this disease .
aspirate smears of plasmacytoma show sheets of plasma cells which have a morphologic spectrum ranging from well - differentiated to anaplastic or blastic .
the well - differentiated plasma cells resemble normal plasma cells and have round to oval eccentric nuclei with a cartwheel chromatin , dense basophilic cytoplasm and perinuclear clear zone in giemsa slides .
plasmablastic morphology is characterized by a high nucleocytoplasmic ratio , round nuclei , fine chromatin , and prominent nucleoli .
the neoplastic plasma cells assuming the form of anaplastic large cells or signet ring cells can mimic metastatic carcinoma . however , the presence of a cogwheel chromatin and prominent golgi zone in at least some of the tumor cells will help in the cytological diagnosis .
anaplastic myeloma is characterized by the presence of pleomorphic and multinucleate plasma cells with brisk mitotic activity and atypical mitotic figures . when there is diagnostic difficulty a careful search
will usually show that even in anaplastic myeloma some cells show clear signs of plasmacytic differentiation .
anaplastic pleomorphic plasma cells are likely to cause confusion when a primary bone origin is unsuspected .
plasmacytomas with anaplastic morphology has to be differentiated from poorly differentiated neoplasms arising from any cell lineage and melanoma .
immunostains for s100 , melan a or hmb 45 will help in diagnosis of melanoma .
literature review has shown that anaplastic plasmacytomas can develop in immunosuppression and epstein - barr virus infection .
reactive plasmacytosis in bone marrow is a common finding in hiv infection , but highly aggressive myeloma can occur rarely in hiv patients . in a study by bangerter et al .
a thorough evaluation of the cytologic smears will help in reaching at a correct diagnosis .
anaplastic myeloma which is a rare and aggressive variant of myeloma mimic poorly differentiated carcinoma .
an extensive search for cells with plasmacytic differentiation with recognition of diagnostic features of anaplastic myeloma is important so as not to miss the diagnosis .
this is more important when plasmacytomas occur in rare sites like mandible without a previous history of myelomatosis .
fine - needle aspiration cytology which is minimally invasive and inexpensive can be used as a front line investigative method in diagnosis of plasmacytoma .
Output:
| multiple myeloma is a disease resulting from clonal proliferation of plasma cells .
a disease of the elderly , jaw lesions are seen in 14% of patients affected with myeloma .
rarely the oral and maxillofacial lesions can be the first manifestation of the disease .
we report the case of a 75-year - old man who presented with mandibular swelling .
fine - needle aspiration cytology was done from the swelling and smears were suggestive of anaplastic myeloma , which is a rare and aggressive variant of myeloma .
the diagnosis of a plasmacytoma was confirmed by biopsy .
further workup of the patient revealed osteolytic lesions in skull , m band in electrophoresis and evidence of renal failure .
peripheral smear and bone marrow findings were also consistent with myeloma . |
PubmedSumm118574 | ***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: tributyltin ( tbt ) is one of the most toxic compounds still used in antifouling paints for large commercial ships thereby distributed within the aquatic environment .
its distribution and accumulation in aquatic organisms leads to severe effects and has already reduced the number of snail species in the near of sea lanes and harbours .
moreover , the trophic transfer has been demonstrated , and the accumulation within the food chain up to the level of marine mammals has reached concentrations that might be biological relevant [ 36 ] .
the most prominent biological effect investigated so far is the so - called imposex within sea snails and dogwhelks [ 1 , 7 , 8 ] , and this mechanism is used as biomonitoring tool for organotin compounds . despite the fact that a lot of studies have been carried out , the underlying molecular mechanism remains unclear [ 10 , 11 ] .
it has been proposed that the inhibition of aromatase activity alters the ratio of the hormones inducing the development of imposex , the imposition of male sex characteristics on female snails [ 1 , 12 ] , but other studies came to other results [ 11 , 13 ] .
as organotin compounds were still used and accumulate in the environment as well as in the food chain , the exposure of mammals and humans increases steadily . moreover , it has been described earlier that organotin compounds , especially tbt , have a clear immunotoxic effect in mammals [ 1416 ] , and this might be due to their exorbitant induction of apoptosis [ 17 , 18 ] .
the effective concentration of tbt to induce apoptosis in the majority of treated cells is around or below 1 m and has been shown in vitro [ 14 , 1827 ] as well as in vivo [ 28 , 29 ] .
the question whether the disturbance of the intracellular calcium homeostasis is responsible for the onset of apoptosis [ 22 , 27 , 3034 ] or the direct effect on mitochondrial functions is the first event [ 18 , 20 , 24 , 32 , 33 , 35 ] is under discussion for a long time .
[ 18 , 23 ] have shown a decade ago that tbt induces apoptosis via the activation of caspases in various human cells , the link for this caspase activation was not yet found .
the most obvious players have been discussed to be the increase in calcium concentration or the opening of the permeability pore of the mitochondria . but induction of apoptosis has been demonstrated for very low concentrations of tbt which do not induce calcium influx , and caspases are often inhibited by high calcium concentrations .
some years ago , evidence arose that mitochondria - independent mechanisms contribute to the induction of apoptosis and possibly death receptors or direct caspase activation are involved in the tbt induced effect [ 3639 ] .
it is now generally accepted that the programmed cell death can be physiologically induced via death receptors on the surface of the cells , activated by specific ligands that are strictly controlled for instance during development or inflammation leading to the formation of the so - called death - inducing signalling complex or disc .
moreover , it has been shown that at least lymphoid cells can be discriminated into type i and type ii cells and only type ii cells are strongly dependent on functional mitochondria for their apoptotic machinery .
jurkat t - lymphoblastoid cells are type ii cells and present a special tool for the investigation of mitochondrial - dependent cell death characteristics .
additionally , genetic modifications of the disc within these cells enable a closer look at which point the sequence of events is started after tbt - treatment . in the present study ,
the mechanism of tbt - induced apoptosis has been investigated by the use of jurkat t - cells and two variants , caspase-8 and fadd - deficient jurkat cells , that provide a direct insight into the death - receptor - coupled mechanisms .
the data presented here point to the involvement of initiator caspase activation , especially from caspase-10 , and are discussed in terms of the potential immunotoxic role of tbt in exposed mammals .
when human immune cells were treated with tbt , changes of morphological as well as biochemical parameters of apoptosis can be observed . in all experiments done in this study , we used 1 m tbt , a concentration that induces apoptosis in the majority of the treated cells within 4 hours .
after that , time membrane blebbing and the externalisation of phosphatidylserine ( ps ) occur and chromatin condensation could be observed in jurkat a3 t - cells ( figures 1(a ) and 1(b ) ) .
chromatin condensation was shown by the use of the dna dye hoechst 33342 , and ps on the outer leaflet of the plasma membrane is detected with annexin v - fitc by flow cytometry ( facs ) and fluorescence microscopy ( figures 1(c)1(h ) ) . as demonstrated by two typical facs dot blots , more than 60% of the treated cells undergo apoptosis and exhibit green fluorescence at the plasma membrane without being necrotic as the counter staining with propidium iodide demonstrates clearly .
looking closer to the different proteins that are involved in the apoptotic machinery , the complete sequence of events from initiator caspases down to death substrates is switched on .
focussing at the level of initiator caspases , both , caspase-8 and caspase-10 , are cleaved and their active subunits can be detected by western blotting ( figure 1 , left ) .
downstream the initiator caspases , the bid protein is an important linker to the mitochondrial pathway in type ii cells and this protein is cleaved after tbt treatment .
from the multitude of caspases downstream of the mitochondria we tested for procaspase-9 , -7 , -6 , and -3 and found all these proteases cleaved . as one of the most prominent death substrates poly(adp - ribose ) polymerase ( parp ) has also been shown to be cleaved within this series of events ( figure 1 , left ) . moreover , we tested hepatocytes transfected with a fusion protein of cytochrome c / green fluorescent protein ( kindly provided by d. green , la jolla institute for allergy and immunology , san diego , usa ) and found the release of cytochrome c after tbt treatment ( data not shown ) .
the extrinsic pathway upstream the mitochondria is further characterised by use of two genetically modified jurkat cell lines where one is caspase-8 deficient and the other is fadd adaptor protein deficient .
furthermore , various caspase inhibitors were used to dissect their roles as possible starting point of the apoptotic sequence of events induced by tbt .
firstly , caspase-8 deficient cells exhibit only a slight reduction of apoptosis in all three cell lines when incubated with 1 or 1.5 m tbt ( figure 2 ) , whereas fas - ligand - induced apoptosis was completely abolished ( not shown ) . without caspase-8 ,
the only measurable protection was found for ps externalisation that is reduced by one third ( figure 3 ) .
secondly , fadd deficiency affords an improved protection against the effects caused by tbt exposure , especially at lower concentrations ( figure 2 , 1 m tbt ) .
this is further corroborated by analysis of ps externalisation and the total caspase activity by a fluorescence assay in living cells .
the externalisation of ps was reduced in the same order of magnitude as in the caspase-8-deficient cells ( figure 3 ) , but the caspatag assay demonstrates high protease activity in tbt - treated wild - type cells as well as in the caspase-8-deficient variant , whereas in fadd - deficient cells , this activity is obviously reduced ( figure 4 ) . the importance of caspases for organotin - provoked apoptosis has been investigated by use of several inhibitors . the overall caspase inhibitor zvad - fmk blocks totally all described effects that normally can be detected after tbt exposure ( data not shown ) . in this study , we used further specific inhibitors of caspases downstream as well as upstream of mitochondria .
when caspase-9 and caspase-3 were inhibited as most potent elements of the caspase cascade downstream of the mitochondria , tbt - induced apoptosis is fully prevented in all three cell lines ( figure 2 ) .
preincubation of the jurkat cells with zlehd - fmk ( caspase-9 inhibitor ) and zdevd - fmk ( caspase-3 inhibitor ) rescues all viable functions .
nevertheless , a closer look at the western blots revealed often a slight reduction of those elements that were cleaved upstream of the mitochondria , especially bid , even though at slightly higher concentrations of tbt ( figure 2 , 1.5 m ) .
while caspase-8 is activated in fact after tbt treatment of wild - type jurkat cells , caspase-8 deficient cells undergo apoptosis to a comparable extent .
this result suggests that caspase-8 can not play a substantial role within this concert of effects after tbt treatment .
therefore , we looked closer for caspase-10 , the second initiator caspase at the receptor level . when caspase-10 is inhibited by zaevd - fmk , ps externalisation ( figure 3 ) and overall caspase activity is drastically reduced in all cell lines investigated in this study ( figure 4 ) .
next , we wanted to know if initiator caspases could be found in an activated disc and which ones .
immunoprecipitations ( ip ) with an antibody against the fas - receptor coprecipitated caspase-8 ( data not shown ) , but this caspase has no substantial relevance for the tbt effect in jurkat cells as shown above .
therefore , we tested jurkat cells for other death receptors and found additionally trail - r1 , trail - r2 , trail - r3 , trail - r4 , and tnf - r1 .
as trail - r2 was the dominant form and trail - r3 and trail - r4 are decoy receptors , we used a trail - r2 antibody for our ips . with this antibody
, we could precipitate both initiator caspases after 3 h of treatment with 1 m tbt ( figure 5(a ) ) .
additionally , we detected the procaspases-8 and -10 in the untreated controls but to a much lesser extent and we never found the activated subunits .
analysing the three different cell lines reveals the fact that caspase-10 could be found in all activated disc forms even though at different levels ( figure 5(b ) ) . a direct comparison of the effects of fas - ligand and tbt in all three cell lines pre - treated with and without the caspase-10 inhibitor zaevd - fmk provides a detailed insight into the different roles of the two initiator caspases in human jurkat t cells .
fas - ligand treatment of the two deficient cell lines has no effect at all , and , thus , these data were not included in figure 6 .
the jurkat a3 wild - type cells , however , were driven into apoptosis , and this effect is only to a minor degree diminished by the pretreatment with the caspase-10 inhibitor , and apoptosis still proceeds .
tbt treatment , however , has approximately the same effect as fas - ligand in the absence of zaevd - fmk , but all consequences of this treatment were prevented in the presence of aevd .
phosphatidylserine externalisation is reduced to nearly control levels ( figure 3 ) , and activation of caspases is strongly decreased in all three cell lines ( figure 4 ) . in addition ,
the cleavage of important caspases is prevented ( caspase-8 and caspase-3 , figure 6 ) , bid cleavage is drastically diminished , parp is completely rescued , and dna fragmentation does not proceed anymore ( figure 6 ) .
trialkylated tin compounds , especially tbt , are distributed all over the environment , and were taken up by cells in vitro fast and effectively and their toxicity is a function of both concentration and duration of exposure .
it has long been discussed that this cytotoxicity of organotin compounds might be the result of a massive alteration of the intracellular calcium concentration [ ca]i .
various investigations demonstrated an increase of [ ca]i after exposure to a variety of trialkytins , and this effect should be responsible for their cytotoxicity , immunotoxicity , and neurotoxicity not only in mammalian [ 14 , 17 , 3032 ] but also in fish cell systems . but
more and more evidence has been supplied that alteration of [ ca]i is not the major event in the nonacute cytotoxic scenario [ 43 , 44 ] .
numerous studies have been carried out during the last two decades indicating the induction of apoptosis in various biological systems without elucidating the starting point of the involved molecular mechanism [ 14 , 1725 , 27 , 28 , 36 ] . as early as in 2001
, the first publication demonstrated a possible involvement of the death receptors , and this was confirmed a few years later .
nevertheless , recently published data connect developmental abnormalities of fish larvae with the induction of apoptosis on the level of caspase 3 , and the initiating molecular mechanism by which tbt induces apoptosis is not described .
thus , this study was carried out to enlighten the mechanism in more detail . there
exist two different pathways for apoptosis that can be distinguished from each other , the extrinsic and the intrinsic pathway .
the intrinsic pathway is dependent from proapoptotic events on the level of the mitochondria and is mostly affected by environmental chemicals or stress factors .
thus , it seems to be obvious that toxic substances such as tbt exert their effect on mitochondria .
a multitude of studies have shown that different parameters of mitochondria were altered after treatment of cells with tbt [ 18 , 32 , 37 ] .
nonetheless , the induction of apoptosis could not be explained sufficiently by all these examinations because mitochondria - independent apoptosis has been described as well [ 37 , 47 ] and inhibition of the intrinsic pathway by bcl-2 overexpression protects only type ii cells but not type i cells from apoptosis although the mitochondrial membrane potential m is still high .
moreover , it has been published earlier that various metal compounds may activate the extrinsic apoptotic pathway [ 3739 , 49 ]
. a closer look on the formation of the death - inducing signalling complex
( disc ) reveals its formation within 1 to 3 h after treatment with tbt ( figure 5 ) .
normally , in jurkat t cells , the disc consists out of the fas - receptor molecules to which the adaptor molecules fadd and initiator caspase-8 are bound .
but the caspase-8-deficient jurkat cells showed no or only little reduction in apoptosis after tbt treatment , and solely fadd deficiency decreases substantially the apoptotic cell number although not all .
so we looked for other elements as possible constituents of the disc . as it was published by several groups that not only caspase-8 but also caspase-10 can be recruited to death receptors [ 50 , 51 ] , apo2l / trail is able to activate both initiator caspases , and caspase-10 is described as important caspase in hct 116 colon carcinoma cells , we analysed the disc formation in more detail .
as mentioned above , caspase-10 could be found in the disc and is co - precipitated by anti - trail - r2 antibody .
these results were confirmed by measuring various caspase activities in lysates using the substrates ietd - pna ( caspase-8 ) , aevd - pna ( caspase-10 ) , and devd - pna ( caspase-3 ) , respectively . in lysates of tbt - treated cells , all caspases have been found to be active ( data not shown ) .
thus , tbt leads not only to unspecific cleavage of caspases but directly to their activation .
because caspase-8-deficient jurkat cells express lower amounts of caspase-10 compared to their parental cell line , these cells might be somewhat less sensitive to tbt as demonstrated here ( figure 3 ) .
but determination of all apoptotic markers revealed a nearly unchanged sensitivity to tbt of jurkat cells lacking caspase-8 when treatment is prolonged to a minimum of 4 h. another set of experiments focuses on caspases in more detail . overall inhibition of caspases with zvad - fmk , an unspecific inhibitor of all cellular caspases , inhibits totally tbt - induced apoptosis in human neutrophils as well as in jurkat cells ( data not shown ) .
a strong evidence for a specific role of the initiator caspase-10 comes from our experiments with its specific inhibitor zaevd - fmk .
while fas - ligand - induced apoptosis is only slightly prevented after pre - incubation of the cells with aevd ( figure 6 ) , tbt - treatment has no effect at all , when caspase-10 was inactivated before .
nevertheless , kischkel and coworkers described fadd as an obligatory adaptor for both initiator caspases to trail receptor ; thus , we expected the fadd - deficient cells to be protected against tbt - induced apoptosis .
but this is the case only for lower concentrations of tbt up to 1 m . in this case
, the prevention of fadd - deficient cells is apparent ( figure 2 ) , whereas slightly higher concentrations ( 1.5 m ) overcome this protective effect .
this might be due to the fact that these higher concentrations directly affect , on the one hand , the intrinsic machinery of apoptosis or , on the other hand , tbt might be able to activate directly caspases as has been demonstrated earlier [ 36 , 47 ] .
another evidence for caspase-10 dependency with no or only less involvement of fadd - adaptor protein has been described recently for another chemical but with the same set of jurkat cells .
this group found the same total inhibition of all effects by the caspase-10 inhibitor zaevd - fmk and no reduction in caspase-8-deficient cells .
moreover , fadd recruitment was not involved because the fadd - deficient jurkat cells exhibited dna fragmentation and other signs of apoptosis ; thus , these results are obviously congruent with the data presented here .
furthermore , it has been published lately that caspase-10 may cleave specific substrates , as the proapoptotic protein bid , without being cleaved before into its active subunits .
this may be the reason why type ii cells are more sensitive to bcl-2 overexpression than type i cells , as type ii cells are dependent on bid cleavage and the activation of the mitochondrial pathway . in our hands , the type i cell line skw has a higher level of caspase-10 expression , and this is cleaved at the disc in both variants , the wild type as well as in the bcl-2 overexpressing line ( data not shown ) .
the question to what extent the extrinsic or the intrinsic pathway is responsible for the tbt - induced apoptosis in the absence of a functional fadd adaptor protein can be answered by the concentrations of tbt used within the experiments .
lower concentrations not disturbing the lysosomal or mitochondrial systems are more or less totally dependent on the formation of an activated disc , whereas higher concentrations overcome this mechanism and stress the intracellular machinery via lysosomes or / and mitochondria leading to caspase - independent responses [ 5557 ] .
the here described results indicate that tbt in principle activates initiator caspase-10 leading to bid cleavage and activation of the mitochondria inducing the downstream apoptotic machinery ( figure 7 ) . besides mammalian system cells from other species were affected by tbt as well . in trout blood cells ,
15 m tbt induces apoptosis within 1 h , and , in gill tissue of the mussel mytilus galloprovincialis treated with 1 g / g bw tbt ( 3 m ) , apoptosis could be detected after 24 h incubation .
the strongly discussed immunosuppressive properties of tbt in vivo might be the consequence of specific induction of cell death in immunocompetent cells .
such a killing of lymphocytes by tbt can be observed as a loss in thymus weight or thymus atrophy [ 29 , 58 ] that debilitates the immune function of animals , making them vulnerable to infectious diseases [ 5963 ] . on the background of these findings , the deadline for banning tbt
must be possibly reconsidered as not only sea snails but also open water mammals and humans might be affected and new regulatory strategies have to be discussed independent from market forces . whereas the international maritime organisation ( imo ) has banned tbt since 2008 , the european commission has forbidden its use
after 1st of july 2010 in articles where the concentration in the article , or part thereof , is greater than the equivalent of 0.1% by weight of tin , but articles treated with such biocides may still be imported into the community .
all cell culture reagents were purchased from life technologies ( eggenstein , germany ) , petri dishes and multiwell plates were obtained from nunc ( wiesbaden , germany ) .
annexin - fitc is from bd pharmingen ( heidelberg , germany ) , pi and hoechst 33342 from sigma ( deisenhofen , germany ) , and the inhibitors of caspase-10 ( zaevd - fmk ; fmk009 ) , caspase-9 ( zlehd - fmk ; fmk008 ) , and caspase-3 ( zdevd - fmk ; fmk004 ) were from r&d systems ( wiesbaden , germany ) .
9762 ) , anti - caspase-7 ( cat no . 9492 ) and anti - caspase-9 ( cat no .
9502 ) were purchased from cell signaling technology ( frankfurt , germany ) , anti - caspase-3 ( cat no .
551242 clone 3 - 1 - 9 ) from bd pharmingen ( heidelberg , germany ) , anti - caspase-10/a ( cat no .
m059 - 3 ) from mobitec ( mbl ) ( gttingen , germany ) , anti - trail - r2 ( dr5 ) ( cat no .
pc392 ) from calbiochem ( darmstadt , germany ) , anti - bid ( cat no .
af846 ) from r&d systems ( wiesbaden , germany ) , and anti - parp ( cat no .
as secondary reagents , we used : horseradish - peroxidase- ( hrp- ) conjugated goat anti - mouse igg1 ( cat no .
p 0447 ) from dakocytomation ( glostrup , denmark ) and hrp - conjugated donkey anti - rabbit ( cat no .
the jurkat cell line a3 as well as the fadd and caspase-8-deficient cell lines were kindly provided by j. blenis ( harvard medical school , boston , usa ) and were maintained in rpmi 1640 supplemented with 10% fcs and 1 mm hepes .
the cultures were grown with 100 u / ml penicillin and 100 g / ml streptomycin in a humidified atmosphere containing 5% co2 at 37c . during experiments , 10 mm glucose were additionally included in the incubation medium .
for induction of apoptosis , 2 10 cells per ml medium were incubated with 1
l / ml of a 1 mm stock solution of tbt ( merck ) in ethanol to give the final concentration of 1 m .
as a positive control , 100 ng fas - ligand plus 1 g enhancer ( alexis , san diego , usa ) per ml incubation medium were used .
all controls were incubated with the same amount of vehicle ( 1 l ethanol / ml ) to exclude side effects of the solvent .
2 10 were disrupted in 500 l lysis buffer ( 20 mm edta , 1% np 40 , 50 mm tris / hcl , ph 7.5 ) .
after centrifugation at 1600 g for 5 min , supernatants containing the apoptotic dna were transferred into eppendorf tubes .
after addition of 1% sds , samples were treated for 2 h with rnase - a ( 5 g/l ) at 56c and subsequently for further 2 h with proteinase k ( 2.5 g/l ) .
the dna was precipitated by the addition of 50 l of 10 m ammoniumacetate and 250 l ice - cold ethanol , stored overnight at 20c followed by centrifugation .
the pellet was resuspended in 25 l of te - buffer ( 10 mm tris / hcl , 1 mm edta , ph 8.0 ) , and the dna - fragments were analysed by agarose gel electrophoresis ( 1.8% agarose containing ethidium bromide as dna stain ) , and pictures were taken with a mwg gel documentation system .
the assay was carried out as described by the manufacturer ( intergen , heidelberg , germany ) . from
each treated sample , 150 l containing 3 10 cells were washed with fresh medium and 10 l of 30x solution of the caspase substrate fam - vad - fmk were added to give the final concentration of 10 m .
then , 1 ml of washing solution was added , the suspension was centrifuged at 400 g for 5 min at room temperature .
the resulting cell pellet was washed once with washing buffer and finally resuspended in 400 l washing buffer including 1 l pi as counterstain for necrosis .
cells were left for 15 min on ice , and then the microscopic pictures were taken .
trail - associated caspase-10 and caspase-8 were immunoprecipitated as follows : 10 cells ( 2 10/ml ) were treated with 1 m tbt and then lysed in 500 l cell lysis buffer ( 30 mm tris / hcl , ph 7.5 , 150 mm nacl , 1 mm phenylmethylsulfonyl fluoride , 10 g / ml aprotinin and 10 g / ml leupeptin , 1% triton and 10% glycerol ) .
the lysates were centrifuged at 14 000 g for 10 min at 4c .
the supernatants were then incubated for 4 h with protein a - sepharose ( sigma , deisenhofen , germany ) and 1.5 g anti - trail - r2 .
the beads were centrifuged at 7000 g for 6 min at 4c , washed once with the same amount of lysis buffer , and centrifuged again .
after having removed the supernatants carefully , the pellets were resuspended in 100 l electrophoresis buffer and 15 l of each sample were analysed by sds - gel electrophoresis and western blotting .
apoptotic and necrotic cells were determined either microscopically or by flow cytometry using recombinant annexin v conjugated to fitc and propidium iodide .
the determination of apoptosis is based on the binding of annexin v - fitc on the phosphatidylserine exposed at the surface of apoptotic cells .
for the assay , 1 10 cells were pelleted at 1500 g and resuspended in 100 l binding buffer ( 10 mm hepes , ph 7.4 , 140 mm nacl and 5 mm cacl2 ) containing 5 l annexin v - fitc and 100 ng pi .
after 15 min of incubation at 4c in the dark , cells were diluted in 400 l binding buffer and immediately analysed by flow cytometry .
fluorescence was analysed at 530 14 nm ( fitc ) and 610 10 nm ( pi ) and quantified with the cellquest prosoftware ( bd , heidelberg , germany ) . for microscopic assessment of apoptosis and necrosis , 6
10 cells were diluted 1 : 1 with 2x binding buffer , containing 1 l annexin v - fitc and 3 ng pi .
after 15 min of incubation in the dark , cells were analysed with a 63x oil objective and a zeiss axiovert s100 microscope ( carl zeiss gmbh , jena , germany ) , connected to a hamamatsu ccd camera ( c4880 - 80 ) .
fluorescence and differential interference contrast pictures were taken using an automation procedure and merged using openlab software ( improvision , coventry , uk ) .
chromatin condensation was determined after staining of the cells with hoechst 33342 . in short , after treatment , 1 10 cells were washed with phosphate - buffered saline ( pbs ) incubated with a final concentration of 10 m hoechst 33342 for 10 min , washed again with pbs to reduce background fluorescence , and finally visualised with the same system described above with excitation at 364 15 nm and emission at 460 10 nm .
Output:
| tributyltin ( tbt ) is one of the most toxic compounds produced by man and distributed in the environment .
a multitude of toxic activities have been described , for example , immunotoxic , neurotoxic , and endocrine disruptive effects .
moreover , it has been shown for many cell types that they undergo apoptosis after treatment with tbt and the cell death of immune cells could be the molecular background of its immunotoxic effect .
as low as 200 nm up to 1 m of tbt induces all signs of apoptosis in jurkat t cells within 1 to 24 hrs of treatment .
when compared to fas - ligand control stimulation , the same sequence of events occurs : membrane blebbing , phosphatidylserine externalisation , the activation of the death - inducing signalling complex , and the following sequence of cleavage processes . in genetically modified caspase-8-deficient jurkat cells , the apoptotic effects are only slightly reduced , whereas , in fadd - negative jurkat cells , the tbt effect is significantly diminished .
we could show that caspase-10 is recruited by the trail - r2 receptor and apoptosis is totally prevented when caspase-10 is specifically inhibited in all three cell lines . |
PubmedSumm118575 | ***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: moreover , restrictions of physical functioning among
older adults are very important1 , 2 .
spinal pain is the most common of all
chronic pain disorders . in a previous study ,
including back and
neck pain , spinal pain negatively affects mobility and aerobic capacity of the elderly .
chronic diseases and pain in aging can also saliently affect the balance ability of older
adults4 .
physical functioning including
balance ability and aerobic capacity is important for the activities of daily living and
static and dynamic posture .
chronic diseases and aging may affect physical functioning5 , 6 .
musculoskeletal disorders may occur due to many reasons that affect sensorial and motor
control systems and may affect functional capacity negatively . with aging , musculoskeletal
capacity is reduced , which results in loss of muscle mass and strength . a decrease in
aerobic capacity and
physical activity levels can cause changes in gait and balance7 , 8 . in
addition
, chronic musculoskeletal pain negatively affects emotional status and activities of
daily living ( adl)9 , 10 .
the aim of this study was to show the impact of chronic musculoskeletal pain of the spinal
column and lower extremities on physical functioning , emotional status , and independency in
older adults .
the study sample consisted of two hundred and fifty - eight independent older adults who were
randomly selected from volunteers .
the exclusion criteria were being dependent in daily living activities , having a cognitive impairment , having a neurological diseases such as stroke , parkinson disease , multiple sclerosis or
spinal cord injuries .
the study was approved by the ethics committee for non - invasive clinical research of
pamukkale university denizli , turkey ( 2012/16 - 03 ) .
sociodemographic data including age , gender , marital status , and education level were
recorded through a face to face interview with a physiotherapist .
body mass index ( bmi ) was calculated for each older adults to define their obesity
level .
we asked the older adults who reported musculoskeletal pain to indicate the localization on
their pain on a body diagram . only the older adults who reported spinal or lower extremity
pain
the six - minute walk test ( 6mwt ) was used to evaluate aerobic capacity .
the 6mwt was
performed in a 30-m - long corridor , and the participants were instructed to walk as fast as
possible without running .
they could stop walking if they felt any discomfort , fatigue , or
shortness of breath .
the timed up and go ( tug ) test was used to evaluate dynamic balance .
the tug test as
described by podsiadlo and richardson is a simple timed test used to qualify functional
mobility11 . in the tug test ,
participants were asked to stand up from a standard chair with a seat height of between 40
and 50 cm , walk a 3-m distance at a normal pace , turn , walk back to the chair , and sit down .
go and ended when the
participant s back touched the backrest of the chair , with a shorter time indicating better
balance ability12 .
the yesavage geriatric depression scale ( gds ) was used to detect depressive symptoms in
order to describe emotional status .
this scale was developed as a self - report measure for
depression in older adults .
since this version proved both time - consuming and
difficult for some patients to complete , a 15-item version was developed .
the sensitivity
and specificity of the gds-15 have been assessed in a general elderly population13 .
the
turkish internal validity of the gds was confirmed by aktrk et al14 . for the 15-item short form gds ,
04 points is normal , 59
points indicates mild depression , and 1015 points indicates more severe depression .
the lawton - brody instrumental activities of daily living scale ( iadl ) was used to evaluate
independency in daily living activities .
the iadl scale measures complex functional
activities of ability including using a telephone , handling finances , self - administration
medication , use of transportation , shopping , housekeeping , laundry , and cooking .
one point
was awarded if a patient required little / no help in performing a task , and no points were
awarded if significant / total help was required . for the lawton - brody iadl ,
08 points is
evaluated as dependent , 916 points is evaluated as semi - dependant , and 1724 points is
evaluated as independent
the data were analyzed using the statistical package for social science ( spss , chicago ,
il , usa ) version 16.0 software for windows . to evaluate sociodemographic variables ,
descriptive statistical methods were used [ mean standard deviation ( sd ) and frequencies
( count and percentage ) ] . to compare the two groups ,
the data were analyzed using the statistical package for social science ( spss , chicago ,
il , usa ) version 16.0 software for windows . to evaluate sociodemographic variables ,
descriptive statistical methods were used [ mean standard deviation ( sd ) and frequencies
( count and percentage ) ] . to compare the two groups , the independent samples t - test was
used .
table 1table 1 . baseline characteristics of participants with spinal and lower extremity
painspinal pain(group i)lower ext .
pain(group ii)n ( % ) mean ( sd)n ( % ) mean ( sd)total 130 ( 100 ) 82 ( 100 ) gendermale 63 ( 48.4)41 ( 31.5 ) female 67 ( 51.5 ) 41 ( 31.5 ) bmi score27.45 ( 3.95 ) 28.14 ( 4.35)marital statussingle 41 ( 31.5 ) 33 ( 40.2)married 89 ( 68.4 ) 49 ( 59.7 ) chronic illnessno 16 ( 12.3 ) 6 ( 7.3 ) yes 114 ( 87.6 ) 76 ( 92.6 ) body mass index ( bmi , kilograms per square meter ) 30 , sd : standard deviation ,
* significant shows the baseline data of the groups .
spinal pain was reported by 61.3% of the participants ( neck and
lower back ; n=130 ) , and 38.7% reported pain in the lower extremities ( n=82 ) .
the mean age of
the participants was 71.98 5.86 years ; 131 ( 50.4% ) were male , and 127 ( 48.8% ) female .
the
mean vas score during activities was 5.061.89 cm for group i and 5.44 2.24 cm for group
ii .
no differences between the two groups in terms of the vas score were found ( p>0.05 )
( table 2table 2 .
pain(group ii)(n=130)(n=82)mean ( sd)mean ( sd)vas ( cm ) 5.06 ( 1.89 ) 5.44 ( 2.24)tug ( sn ) 24.37 ( 16.49 ) 24.24 ( 11.31)6mwt ( m ) 363.73 ( 278.66 ) 284.17 ( 195.78 ) * * gds - score 6.04 ( 3.63)7.12 ( 4.01)**iadl - score 9.20 ( 4.99)10.76 ( 5.68)***the independent samples t - test was used .
sd , standard deviation ; vas , visuel analog
scale ; tug : timed up and go test ; gds , geriatric depression scale ; iadl , instrumented
activities of daily living . * * significant ) . body mass index ( bmi , kilograms per square meter ) 30 , sd : standard deviation ,
* significant * the independent samples t - test was used .
sd , standard deviation ; vas , visuel analog
scale ; tug : timed up and go test ; gds , geriatric depression scale ; iadl , instrumented
activities of daily living . * * significant table 2 also shows the tug , 6mwt , gds , and iadl
results .
except for the tug scores , all outcome measurements showed significant differences
between the groups .
namely , the participants in group ii ( with lower limb pain ) had a lower
score in terms of aerobic capacity than those in group i ( p=0.027 ) .
although the two groups
had scores below the cutoff point for the gds , group ii had a higher score than group i
( p=0.045 ) .
the two groups had more or less the
same scores in terms of the iadl ( p=0.036 ) .
so , all participants in both groups were
semi - dependent according to the iadl scores .
the partial correlation coeffidents in the spinal pain ( group i ) ( after
correcting for age and gender)control variablesage and gender1 2 31 - 6mwt2- gds0.090 3-iadl0.142 0.3126mwt , 6 minute walk test ; gds , geriatric depression scale ; iadl , instrumental
activities of daily living ; * significant and 4table 4 .
the partial correlation coeffidents in the lower extremity pain ( group ii )
( after correcting for age and gender)control variablesage and gender1231 - 6mwt2-gds0.088 3-iadl0.025 0.420 6mwt , 6 minute walk test ; gds , geriatric depression scale ; iadl , instrumental
activities of daily living ; * significant show that there were significant inverse correlations between the gds and iadl
scores .
6mwt , 6 minute walk test ; gds , geriatric depression scale ; iadl , instrumental
activities of daily living ; * significant 6mwt , 6 minute walk test ; gds , geriatric depression scale ; iadl , instrumental
activities of daily living ; * significant
most of the older adults this study complained of
musculoskeletal pain in their spinal column and lower extremity .
the same complaints can also be found in the literature . moreover , helme and gibson , dawson
et al . , and robin et al .
reported that lower extremity pain including hip , knee , and foot
pain are very common15,16,17 . in our study ,
we studied 258 older adults who reported musculoskeletal pain in their spinal column and
lower extremities ( n=212 ; 82.1% ) . in this descriptive and comparative study
the results showed that lower extremity pain affected functioning ,
especially physical functioning , in older adults more than spinal pain .
in addition to this ,
the results obtained from the 6mwt also showed that the older adults with lower extremity
pain had the worst aerobic capacity compared with those with spinal pain . that is , our
results showed that chronic musculoskeletal pain in the lower extremity led to a decreased
aerobic capacity18,19,20,21,22,23 . on the other hand ,
the older adults evaluated in this study showed decreased independency
in daily living activities .
the same results can be found
in the literature24 , 25 . since depressive symptoms are common during aging , we also detected depressive symptoms in
our study .
although there
have been some finding indicating that chronic musculoskeletal pain increases depressive
symptoms in older adults , our results did not support this idea26 , 27 .
the results obtained in this study also supported the inverse relation between depressive
symptoms and independency in daily living activities .
this show that increased depressive
symptoms led to decreased independency in daily living activities .
this is not an unexpected
result , as it has been reported in previous related literature9 , 25 , 26
. the limitations of this study are as follows : ( 1 ) the sample size was too small to make a general comment .
( 2 ) we studied older adults with spinal or lower extremity pain , but we could not compare
our sample with older adults without pain . despite to the limitations mentioned above , the study has a major strength : this study is
the first one showing the effects of pain localization in older adults completed in
turkey . keeping in mind the limitations of the present study , we plan to perform further research
with a larger sample size so we will be able to make general comments with regard to this
field . in conclusion ,
the results of this study indicate that evaluation and relief of chronic
musculoskeletal pain are vital in geriatric rehabilitation programs . for this reason ,
health
providers , including physiotherapists , ergotherapists , medical doctors , and nurses , should
consider chronic musculoskeletal pain in older adults .
in particular , physiotherapists and
ergotherapists should focus on chronic lower extremity pain to improve physical functioning
and aerobic capacity of older adults to make them more mobile and improve their aerobic
capacity .
Output:
| [ purpose ] the aim of this study was to show the impact of chronic musculoskeletal pain
of the spinal column and lower extremities on physical functioning , emotional status , and
independency in older adults . [ subjects ] in this cross - sectional study , 258 older adults
( mean age , 71.985.86 years , 50.8% males , 49.2% females ) living in their own residences
were evaluated .
[ methods ] pain intensity was analyzed using a visual analogue scale .
physical functioning was evaluated with the timed up and go test ( tug ) and a six - minute
walk test .
the geriatric depression scale was used to determine emotional status .
the
independency in daily living of the participants was evaluated using the lawton brody iadl
scale .
all participants were divided into two groups in accordance with the pain
localization : the ( 1 ) spinal pain and ( 2 ) lower extremity pain groups .
[ results ] when the
pain scores were compared , no significant differences between the two groups were found .
the same results were found in terms of tug scores .
the spinal pain group had higher
scores in terms of aerobic capacity than the lower extremity pain group .
[ conclusion ] the
results indicate that chronic musculoskeletal pain in the lower extremities decreased
aerobic capacity much more than spinal pain in older adults . |
PubmedSumm118576 | ***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: hepatocellular carcinoma ( hcc ) is one of the most common malignancies worldwide . in korea , hcc is the third most common primary malignant tumor and the third leading cause of death in patients with cancer .
spontaneous rupture of hcc is an uncommon , but fatal complication leading to immediate death , and especially for those patients with liver cirrhosis and who may have coagulation deficiencies .
the incidence of spontaneous hcc rupture is different according to the geographical area , and it tends to be higher in areas with endemic viral hepatitis b or c , such as korea [ 2 - 4 ] . in general , the diagnosis of ruptured hcc is based on the findings of ultrasound or ct , and on the presence of bloody ascites as ascertained by performing abdominal paracentesis .
regarding to the management for ruptured hcc , various treatment options , including hepatic resection , hepatic artery ligation and transcatheter arterial embolization ( tae ) , have been proposed in accordance with the situation / state the patient is in . when hypovolemic shock occurs due to massive intraperitoneal hemorrhage , immediate management such as resuscitation for hypovolemic shock followed by hemostasis
although hepatic resection is known to be the most effective treatment for ruptured hcc , the mortality rate for emergency operations in the ruptured patients with hepatic decompensation or hypovolemic shock has been high .
tae is alternatively considered to reduce the initial mortality and to buy a little time for making the decision on the proper treatment for the underlying hcc .
a previous study reported the average survival times for patients treated with emergency resection or with delayed resection were 12 months and 19 months , respectively .
therefore , an additional therapeutic modality is needed to treat any and all micro - metastatic tumor that could exist after ruptured hcc .
herein we report on a case of ruptured hcc that was treated with hepatic resection and subsequent chemotherapy , and the patient continues to enjoy her life 7 years after the operation .
a 57-yr - old woman was admitted to our hospital because of sudden - onset abdominal pain . she was a known chronic hbv carrier .
she had no significant medical history such as diabetes , hypertension or tuberculosis ; she did not smoke or drink any alcohol . on admission , she had a blood pressure of 90/60 mmhg , a 105/min pulse rate , a 20/min respiratory rate and a body temperature of 36.3. on physical examination , the patient had an acutely ill looking appearance with abdominal distension and she felt tenderness on the whole abdomen upon palpation .
the laboratory data on admission showed a white blood cell count of 5,800/mm , a hemoglobin level of 10.8 g / dl , a hematocrit of 30.6% and a platelet count of 123,000/mm .
u / l ) , the serum aspartate transaminase ( ast ) was 122 u / l ( normal : 8 - 40
iu / l ) , the total protein 6.5 g / dl , the serum albumin 3.6 g / dl and the alkaline phosphatase 187 u / l ( normal : 100 - 250
the prothrombin time was 100% ( inr , 0.95 ) and the total bilirubin level was 4.8 mg / dl ( direct bilirubin 1.7 mg / dl ) .
she was positive for hbsag , but negative for hbeag , and the hbv dna level was less than 2.5 pg / ml .
the level of alpha - fetoprotein ( afp ) was 62.3 ng / ml ( normal : 0 - 20 ng / ml ) .
the chest x - ray showed elevation of the right hemidiaphragm and abdominal x - ray showed abdominal distension , centralization and floating of bowel loops and widening of the interloopal space , which suggested ascites .
abdominal enhanced computerized tomography ( ct ) scanning showed a large arterial - phase enhancing mass in the left lobe with ascites ( fig .
she was immediately treated with transarterial chemoembolization ( tace ) by a regimen of adriamycin 50 mg and lipiodol 10 ml ( fig .
one month after the hepatic surgery , to prevent recurrence of hcc by micro - metastasis , the patient subsequently received 8 cycles of adjuvant systemic chemotherapy by a regimen of epirubicin ( 50 mg / m ) , cisplatin ( 60 mg / m ) and 5-fluorouracil ( 5-fu , 200 mg / m ) at monthly intervals . after this , patient has been regularly followed up to date and she shows no signs of tumor recurrence 7 years later ( fig .
this case suggests that surgical resection and subsequent adjuvant systemic chemotherapy using an ecf regimen may provide long - term survival for patients with ruptured hcc .
the ruptured hcc is a life threatening condition that may cause severe bleeding , hypotension and hypoperfusion of the liver , especially in cirrhotic patients who have coagulation deficiencies .
therefore , the mortality for this catastrophic event is very high , and early diagnosis of the ruptured hcc is essential to prolong the survival of these patients .
the most characteristic finding of ruptured hcc is reported to be the sudden - onset of abdominal pain and a physician , when observing such symptoms in geographic areas that are endemic for hepatitis viruses , can have a strong suspicion of ruptured hcc .
the mechanism of hcc rupture is poorly understood . however , several factors such as direct trauma , high intraluminal pressure due to rapid growth of tumor , necrosis , rupture by splitting of the normal hepatic parenchyma or erosion of a vessel , occlusion of the hepatic veins by tumor thrombus , and coagulopathy have been accepted as causes . in general , tumors that protrude beyond the original liver contour may rupture more readily than those that are surrounded by normal parenychma .
furthermore , a peripheral location and protrusion of the tumor or discontinuity of the hepatic surface , and poor liver function should be recognized as high risk factors for hcc rupture . however , the tmn stage , the presence of portal vein thrombosis and the size of the tumor seem to be irrelevant to hcc rupture .
rupture of hcc is confirmed by performing abdominal paracentesis , and the fluid shows blood - stained ascites .
however , an imaging study such as ultrasonography or ct can demonstrate the extent of blood loss , the severity of the liver cirrhosis , the location of the tumor and the patency of the portal vein .
the primary purpose of treatment for ruptured hcc is to stabilize the hypovolemic shock that 's due to massive hemorrhage .
next , the treatment of the underlying hcc using various modalities , including hepatic resection or tae , should be considered . yet
the feasibility of performing hepatic resection is dependent on the hepatic reserve and the underlying liver cirrhosis .
previous studies have demonstrated that the resectability rates of ruptured hcc patients ranged from 12.5% to 59.3% .
in addition , the survival rate was greater in the delayed resection group compared to the emergency resection group ( 19 months vs. 12 months , respectively ) .
however , the longest survival in the emergency group was 33 months and this was 27 months in the delayed resection group . in this regard ,
delayed resection seems to improve the short - term survival , but the long - term survival remains questionable . in the present case ,
the patient immediately received tace after the diagnosis of ruptured hcc , and this was followed by left lateral segmentectomy .
although the efficacy of chemotherapy for hcc is still debatable , our previous study showed a significant anti - tumor effect in selected patients with hcc .
based on this result and with the hope of preventing hcc recurrence , we treated the lady with 8 cycles of adjuvant systemic chemotherapy by a regimen of epirubicin , cisplatin and 5-fluorouracil at monthly intervals .
after this , the patient has been regularly followed up to date and she shows no signs of tumor recurrence 7 years later .
few cases have been reported in the medical literature for which the patients lived 7 years or more after experiencing ruptured hcc , such as our patient has done .
the reason why our patient has survived for such a long time without recurrence of hcc may be attributed to the adjuvant chemotherapy we aggressively administered after surgical resection . in addition
, her good liver function and lower viral load may have contributed to the good prognosis .
it is essential that the chosen treatment be tailored to a ruptured hcc patient 's individual needs to prolong the survival time . in summary , performing surgical resection and subsequently adjuvant systemic combination chemotherapy may provide a fighting chance for patients with ruptured hcc to achieve long - term survival .
Output:
| a 57-yr - old woman previously diagnosed with chronic hepatitis b was admitted via the emergency room because she suddenly developed epigastric pain with abdominal distension . on computed tomography ( ct ) ,
a round enhancing mass was found on the left hepatic lobe with ascites in the peritoneal space .
bloody ascites were found upon tapping the ascites , and this led to the diagnosis of ruptured hepatocellular carcinoma ( hcc ) .
the patient was immediately treated with transcatheter arterial chemoembolization ( tace ) including 50 mg of adriamycin and 10 ml of lipiodol , and then we performed left lateral segmentectomy 20 days later . to prevent recurrence of hcc by any micrometastasis , the patient subsequently received 8 cycles of adjuvant systemic chemotherapy ( a regimen of epirubicin ( 50 mg / m2 ) , cisplatin ( 60 mg / m2 ) and 5-fluorouracil ( 200 mg / m2 ) ) at monthly intervals .
after this , the patient has been regularly followed up and she shows no signs of tumor recurrence 7 years later .
this case suggests that surgical resection and subsequent adjuvant systemic chemotherapy with using an ecf regimen may provide long - term survival for patients ruptured hcc . |
PubmedSumm118577 | ***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: s. paucimobilis is a gram - negative , slightly motile , non - fermentative , oxidase positive opportunistic pathogen that rarely causes infections in humans , and forms yellow - pigmented s colony in blood agar 1 .
it was first discovered as an agent in humans in 1977 and named pseudomonas paucimobilis .
varieties of sphingomonas are widely used in biotechnology due to their ability for synthesis and decomposition of macromolecules 3 . in various studies ,
s. paucimobilis has been shown to be a causative agent of infection in immune - compromised patients , and in hospital acquired postoperative endophtalmitis , septic shock , septic arthritis and osteomyelitis 1,4,5 . in this report ,
the first case of s. paucimobilis identified in turkey in a pediatric patient with down syndrome is presented .
a twelve - month - old male patient who was brought to the pediatric outpatient clinic in march 2010 with complaints of high temperature , cough and wheezing was hospitalized with a presumptive diagnosis of pneumonia . since the patient had exhibited stigmas of down syndrome at birth , a cytogenetic examination was conducted and he was diagnosed with 47 xy+21 chromosome and regular type down syndrome .
the echocardiography conducted on the patient revealed enlargement of right heart cavities , secundum atrial septal defect ( asd ) , apical muscular ventricular septal defect ( vsd ) , patent ductus arteriosis and pulmonary hypertension .
after an angiography conducted in october 2009 , it was decided that surgery be performed and asd - vsd primary repair , patent foramen ovale ( pfo ) ligation , and banding of pulmonary artery were performed in november 2009 .
the patient , who was cognitively impaired in terms of neurological development stages and had a history of frequent infections , was hospitalized with the presumptive of bronchopneumonia .
chest x - ray of patient showed infiltration in left apex and by the auscultation bilateral rale and rhonchus were detected .
on the 12th day of the patient 's hospitalization , blood cultures ( bactec , becton dickinson , usa ) were taken .
on the 2nd day of incubation , passages were performed from the bottle where growth was identified to emb and sheep blood agar ( biomerieux , france ) .
yellow - pigmented smooth colonies were seen on the blood agar . in gram staining of these colonies , thin gram
the microorganism was positive for motility test , oxidase reaction , citrate reduction and esculin hydrolysis and negative for urea and nitrate reductions .
the isolate was identified as s.paucimobilis by using vitek 2 ( biomerieux , france ) system .
the microorganism was identified two different times from the the peripheral blood and no central venous catheter .
antibiotic susceptibility test was also performed with vitek 2 ( biomerieux , france ) system and the strain was found to be susceptible to amikasin , gentamicin , levofloxacin , tigecycline , trimethoprim - sulfamethoxazol piperacillin - tazobactam , ampisilin , amoxicilin - clavunate , cefuroxime , cefuroxime - axetil , cefepime , imipenem , meropenem and resistant to ceftriaxone , cefepime cephoxitin and cephtazidim .
a 15-day treatment of intravenous piperacillin - tazobactam ( 150 mg / kg / day ) was initiated .
s. paucimobilis is a yellow - pigmented , aerobic , gram negative bacillus that is motile with polar flagellation , non fermentative and is non spore forming 5 - 8 .
the bacteria is widely found in natural environment , especially in water and soil 3,5,8 . at the same time , it was isolated from respirators , hemodialysis devices , distilled water containers and thermometer props in hospital environments 3,5,8,9 .
s. paucimobilis was shown to be an infective agent in cases of sepsis , peritonitis , catheter - related infections , osteomyelitis , and endophthalmitis 9,10 .
a case of a postoperative endophthalmitis that was caused by sphingomonas paucimobilis was reported by seo et al in 2008 in korea .
this case demonstrates a delayed onset of postoperative endophthalmitis at 3 months after cataract extraction and posterior chamber intraocular lens implantation 1 .
another case report was the 50-year - old male with end - stage renal disease who had been receiving continuous ambulatory peritoneal dialysis for peritonitis from kocaeli , turkey .
a rare case of nosocomial bacteriemia agent in bronchopneumonia patient who had a history hydrocephalus and experienced two ventriculoperitoneal shunt surgery was reported from ankara , turkey in 2008 3 .
reported another case is a patient with acute myeloid leukemia who developed s.paucimobilis bacteriemia complicated by septic shock just before receiving an autologous hematopoietic stem cell transplant at king faisal specialist hospital and research centre in riyadh 5 . a nosocomial outbreak of s.paucimobilis bacteriemia in hemato / oncology unit was also reported in ankara , turkey in 2007 .
. it can be pathogen in immune - suppressed patients such as hematology and oncology patients and in patients with an underlying disease . in our case , too , since the patient suffers from down syndrome and underlying diseases , he is susceptible to infection caused by this microorganism 3 - 6,10,11 . on the basis of the relevant literature we have reviewed
, we can say that this is the first case of s. paucimobilis in a patient with down syndrome in turkey and probably in the world .
there are cases in which this microorganism causes epidemics in hospitals 8 . in such patients ,
the cause usually can not be determined and are considered to have endogenous origin 3 .
however , s.paucimobilis may be found in tap water , distilled water , nebulizer , respirator , dialysis liquids and other equipment in hospitals and lead to nosocomial infection 8 . among these species , there are also microorganisms like s. mucosissima and s. adhesiva which are not very important clinically .
however , the best known and the main pathogen within this genus is s. paucimobilis 5,6 .
s.paucimobilis is rare in comparison to pseudomonas and other related species and has less pathogenic effect .
this situation is accounted for by a lack of lipopolysaccharide in the cell wall and existence of glycosphingolipids instead 1,3 .
, it was found to be susceptible to aminoglycosides , quinolones , trimetoprim - sulfamethoxazoles and cephalosporin apart from cephoxitin and cephtazidime . in conclusion , although s. paucimobilis is a rare hospital infection , it should be kept in mind as a cause , by virtue of the fact that it is a part of the flora in natural environment , especially in patients with immunosuppressive diseases and patients who have other underlying diseases .
since antibiotic susceptibility also exhibits variation , patients should be treated in accordance with the antibiotic susceptibility results .
Output:
| sphingomonas paucimobilis , is a yellow - pigmented , aerobic , non fermentative , gram negative motile bacillus .
s. paucimobilis which is widely found in nature and hospital environments rarely cause serious or life threatening infections . in this report , a case of hospital
acquired bloodstream infection due to s. paucimobilis in a patient with down syndrome who was on treatment for presumed pneumonia is presented.a one year - old child patient who was a known case of down syndrome and had previously experienced cardiac surgery was hospitalized and treated for pneumonia . on the 12th day of hospitalization , blood cultures were taken because of a high body temperature .
one of the blood cultures was positive for gram - negative rods .
after 48 hour of incubation , the sub - cultures on blood agar medium yielded pure growth of a yellow , non - fermentative , gram - negative , rod - shaped bacterium .
the microorganism was positive for oxidase , and esculin hydrolysis , while negative for urea and nitrate reduction , citrate utilisation and motility .
the isolate had been identified as s. paucimobilis by using vitek 2 system .
the antibiotic susceptibility test was also performed with the same system and the strain was found to be susceptible to piperacillin - tazobactam and other antibiotics .
treatment with intravenous piperacilin - tazobactam ( 150 mg / kg / day ) was initiated .
he responded well to the treatment and was discharged after 10 days .
this case is reported to emphasize that s. paucimobilis should be kept in mind as a nosocomial infectious agent in patients with down syndrome and immunosuppressive patients and the infections should be treated according to the sensitivity test results . |
PubmedSumm118578 | ***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: elderly people are vulnerable subgroups in different populations and their health
conditions are a matter of concern . in the state of demographic transition , iranian
population has been changing toward elderly in the two recent decades .
the national census
data in islamic republic of iran showed that about 5.2% of population was at aged 60 years
or older in 1986 while it was increased to 7.3% in 2006 .
elderly age
is a sensitive stage of individual life that influences on physical , emotional ,
psychological and social ability .
the
health related quality of life that convey an overall sense of wellbeing including aspects
of happiness and satisfaction of life all physical , mental , psychological and social
perceptions . through demographic transition ,
increasing the elderly rate is accompanied with tremendous
changes on the rate of non - communicable diseases such as hypertension , diabetes , heart
disease , and cancers . moreover ,
the increasing rate of morbidity can be explained by
changing modern life style and civilization such as consumption of high caloric foods in
particular using fast foods with low physical activities have leaded to epidemic of
overweight and obesity in recent decades in both developed and developing
countries .
these evidences have been documented in different populations . besides the high cost
of management of induced co - morbidity such as diabetes and cardiovascular disease and
cancers , all aspects of health related qol are influenced at 7 and
8 decades of life .
populations living in urban area in the north of iran have experience of changing toward
modern life style in the recent decades .
it has been documented that the rate of obesity and
overweight has been increased significantly .
the consequences were that the rate of metabolic syndrome has increased
dramatically . in particular , it was
more prevalence among female compared to male in age group of 60 - 70 years
. however , the data regarding different subscales
of quality of life and its determinants are sparse in elderly people living in community in
the north of iran .
thus , the objective of this study was to determine the health related
quality of life and the associated socio - demographic characteristics among elderly people
who are community dwelling in the north of iran .
this population based cross - sectional study was conducted with representative samples of
750 elderly people ( 375 men and 375 women ) aged 60 years or older who were dwelling in urban
community of babol , the north of iran , during the 1 of september until the end
of december in 2014 . with presumption of standard deviation of qol scores of 15
, this
allocated sample size estimates the mean scores of qol in each subscales with maximum
marginal errors of 2 in the estimates at 95% confidence level .
we used two stage cluster
sample techniques in subject selection . in the first stage , 25 clusters were selected randomly based on cumulative frequencies of
population size under the coverage of health centers . then around the center of each
cluster , 30 elderly people ( 15 men and 15 women )
subjects
who had sever disability and those with sever dementia who were not able to participate in
the interview were excluded from the study .
the five trained nurses with similar instructions were used to collect the data by
interview .
the demographic data such as age , gender , educational level , occupation , marital
status and living condition were collected by a researcher made questionnaire . for
assessment of health related qol , a standard short form of qol questionnaire ( sf36 )
all interviews were performed in a family health survey at home visit . the validity
and reliability of this questionnaire
this questionnaire measures the health related quality of life in 8
subscales including physical functioning ( 10 items ) , physical role limitations ( 4 items ) ,
emotional role limitations ( 3 items ) , bodily pain ( 3 items ) , social functioning ( 2 items ) ,
vitality ( 4 items ) , mental health ( 5 items ) and general health ( 6 items ) .
the score of each subscale were converted from 0 ( the worst ) to
100 ( the best ) conditions of qol .
the
reliability coefficient as measured by cronbach s alpha was ranged from 0.68 to 0.92 for
subscales of sf36 .
the study protocol was approved by the ethical research committee of
babol university of medical sciences .
22 , 2014 ) data were analyzed by spss software ( version 13.0 ) .
the descriptive statistics of the
score of qol were calculated as mean ( sd ) in different subscales .
the normality of data of
qol was assessed using kolmogorov - smirnov test . in the univariate analysis
the two
independent samples t - test and analysis of variance ( anova model ) were used to compare the
mean score of qol in different subgroups .
we also performed the linear regression model to
quantify the predictive ability of demographic characteristics in the scores of qol in
different subscales . in the multiple regression model ,
the binary variables were defined as
gender ( female versus male ) , age group 70 - 79 vs. 60 - 69 years , aged > = 80 vs. 60 - 69 years ,
educational level of high school or higher vs. < high school , and marital status ( couple
v.s . not ) .
the adjusted regression coefficients and the 95% confidence interval were
estimated . the p - value less than 0.05 was considered as significant level .
the mean age of participants was 68.0 ) 7.6 ( years for men and 67.7 ( 7.9 ) years for
women .
table 1 shows that the distribution of age
group was rather similar ( p=0.681 ) but the distribution of other demographic characteristics
were significant between sexes ( p=0.001 ) .
the mean ( sd ) of scores of various domains of qol
have been presented in table 2 .
the mean scores of
qol in all dimensions in men had significantly higher than women ( p=0.001 ) .
the highest
score of qol was observed for subscales of social functioning and the lowest score in
general health in both genders .
table 3 presents that
the overall health related qol scores were significantly higher in age group of 60 - 69 years
( p=0.001 ) compared to higher age groups and also in higher educational level compared with
lower level or illiterate in both sexes ( p=0.001 ) .
elderly subjects who had partner ( married ) showed significantly higher scores of qol than
others ( p=0.001 ) in either of gender . in addition , among those who live alone a poorer qol
have been observed significantly ( p=0.001 ) .
table 4 shows the adjusted regression coefficients of
demographic characteristics in predicting of different subscale of qol .
male gender versus
female is positively associated with all subscale of qol while age group of 70 - 79 and 80 or
older were inversely associated compared with age of 60 - 69 years .
education level at high
school or higher almost is positively associated but its effect on subscales of emotional
role limitation , social functioning , and bodily pain was not significant ( p<0.05 ) .
regarding to the marital status , being couple is positively associated with the score of
qol in subscales of physical function , social functioning , vitality and mental health . in
addition , the adjusted regression coefficients of all demographic characteristics were
significant on the overall score of health related qol ( table 5 ) .
chi - square test ; statistically significant
two independent sample t - test ; statistically significant
analysis of variance and f test ; statistically significant
p<0.001 ; p<0.05 ; pf : physical functioning ; pr : physical
role limitation ; er : emotional role limitation ; sf : social functioning ; bp : bodily
pain ; vt : vitality ; mh : mental health ; gh : general health , all variables are
coefficients ( 95%ci )
t - test ; statistically significant
according to our findings , the highest mean score of qol was observed in subscale of
social functioning in both sexes and the lowest score was found in the domain of general
health . on overall , the mean score of qol
was slightly higher than median point of
measurement scale studied while the mean score for women are closer to median point of
scale . in all subscale , elderly women had significantly lower score of qol .
elderly people
with low education , older age , being single or living alone had significantly poorer scores
of qol .
the findings of present study revealed that the health related qol of women was
significantly poorer than men with similar mean age in all domains .
this result is in
accordance with those reported in other studies.one possible explanation of
the lower level of qol in elderly women may be related to the higher prevalence of trait of
anxiety and depression symptoms in iranian women .
our results show that women
are more susceptible to physical function disability and physical role limitations which
leads to lower score of subscale of bodily pain .
they are also more vulnerable to emotional
role limitations and they have less social functioning relationship because of the lack of
outdoor activities and lower financial resources .
additional to physical conditions , on overall the higher rate of psychological disorders
have been reported in women compared with men .
this explains that rationale
of lower score of qol in the subscales of mental health and vitality and all resulting the
poorer score of general health among women in our findings .
in contrast , in the elderly people who live in south of iran ( bandar
abbas ) , the score of qol was lower in women only in subscales of physical functioning ,
vitality and general health than not other domains .
the lower score of overall qol in elderly in south of iran compared
with north might be explained by differences in socio - economics status , the life styles and
the living conditions .
the highest score in the domain of social functioning that was observed in present study
may reflect the social cultural position that elderly people possess in islamic culture in
iran . this higher rate of social functioning score may be originated from islamic point of
view that emphasizes on the social interaction with members of family , neighbors and
relatives that considers as social values . based on our findings , older age ( > 80 years and 70 - 79 years ) had significantly lower
qol than age group of 60 - 69 years .
these results are consistent with other studies in
iranian elderly people and asian populations .
aging influences on the lower score of qol because of high rate of
comorbidity due to diabetes , renal failure , heart diseases , stroke and cancers in older age .
these comorbidities are almost more prevalent in 6 and 7 decades
of life in iranian elderly people .
in addition , aging process itself deteriorates
functional disability , mental health and psychological disorders . in present study , a positive association has been observed between educational level and
qol . in particular , elderly people with higher level of education at university level had
significantly better qol than illiterate .
similar results were found in other studies in
elderly . on the other hand ,
the lower
educational level is accompanied with poorer social activities , less vitality and less
self - esteem resulting poor qol .
elderly people with higher education are more aware for preventive measures for chronic
conditions such as diabetes , renal diseases , heart diseases , stroke and cancers and they may
have a positive attitude and their life styles may differ with illiterate elderly people .
this prompts the lower rate of obesity and the corresponding co morbidities that influence
on physical functioning in elderly .
the present study showed that elderly people who live with their husband / wife had a better
score of qol than those who live alone .
obviously , married people enjoy their life more than who are widowed or
divorced in elderly .
the emotional turbulence " that comprises three subthemes including
uncertainty , perceived worries , and living with fears influence on qol .
the implication of our findings is that the
social interaction in the family , particular with spouse increases the degree of happiness
to enjoy their life .
being married makes couple to be happy and to have more relaxation in
their lives and thus it brings more vital energy . on the other hand , loneliness and being
single with no relationship with spouse
thus , it influences on some aspects of qol in
particular , and emotional and psychological domains of health related qol .
hopefully , based
on our culture and religious background , in our study , the majority of elderly subjects were
being married ; only 7.7% of elderly men and 18.5% of elderly women lived alone .
the apparent
findings may originate from the islamic religious orders to the young people that to take
care of their parents in elderly .
this is in contrast with western culture that elderly
people almost live alone or they live in elderly institute / nursing home .
however , the value of take caring elderly people
within families may change toward western culture due to accommodation problems and
modernization of life styles .
the cross sectional nature of study limits any causal
interpretations in apparent association between demographic profiles and qol .
we used
community based and a standard sample procedure in household survey ; thus our samples
excluded those who live in instutionalized nursing home in elderly or hospitalized . however ,
iranians are family centered , and respect elderly people with their families . according to
iranian culture , providing cares to elderly and respecting to them
thus , most iranian are
willing to provide cares of elderly at home and the rates of elderly people who live in
nursing home is almost low .
there is possibility the collected data in different subscales of qol
to be under report or equivalently it may be exaggerated by some other people .
however , such misclassification is almost non differential with respect to
socio - demographic profiles .
the
advantages of our study were that we used a well standard sampling procedure with relative
high sample size and the desired degree of precision . also , we used the trained interviewers
in order to minimize the inter observer variability .
this study indicates that the health related qol is rather poor in particular in women ,
older age , low education level and being single .
the results imply that health policy makers
should consider an urgent health interventional program among elderly people at present
stage of demographic transition with emphasis on high risk demographic profiles .
would like to acknowledge the deputy of research council of babol university of medical
science for their supports and we also thank the nursing students of babol university of
medical sciences for their assistance in data collection .
Output:
| introduction : in the stage of demographic transition , the
rate of elderly is increasing and their health condition is a matter of concern .
thus , the
objective of this study was to investigate the health related quality of life ( qol ) and
the associated socio - demographic determinants among iranian elderly people .
methods : we conducted a cross - sectional study with a
representative samples of 750 elderly people whom community dwelling in urban area of
babol , in the north of iran . in a household survey ,
the demographic data were collected
and the health related qol was assessed with a validated standard short form questionnaire
( sf-36 ) .
the multiple linear regression analysis was performed to determine the
demographic characteristics in predicting qol using spss ver 13 .
results : the overall mean ( sd ) scores of qol was 62.4(17.2 )
for men and 51.2 ( 17.9 ) for women . the mean scores of qol in all dimensions in men had
significantly higher than women . the adjusted regression coefficient of gender , age ,
educational level , being couple were significant on overall scores of qol .
aging is
inversely associated while male gender and education at high school or higher and being
couple are positively associated in prediction of overall scores of qol .
conclusion : the findings indicate that the health related
qol is rather poor in old people particular in women , elderly with low education level and
being single .
therefore , healthcare policy makers should consider an urgent health
interventional program among elderly people at present stage of demographic transition
with emphasis on high risk demographic profiles . |
PubmedSumm118579 | ***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 55-year - old man with hypertension was admitted to a local hospital with a 2-day history of persistent nausea , myalgia , and epigastric pain following vomiting after drinking alcohol .
he had been receiving anticoagulant medication due to thrombosis of the portal vein , superior mesenteric vein , and splenic vein and had a history of admission 3 months prior due to acute pancreatitis .
a chest computed tomographic ( ct ) scan performed 5 days later revealed a suspicious wall defect on the left side of the lower esophagus with an adjacent extraluminal air bubble and a large left pleural effusion .
the patient was transferred to severance hospital 8 days after the onset of symptoms . upon arrival ,
his blood pressure was 148/81 mm hg and his heart rate was 137 bpm , and he had a fever of 38c .
laboratory tests revealed a low hemoglobin level of 9.6 g / dl , a leukocyte count of 18,250/l , an elevated prothrombin time of 19.7 seconds , and an elevated international normalized ratio of 1.72 .
1 ) . he underwent an emergency operation under the suspicion of esophageal rupture . on the operating table ,
upper gastrointestinal endoscopy revealed an ulcerative fistula lesion measuring approximately 2.5 cm at the gastroesophageal junction .
after decontamination with saline irrigation , a 2.5-cm transmural perforation of the esophagus was identified 2 cm above the diaphragm ( fig .
after the defect was debrided , a rubber t - tube ( 16 fr ) , generally used for biliary tree disease , was positioned into the rupture and the esophageal wall was closed with polypropylene sutures ( prolene ; ethicon , somerville , nj , usa ) .
the t - tube was then brought out through the lateral chest wall and connected to a drain .
in addition , a jackson - pratt drain was placed next to the lower esophagus for irrigation .
after surgery , the patient was transferred from the operating room to the intensive care unit .
the total operation time was 220 minutes , and the total anesthesia time was 290 minutes .
on postoperative day ( pod ) 1 , the patient was weaned from a mechanical ventilator and transferred to the general ward on pod 8 .
he was discharged on pod 41 with a t - tube and a jackson - pratt drainage in good general condition . after confirming the absence of discharge through the jackson - pratt drain on pod 68 , the t - tube
was gradually withdrawn every week and finally removed on pod 98 in an outpatient clinic ( fig .
an esophagogram on pod 94 showed no leakage but a slightly stenotic appearance ( fig .
, he restarted an oral diet , and the feeding jejunostomy was removed on pod 129 at an outpatient clinic .
prompt decision - making in the management of boerhaave syndrome is crucial because it is a life - threatening condition characterized by the disruption of the distal esophagus due to a barotrauma , resulting in the contamination of the mediastinum and pleural cavity with gastric contents .
left untreated , the mortality rate exceeds 90% , and has been reported to be as high as 40% even after appropriate surgical intervention .
patients with boerhaave syndrome complain of a tearing substernal or epigastric pain , which may radiate to the left chest , shoulder , or back . however , some patients present with atypical symptoms such as shock or respiratory distress , and physical exam findings are often non - specific .
unfortunately , the condition is often misdiagnosed as a perforated peptic ulcer or pancreatitis , which can lead to a delay in receiving appropriate treatment .
further evaluation with a chest x - ray , contrast - enhanced ct scan , or gastrointestinal endoscopy should be performed in any patient suspected to have boerhaave syndrome .
it is clear that primary surgical repair within 24 hours of spontaneous esophageal perforation reduces mortality .
some authors have reported that good outcomes can be obtained with surgical repair , even after 24 hours [ 5 ] . however , delayed management of boerhaave syndrome is clearly associated with an increased risk of mortality .
compared t - tube repair and primary repair for the management of boerhaave syndrome and found no difference between the 2 treatment strategies , even though the time from symptom onset to surgery was longer for t - tube repair . in our case ,
surgical management was performed 8 days after symptom onset and the mucosa appeared too friable to hold sutures .
for that reason , we inserted a t - tube and closed the esophagus wall around it for the purpose of controlling salivary drainage , with the hope that the patient could be managed successfully .
in addition to surgical drainage and debridement , adequate postoperative nutritional support is important for the management of boerhaave syndrome . in this case ,
previously , open thoracotomy was considered the only option for the surgical management of boerhaave syndrome .
however , recent advances and experiences in vats has led to vats being used to treat boerhaave syndrome .
specifically , haveman et al . showed that vats can be used as the first choice for boerhaave syndrome .
indeed , vats is a safe procedure associated with a lower rate of complications and similar results in comparison with open surgery . in the present case , we performed vats to minimize additional surgical trauma for an already critically ill patient . in conclusion , by inserting a t - tube into the ruptured esophagus , we successfully managed a late - diagnosed case of boerhaave syndrome .
Output:
| spontaneous perforation of the esophagus after forceful vomiting is known as boerhaave syndrome , a rare and life - threatening condition associated with a high rate of mortality .
the management of boerhaave syndrome is challenging , especially when diagnosed late .
herein , we report the successful management of late - diagnosed boerhaave syndrome with t - tube drainage in a 55-year - old man .
the patient was transferred to our institution 8 days after the onset of symptoms , successfully managed by placing a t - tube , and was discharged on postoperative day 46 without complications . |
PubmedSumm118580 | ***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: maturity onset diabetes of the young ( mody ) is a monogenic form of diabetes characterized by absence of ketosis , autosomal dominant inheritance , primary defect in pancreatic beta - cell function , and onset before the age of 25.1,2 mody type 3 is the most common form and is caused by mutations in the hnf4a gene.1 mody type 1 is caused by mutations in the related hnf1a gene.1 mody type 2 is also common and is caused by a mutation in the glucokinase ( gck ) gene , leading to hyperglycemia , which is usually treated with diet alone.1 mody type 5 is caused by mutations in the hnf1b gene and is associated with diabetes mellitus and pancreatic atrophy with renal and genital defects.1 mody type 4 is caused by mutations in the pdx1 gene , which encodes the insulin promoter factor-1 ( ipf1 ) , a homeodomain - containing transcription factor.3 it is a rare form of mody , with collective literature stemming from a few families known with this gene mutation.3,4 management of mody4 in a nonobese adult has not been previously described , and the particular genetic mutation in this case report appears novel .
this case offers insight into a rare disease entity with few case reports and very little known therapeutics .
while mody4 itself is a rare disease entity , our mody4 patient is particularly unique in that he displays a novel pdx1 mutation not cited in previous literature , does not display obesity typically seen in mody4 , presented at an earlier age with diabetes than typical mody4 cases , and required treatment for diabetes at the time of diagnosis .
our case report is also particularly significant in that the therapeutics prescribed herein were based on the genetic mutations inherent in this rare form of diabetes ; which has not been previously postulated in other case reports of mody4 . as this patient responded favor - ably to a therapeutic regimen based on this particular genetic mutation
, this case proposes a therapeutic modality for a disease that has minimal recommended therapeutics .
a 26-year - old nonobese ( bmi 23 kg / m ) male presented with symptoms of polyuria , fatigue , and visual changes over several months .
in addition to his antihypertensive medications ( lisinopril and metoprolol ) , he was taking multivitamin and loratadine pseudophedrine ( prn ) on a daily basis .
basic metabolic profile showed nonfasting glucose of 511 mg / dl , c - peptide of 1.6 ng / ml ( 1.07.6 ng / ml ) , hba1c of 9.3% , negative urine ketones , and negative screening antibodies ( islet cell and glutamic acid decarboxylase antibodies ) .
family history revealed a paternal uncle diagnosed with diabetes in his 20s who died of a diabetic coma in his 40s as well as multiple obese relatives in the patient s paternal grandmother s family with type 2 diabetes .
the patient s father has had episodic hyperglycemia although does not carry a diagnosis of diabetes .
the patient was started on metformin and pioglitazone with improvement in his glycemic control after one month of therapy with twice daily blood sugar readings ranging between 120 mg / dl and 220 mg / dl .
given the patient s age , habitus , and presentation , there was high suspicion of mody as the underlying etiology for his diabetes ; however , genetic testing took several months for insurance approval .
after optimizing metformin and pioglitazone , his a1c improved rapidly to 5.9% within 3 months of therapy and the patient decided to follow up with his primary care physician for further management .
however , the patient eventually became intolerant to metformin because of nausea and diarrhea and was switched to glyburide 5 mg while continuing pioglitazone by his primary physician .
it is unclear as to when he developed the intolerance to metformin as this was noted by his primary care physician outside of our hospital system .
this new regimen led to worsened glycemic control , with blood sugars ranging between 200 mg / dl and 300 mg / dl .
once authorized , genetic testing was undertaken and showed a heterozygous mutation in the pdx1 gene ( c.694_697delggcginsagct p.gly232serfsx2 ) , consistent with mody type 4 .
this mutation caused a deletion of four nucleotides and insertion of four different nucleotides , causing the wildtype glycine to be substituted by serine at position 232 and introducing a novel stop codon at position 233 ( fig .
1).5 given this subtype of mody with its potential to impair incretin pathway,6 as well as the patient s desire to avoid injectable therapy , the patient was recommended to start 100 mg sitagliptin , discontinue the sulfonylurea , and continue the thiazolidinedione .
following initiation of sitagliptin , the patient had significantly improved glycemic control , particularly with improved postprandial blood sugar readings .
the patient reported frequent postprandial blood glucoses well into the 300s prior to the initiation of sitagliptin ( approximate a1c 1011% ) , which improved to postprandial glucoses in the 150180 mg / dl range , within a month of sitagliptin initiation .
the patient has remained on sitagliptin since its initiation and has had no side effects on therapy . despite the improvement in postprandial hyperglycemia , the patient s fasting glucoses eventually began to rise ( three months after sitagliptin and pioglitazone combination ) , necessitating initiation of basal insulin with 10 units of glargine each morning .
we had anticipated that the sitagliptin would have had more of an effect on fasting glucose as well , but considering that direct transcription of insulin was likely impaired by ipf1 dysfunction,7 it was decided that basal insulin glargine would be optimal for maintenance of euglycemia .
owing to the rarity of mody4 , a significant portion of medical knowledge of its diagnostics and therapeutics reside in several large kindreds .
both obese and nonobese patients with mody4 have been described at a variety of ages .
the relatively small number of patients who have been fully characterized does not allow the authors to definitively describe phenotype of age and body habitus in this condition .
two families have been reported to have similar pdx1 mutations involving deletion of a single nucleotide causing frameshift and downstream truncation ( pro63fsx60 ; c.188delc).3,4 one of the familial cohorts with mody4 showed obesity , which was not observed in the other family of mody4 patients.4 another pdx1 mutation ( p.pro33thr;c.97c>a ) has also been isolated in an italian family with predominance of type 2 dm , mody4 , or gestational diabetes mellitus.8 there is a paucity of literature concerning the correlation of therapeutics with mody4 , though unspecified oral hypoglycemic agents and insulin have both been cited.4 our mody4 patient is unique in that he displays a novel pdx1 mutation , does not display obesity , presented at an early age with diabetes , and required treatment for diabetes .
mutations in the pdx1 gene cause impaired ipf1 protein function with resultant globally impaired insulin production due to direct effects on gene transcription.7 the ipf1 protein plays a central role in pancreatic development and beta - cell function and interacts with multiple genes as a transcriptional activator binding to the promoter region of genes encoding glucokinase , islet amyloid polypeptide , and glucose transporter.9 the indirect effects of ipf1 appear to be crucial for glucose - stimulated insulin release , which appears to have major implications for postprandial hyperglycemia that our patient experienced.6 importantly , the incretin pathway appears to be indirectly impaired in pdx1 mutations ( fig .
2 ) . pdx has a direct activating effect on the transcription of insulin by binding to at - rich regions , which are located upstream of the insulin and somatostatin genes.7 interestingly , ipf1 also appears to exert indirect influence on insulin secretion through other pathways .
the fgfr1 pathway in beta islet cells is important for proper sensing of blood glucose level and would appear to be important in maintenance of postprandial glucose levels .
ipf1 is required for maintenance of this pathway as an upstream regulator.10 most importantly , it has also been shown that ipf1 also exerts indirect control over insulin secretion by binding to an enhancer site of the g - protein - coupled protein gpr40 .
gpr40 itself responds to the presence of free fatty acids and contributes to insulin secretion after glucose load both directly and indirectly through the mediation of incretin hormones glucagon - like peptide-1 ( glp-1 ) and glucose - dependent insulinotropic polypeptide ( gip).6 incretin hormones are important regulators of postprandial glucose homeostasis as they increase insulin secretion and reduce glucagon secretion.11 pharmacologic incretin therapy could be initiated through one of two methods : either directly through synthetic analogs such as glp-1 via injection or through inhibition of endogenous dpp4 through dpp4 inhibitors .
while either therapy might be efficacious for this genetic mutation pathway , glp-1 therapy usually involves less desirable side effects such as nausea , vomiting , and is available only via injectable therapy .
dpp4 inhibitors on the other hand are given via oral administration and do not have side effects of nausea , vomiting , and potential weight loss .
owing to the identification of this mutation and what we know from literature , we initiated a dpp4-inhibitor .
we did not assess the glp-1/gip levels , before or after treatment , as it is not part of routine management of patients with diabetes .
glp-1r signaling has been shown to modulate the endoplasmic reticulum ( er ) stress response , which can promote beta - cell adaptation and survival .
since dpp4 inhibition increase glp-1 levels , it is likely that modulation of er stress response played a role in this patient s therapeutic response to dpp4 inhibition.12 the rapid worsening of glycemic control in this patient , eventually requiring insulin therapy , was a puzzling phenomenon .
sulfonylureas have the potential to induce beta - cell apoptosis.13 this , along with the potential of this patient s mutation to affect pancreatic development , may provide some explanation to the rapid worsening of glycemic control in this patient . in conclusion , patients with mody often present differently than patients with type 2 diabetes , have unique genetic mutations causative for their diabetes , and respond differently to treatment .
understanding the biochemical pathways inherent in various mutations of mody is crucial for its optimal treatment . in this patient , we hypothesized a treatment protocol of sitagliptin , which was suggested by the patient s molecular mutation with its defect in the incretin pathway .
dipeptidyl peptidase-4 inhibitors as a class of antihyperglycemics have not previously been recommended as a therapeutic agent in other literature sources about mody4 .
this therapy resulted in significant improvement in glycemic control and may be a source of recommended therapeutics for other patients with mody4 .
Output:
| maturity onset diabetes of the young ( mody ) is a rare form of diabetes mellitus typically seen in young adults that results from pancreatic beta - cell dysfunction .
mody4 is a rare subtype caused by a pdx1 mutation . in this case , we present a nonobese 26-year - old male with polyuria and polydipsia .
lab work showed a blood glucose of 511 mg / dl , no ketones or antibodies ( insulin , islet cell , and glutamic acid decarboxylase [ gad ] ) , c - peptide of 1.6 ng / ml , and a1c 9.3% .
genetic analysis revealed a novel nonsense mutation in the pdx1 gene , consistent with mody type 4 . given this patient s particular genetic mutation affecting the incretin pathway , sitagliptin was substituted for glyburide , which led to significant improvement in glycemic control .
our case report identifies a unique mutation in a rare form of mody and outlines management of ensuing diabetes through targeting its inherent genetic mutation . |
PubmedSumm118581 | ***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: henoch - schnlein purpura ( hsp ) is the most common vasculitis in children with an incidence of approximately 10 per 100,000 children per year and is slightly common among boys ( 60% ) than girls ( 40% ) .
the diagnosis is based on the palpable purpura in the presence of one of either diffuse abdominal pain , a biopsy showing predominant immunoglobulin a ( iga ) deposition , arthritis , or arthralgia and/or renal involvement ( hematuria and/or proteinuria ) .
typically , patient is a young child presenting with clinical manifestations including palpable purpura , arthritis , abdominal pain and gastrointestinal bleeding .
the etiology of hsp is mainly unknown and antecedent upper respiratory tract infection , usually viral , has been reported and streptococcal infection has been emphasized as an important triggering factor .
also it is known that iga plays an important role in the pathogenesis of the disease .
most cases are self - limiting and require no treatment apart from symptomatic relief , but recurrence of symptoms occurs in about 33% of the cases .
it seems that relapse often occurs between two weeks and 18 months after initial resolution of symptoms and children with kidney involvement are more likely to have recurrences . in some patients , nephritis occurs due to iga deposition in the renal mesangium .
more serious complications such as the involvement of central nervous system , renal failure , and intussusception may also occur .
there is no consensus on the optimal treatment in the case of significant renal or other organs involvement where treatment may have a significant impact on the long - term outcome .
the routine use of corticosteroids in hsp is controversial . in a randomized placebo controlled study of oral prednisolone ,
further , there was no significant difference in the development of gastrointestinal complications the exception was the development of two intussusceptions in the placebo group and none in the steroid group . on the contrary ,
some retrospective studies and case reports have suggested a benefit of steroids such as prednisolone in the treatment of abdominal pain [ 6 , 7 ] , hsp nephritis , and as prophylaxis for nephropathy [ 8 , 9 ] .
hsp nephritis accounts for 1.83% of children with chronic kidney disease and the presence of nephrotic / nephritic syndrome has been associated with a poor prognosis .
long - term renal impairment occurs in 19.5% of those with a history of nephritic or nephrotic syndrome which may imply a necessity for a more aggressive treatment to improve the outcome .
mycophenolate mofetil ( mmf ) , an immunosuppressive agent , has been widely used in the organ transplantation including pediatric renal transplantation .
mmf also appears to be a promising therapeutic agent in many autoimmune diseases such as lupus nephritis and in iga nephropathy which is a form of primary glomerulonephritis .
hitherto , the available evidence to support the use of mmf in hsp is limited to some case study reports . in this case
series study , we report the benefit effect of mmf in the treatment of some complicated hsp cases .
the study subjects include six patients admitted into pediatric nephrology ward in a public hospital in urmia - iran .
the patients were admitted with the diagnosis of hsp from march 2007 through march 2008 .
all the patients had been administrated steroid initially to control their complications including severe abdominal pain , gastrointestinal bleeding , and severe nephritis .
subsequently , medication changed to mmf regarding the following criteria ( 1 ) unresponsive to steroid , ( 2 ) steroid side effects , and ( 3 ) steroid dependency ( two times of relapse during steroid tapering ) .
a 6-year - old boy referred to our hospital with the exacerbation of hsp symptoms including typical diffuse palpable purpuric and hemorrhagic lesions , abdominal pain , and arthritis .
the patient had moon face , body weight gain , relapse of gastrointestinal bleeding , and severe abdominal pain despite taking prednisolone for eight weeks ( 2 mg / kg / day for the first four weeks and 2 mg / kg / every other day for the last four weeks ) .
antistreptolysin - o ( aso ) titer was 250 todd , c reactive protein ( crp ) was qualitatively positive ( + 2 ) , erythrocyte sedimentation rate ( esr ) was 55 mm / h , and antineutrophil cytoplasmic antibody ( anca ) as well as antinuclear antibodies ( anas ) yielded negative results .
we tapered off the prednisolone gradually and switched to mmf 30 mg / kg / day .
the gastrointestinal bleeding stopped during the first 48 hours of treatment and all symptoms and cutaneous manifestations resolved during the first week .
a 21-month - old boy presented with typical diffuse palpable purpuric and hemorrhagic lesions , hematuria , gastrointestinal bleeding , abdominal pain , and arthralgia . abdominal ct scan and sonography were normal .
aso titer was 166 todd , crp was + 1 , and esr was 61 mm / h . despite treatment with prednisolone for two months ( 2 mg / kg / day for the first month and 2 mg / kg / every other day for the second month ) , there was no lasting improvement in hsp symptoms ( abdominal pain , arthralgia , purpuric and hemorrhagic lesions ) .
steroid therapy changed to mmf 30 mg / kg / day . abdominal pain and gastrointestinal bleeding resolved in one week .
treatment with mmf was continued for the next two weeks and then tapered off in the next month .
a 2-year - old boy presented with typical diffuse palpable purpuric and hemorrhagic lesions , ankle and elbow arthritis , hematuria , gastrointestinal bleeding , and abdominal pain .
abnormal laboratory tests were crp = + 3 , esr = 42 mm / h . abdominal sonography and other laboratory tests were normal .
the patient was under steroid therapy for eight weeks ( 2 mg / kg / day ) and he had moon face and body weight gain .
with tapering steroid , exacerbation and recurrence occurred for three times ( steroid dependency ) .
mmf 30 mg / kg / day was administered and tapering of steroid commenced and discontinued after three weeks .
all the clinical manifestations resolved in one month of the treatment and mmf was tapered during the next month .
the patient had palpable purpura , gastrointestinal bleeding , abdominal pain , and arthralgia in spite of taking prednisolone ( 2 mg / kg / day ) for weeks .
abnormal laboratory tests were aso = 333 todd , crp = + 1 , esr = 29 mm / h . abdominal sonography and other laboratory tests were normal .
we administered mmf 30 mg / kg / day while tapering steroid therapy gradually .
a 7-year - old girl referred to our hospital due to developing nephrotic level of proteinuria ( above 2 gr / day ) and microscopic hematuria following steroid tapering . before admission to our hospital , the patient had diffuse palpable purpuric and hemorrhagic lesions , arthritis , generalize edema , microscopic hematuria , gastrointestinal bleeding , and severe abdominal pain . at the beginning of the disease , methylprednisolone pulse ( 20 mg / kg / day )
had been started intravenously for three times ( every other day ) and continued with oral prednisolone 2 mg / kg / day for the first month and 2 mg / kg / every other day for the second month .
abnormal laboratory findings were crp = + 3 , esr = 74 mm / h ; see table 2 .
other laboratory tests including serum lipids , serum albumin , aso , anca , ana , c3 , c4 , bun , and scr were normal .
due to continuing significant proteinuria ( above 2 gr / day ) and microscopic hematuria , renal biopsy was performed and showed diffuse mesangial cell proliferation ( light microscope ) and predominant deposition of iga in mesangial matrix and basement membrane of glomerulus ( immunofluorescence microscope ) .
after admission of the patient to our hospital , treatment with mmf 30 mg / kg / day commenced and the oral prednisolone ( 2 mg / kg / every other day ) which had been started since 2 months ago was discontinued .
after treatment with mmf for two months , proteinuria diminished from 2 gr / day to 130 mg / day , but microscopic hematuria continued .
after six months , mmf was discontinued and after a six - month follow - up there was not any clinical and laboratory abnormality except mild microscopic hematuria .
an 18-month - old boy referred to us due to steroid dependency and frequent recurrences while taping steroid .
the patient presented with diffuse purpuric lesions , gastrointestinal bleeding , severe abdominal pain , and microscopic hematuria in spite of taking prednisolone ( 2 mg / kg / day for four weeks and 2 mg / kg / every other day for six weeks ) .
the patient was readmitted again to hospital with gastrointestinal bleeding and arthritis for fourth times .
after admission of the patient to our hospital , mmf 30 mg / kg / day commenced and steroid was tapered off gradually .
all clinical manifestations resolved within one week and hematuria improved after one month of the treatment with mmf .
mmf gains increasing popularity in the treatment of autoimmune disorders such as lupus nephritis , vasculitis , necrotizing glomerulonephritis , corticosteroid resistant glomerulonephritis , and iga nephropathy [ 12 , 13 , 15 ] .
it has been shown that mmf suppresses lymphocyte proliferation and decreases antibody production in the kidney diseases .
recent studies suggest that mycophenolatic acid ( mpa ) , the active metabolite of mmf , can significantly inhibit the adhesion of leukocytes to endothelial cells , which is a key process in the development of anca - associated vasculitis .
hu et al . found that mmf was effective in controlling disease activity and improving renal function in chinese patients with mpo - anca - associated vasculitis . in another report
, a patient with adult crescentic progressive glomerulonephritis in whom long - term complete remission was achieved after mmf therapy was discussed by dede . a case of hsp that manifested after
the clinical manifestations including terminal ileitis and rapidly progressive glomerulonephritis were initially unresponsive to intravenous pulse steroids , whereas , his renal function recovered after treatment with mmf . in a study ,
the clinical courses of six patients ( four boys and two girls with mean age of 13.2 years ) with hsp and nephrotic syndrome were reviewed . in this study ,
the treatment protocols included oral prednisolone , and in the nonresponders included cyclosporine a , cyclophosphamide , mmf , or tacrolimus ; see table 3 . they suggested that an early aggressive immunosuppressive approach improves long - term renal outcome in hsp patients with nephrotic syndrome .
filler et al . described the pharmacokinetics of mmf in 15 pediatric patients with vasculitis and connective tissue diseases involving the kidney .
there were few side effects including diarrhea and leukocytopenia in one case and viral infections in two cases .
they conclude that mmf at 900 mg / m per day appears to be effective in these patients . in our case
series study , we report six cases with hsp in whom steroid therapy failed to treat complications and keep in persistent remission so , medication switched to mmf ( table 1 ) .
all patients were closely followed up at least for six months for any complaint , symptoms , and signs of hsp such as palpable purpura , and arthritis .
blood pressure , serum creatinine level , complete blood count , platelet count , hematocrit , urine analysis , urine protein measurement , and side effects of mmf have been checked in the patients . in our study , mmf was found to be a useful immunosuppressant due to its fewer undesirable effects and good treatment effects for control of complication and relapse of hsp .
there was not any significant side effect , except mild anemia in the case 2 ( not required any intervention ) and mild diarrhea in the case 3 which relived by changing mfm to four divided doses .
hsp manifestations disappeared mainly during the first week of treatment with mmf . with the exception of one patient with persistent hematuria for a long time , all the patients achieved complete remission at the end and after discontinuation of the therapy . in our experience
there is some evidence to support steroid therapy in the treatment of severe abdominal pain , gastrointestinal bleeding , severe nephritis , and central nervous system involvement .
however , as seen in our patients , frequent relapses , lack of response to steroid , steroid dependency , and steroid side effects have been reported [ 14 , 15 ] . in literature the other treatment choices in complicated and sever hsp patients varied from combined heavy immunosuppressant ( cyclosporine , cyclophosphmide ) therapy to plasmapheresis .
so , we considered a more specific alternative to steroid therapy for hsp patients .
on the other hand , considering favorable experiences with mmf such as less adverse effects than other immunosuppressive drugs , benefit effects in the treatment of many immunologically mediated renal diseases , and the antifibrotic and antiproliferative effects of it [ 22 , 23 ] , it is suggested that mmf can be especially valuable in the treatment of the complicated hsp . according to this case series study , mmf can be a safe and effective medication in the treatment of the complicated hsp .
so , therapy could be changed to mmf considering the following criteria : unresponsive to steroid , steroid side effects , and steroid dependency ( two relapses during steroid tapering ) . however , there are some important factors that may influence the results of our study including the possibility of spontaneous improvement of hsp without intervention , therapeutic effects of antecedent steroid before starting mmf .
it is important to point out that we do not claim mmf works in all patients and some patients with hsp may fail mmf and may require more aggressive treatment .
so , more controlled prospective studies are necessary to prove the efficacy of this medication in the hsp treatment .
the results of this case series study suggest that mycophenolate mofetil would be a promising therapeutic alternative in the treatment of the complicated hsp .
however , multicentre clinical trials with long - term followup will be necessary to confirm effectiveness of mmf in the treatment of the complicated hsp patients .
Output:
| background .
henoch - schnlein purpura ( hsp ) is the most common childhood vasculitis with an incidence of approximately 10 per 100 000 children .
there is some evidence to support steroid therapy in the treatment of severe abdominal pain , severe nephritis , and central nervous system involvement .
however , the routine use of corticosteroids is controversial .
frequent relapses , lack of response to steroid , steroid dependency , and steroid side effects may occur in some patients .
mycophenolate mofetil ( mmf ) gains increasing popularity in the treatment of autoimmune disorders , but hitherto , the available evidence to support the use of mmf in hsp is limited to some case study reports .
case presentation .
we report six children with hsp who failed to respond to systemic steroid therapy , whereas mmf successfully treated the manifestations of the disease .
conclusion .
the manifestations of hsp disappeared mainly during the first week of treatment with mmf and all the patients were in a complete remission at the end and after discontinuation of the therapy . in our experience , mmf appeared to be safe and effective for the maintenance of remission in the hsp patients . |
PubmedSumm118582 | ***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: because of the emergence and spread of
multidrug resistant microorganisms and pathogenic bacterial infections ,
novel chemotype antibacterial agents demonstrating distinct modes
of action from existing antibiotics are urgently needed .
natural products
are known as rich sources of bioactive molecules and chemical diversity
and have thus provided invaluable chemical scaffolds as well as served
as an inspiration toward antibacterial drug discovery and development . in this context ,
synthesis and evaluation of natural - product - inspired
compound libraries represent an attractive approach for discovering
novel antibacterial agents .
flavonoids
are a large family of polyphenolic phytochemicals , which widely exist
in the plant kingdom . as such ,
flavonoids
have been the focus of numerous basic biomedical research as well
as clinical investigation . as examples ,
high dietary
intake of flavonoids may offer potential to reduce the risk of various
cancers according to a number of epidemiological studies .
in addition , flavonoids have been reported to display a broad spectrum
of pharmacological activities , such as antimicrobial , anti - inflammatory , cancer preventive and anticancer , and antioxidant activities .
it is also noteworthy that some widely investigated flavonoids ,
such as flavone acetic acid ( faa ) , flavopiridol , silibinin ( silybin ) , and quercetin and its derivatives ( figure 1 ) , have progressed to various stages of clinical
trials . in this
regard , plant - derived
phytochemicals including chemically modified flavonoids and derivatives
continue to attract great interest in the development of novel antibiotics .
skeleton structures of chalcones , 4-chromanones , and representative
structures of naturally occurring flavonoids including abyssinone
ii and olympicin a. furthermore , chalcones
( 1,3-diaryl-2-propen-1-ones ) , one subclass of structural analogues
of flavonoids , have been reported to exhibit diverse biological activities , in which the enone functional group and the 2-hydroxy group
constitute important structural motifs for antibiotic activity . from
a chemistry point of view , chalcones and 4-chromanones are structurally
related , and 2-hydroxychalcones serve as important synthetic
precursors for the synthesis of 4-chromanones following an intramolecular
conjugate addition of the phenol on the ,-unsaturated
system .
notably , the 4-chromanone derivatives
containing an aromatic substituent at the 2-position , so - called flavanones ,
have been identified as an important class of bioactive heterocycles . as a result of our longstanding interest in developing
natural - product - inspired
new antibacterial agents , we recently reported the identification
of abyssinone ii as a promising antibacterial lead by screening a
focused flavonoid and resveratrol library .
in addition , olympicin a , a member of the natural acylphloroglucinol
chemical class , was recently isolated from the plant hypericum
olympicum and reported to exhibit potent antibacterial activity
against a panel of multidrug - resistant ( mdr ) strains of clinically
relevant staphylococcus aureus , with minimum inhibitory
concentration ( mic ) values ranging from 0.5 to 1 g / ml . very recently , we have shown that synthetic olympicin a also exhibited
good activity against clostridium difficile ( mic
= 12 g / ml ) .
inspired by
the antibacterial activity of the natural products abyssinone ii and
olympicin a , in this work we employed the 4-chromanone and chalcone
structural scaffolds as chemical starting points to design and synthesize
chemically modified flavonoid analogues .
subsequently , several series
of structurally related flavonoids were synthesized and evaluated
in vitro against a broad set of bacterial pathogens and a detailed
structure activity relationship ( sar ) has been obtained . furthermore ,
the antibacterial basis of promising lead compounds and their ability
to inhibit bacterial topoisomerases such as dna gyrase or topo iv
have also been examined .
the isolation and chemical synthesis of
olympicin a ( 2a ) was originally reported by shiu et al . ,
and its synthesis involved a four - step reaction sequence .
however ,
the overall yield was only 3.3% from 1a . to improve the reaction efficiency and develop a modular
synthesis toward olympicin a and derivatives
, we evaluated diverse
protecting schemes including the tert - butyldimethylsilyl
( tbdms ) , the base - stable methoxymethyl ( mom ) , and the p - toluenesulfonyl ( ts ) groups and developed an improved synthesis
of 2a by using the ts protecting strategy , improving
the overall yield to 40% from 1a ( scheme 1 ) .
in particular , we found that the reported low yield may
be largely due to the instability of the tbdms protecting group under
basic reaction conditions ( k2co3 , 80 c )
when introducing the geranyl group . to address this ,
the base - stable
mom group was next applied instead of tbdms . following the o - geranylation
reaction ,
it was found that 2a decomposed during the
deprotection of the mom groups because of the instability of o - geranyl group under the acidic condition , and the deprotected 1a was recovered from the reaction .
subsequently the ts group
was used to protect the hydroxy group , and only the tris(tosylate ) 1b was obtained as the
major product because of the lack of selectivity of the ts group under
the reaction condition .
nevertheless , we found that the tosylate group
at the 2-position of 1b was very labile , and the geranyl
group could be selectively introduced with sodium hydride as the base .
final removal of the ts group was performed with excess sodium methoxide
in methanol under reflux to afford the
chiral olympicin a ( 2a ) .
the spectroscopic data of our
synthetic olympicin a were in good agreement with those of the natural
product .
for comparison , the racemic
olympicin a ( 2b ) was also synthesized under the same
conditions to study the potential effect of stereochemistry on antibacterial
property .
reagents and conditions : ( i ) socl2 , 80 c , 2 h ; ( ii ) alcl3 , cs2 ,
phno2 , 0.5 h ; ( iii ) tscl , k2co3 ,
acetone , 1 h , 73% ; ( iv ) geranyl bromide , nah , dmf , 1 h ; ( v ) ch3ona , meoh , reflux , 8 h , 55% ( two - step overall yield ) ; 52%
for 2b ( two - step overall yield ) .
next , to further expand the chemical diversity and investigate the
influence of 2-substitution on antibacterial activity in the scaffold ,
an array of racemic olympicin derivatives ( 2c e ) and enantiomeric form 2f were designed and
synthesized ( scheme 2 ) . compounds 1a and 1a were first protected by reacting with momcl
in the presence of diisopropylethylamine ( dipea ) to provide 1c and 1c in moderate yields .
the o - alkylation
reaction was subsequently carried out with appropriate alkyl bromide
using sodium hydride as a base , after which the mom groups were removed
with hydrochloric acid to give 2c f in moderate to high yields ( 6693% ) .
reagents and conditions : ( i ) momcl ,
dipea , dcm , 1 h ; ( ii ) r - br , nah , dmf ; ( iii ) hcl , meoh , overnight .
4-chromanone derivatives bearing an aryl substituent
in the 2-position are normally synthesized by reacting an acetophenone
with an arylaldehyde under strong basic or acidic conditions . however , because of the side reaction of self - condensation of the
aliphatic aldehyde , these conditions
are not ideal for the synthesis of 2-alkyl substituted 4-chromanones .
several different synthetic methods to prepare such 4-chromanone derivatives
have been reported , either involving microwave irradiation or requiring
very long reaction times . here , a sealed pressure tube was introduced
as a reaction vessel for the preparation of 2-alkyl substituted 4-chromanones .
on the basis of the scaffold , several modification strategies ( figure 2 )
modifications based on the 4-chromanone scaffold . as shown in scheme 3 , a series of 2-alkyl-4-chromanone derivatives 3a f were synthesized by reacting 2,4-dihydroxyacetophenone
( 1d ) with an appropriate aliphatic aldehyde in the presence
of pyrrolidine in ethanol .
this reaction was performed in a sealed
pressure tube at 150 c for 1 h , obtaining yields over 30% .
in contrast , a lower
yield ( 12% ) was afforded despite a longer reaction time ( 72 h ) for
the synthesis of 3b under the conditions ( ethanol , 60
c , pyrrolidine ) . to optimize the reaction conditions , a panel
of different amine bases was screened .
we noted that under the same
conditions , no product was detected using dipea and only traces of
product were formed when using morpholine as a base monitored by hplc ,
respectively .
to investigate the potential effects of the 4-carbonyl
group as a hydrogen bond acceptor , the 4-chromanones 3a d were further reduced by nabh4 in
methanol to provide 4-chromanol derivatives 4a d in moderate to good yields ( 6481% ) .
reagents and conditions : ( i ) pyrrolidine ,
etoh , 150 c , pressure tube , 1 h ; ( ii ) nabh4 , meoh ,
rt , 24 h. accordingly , when the bicyclic ( )-myrtenal
( 1f ) was used as the substrate under these reaction conditions
( scheme 3 , step i ) , no product was obtained .
subsequently , a lower temperature ( 75 c ) was applied ( scheme 4 ) to optimize the reaction conditions .
the corresponding
chalcone intermediate 3 g was obtained in low yield ( 9.5% ) .
to improve the reaction yield ,
1d was first regioselectively
protected by reacting with momcl in the presence of dipea to provide
the mom - protected acetophenone 1e in 86% yield .
again ,
when the reaction was performed at 150 c , only traces of 3h were detected by hplc .
in contrast , a much higher yield
( 48% ) was obtained when the reaction temperature was reduced to 75
c .
the mom - protected 3h can be further cyclized
in ethanol in the presence of sodium acetate to yield 4-chromanone 3i as a mixture of two diastereomers .
final deprotection of the o - mom group was performed
in methanol using concentrated hcl at room temperature to give 3j in 90% yield .
reagents and conditions : ( i ) dipea ,
momcl , 0 c , 1 h ; ( ii ) pyrrolidine , etoh , 75 c , pressure
tube , 1 h ; ( iii ) naoac , etoh , reflux , 24 h ; ( iv ) concentrated hcl ,
meoh , rt , overnight .
next , on the basis of
the promising antibacterial activity of 3f , a focused
set of 4-chromanone analogues ( scheme 5 ) were subsequently designed
and synthesized to investigate the antibacterial effect of the phenol
free hydroxy group at different positions .
compound 3f was resynthesized from the mom - protected 1e by using
diethylamine ( dea ) as a base in an overall 58% yield following o - mom deprotection .
accordingly , 3k , l with the 5- or 6-hydroxy group were also synthesized using appropriate
mom - protected 1g , h in moderate yields ( 5875% ) .
reagents and conditions :
( i ) dea , etoh , 150 c , pressure tube , 1 h ; ( ii ) concentrated
hcl , meoh , rt , overnight .
to further expand
the sar and evaluate the influence of the 5-hydroxy group , an array
of 5,7-dihydroxy-4-chromanones were synthesized .
accordingly , 2,4,6-trihydroxyacetophenone
( 1j ) was used to prepare 4-chromanone derivatives 5 ( scheme 6 ) .
unfortunately , no product
was obtained under the reaction conditions of pyrrolidine in ethanol
at 150 c in a pressure tube .
therefore , the bis - mom - protected
acetophenone 1k was next prepared in 79% yield .
the corresponding mom - protected 4-chromanones 5 were obtained by reacting 1k with an appropriate
aldehyde in the presence of dea in ethanol in a pressure tube at 150
c in moderate yields ( 5570% ) .
subsequent removal of
the mom groups using concentrated hcl in methanol at room temperature
afforded the corresponding 4-chromanones in 7594% yields .
next , to evaluate the role of the carbonyl group at the 4-position
and further explore the chemical diversity of the 4-chromanone scaffold ,
a panel of 4-oximinochromanes 6a f were produced by reacting the corresponding 5 with
an appropriate hydroxylamine in ethanol in the presence of pyridine
in high yields ( 8090% ) .
notably , the reaction time in this
series differed from 26 to 72 h , and the electron donating group such
as meo in 6b greatly facilitated the reaction and reduced
the reaction time ( 26 h ) . reagents and conditions :
( i ) dipea , momcl , 0 c , 1 h , 79% ; ( ii ) dea , etoh , 150 c ,
pressure tube , 1 h ; ( iii ) concentrated hcl , meoh , rt , 24 h ; ( iv ) pyridine ,
etoh , rt , 2672 h. without isolating the mom - protected intermediate .
as illustrated in scheme 7 , to synthesize
the bicyclic compound 5n bearing the myrtenal motif ,
the reaction time needed to be extended to 4 h under the reaction
conditions , and the chalcone 5 m was obtained in overall
two - step 34% yield after o - mom deprotection .
subsequent
intramolecular conjugate addition of the phenol on the ,-unsaturated
system was performed under microwave irradiation in the presence of
catalytic amounts of concentrated hcl to give 5n in 72%
yield as a mixture of two diastereomers .
we also noted that the reaction was completed in 0.5 h , which was
a great improvement in comparison to the condition of refluxing with
sodium acetate in ethanol in scheme 4 .
reagents and conditions : ( i ) dea ,
etoh , 150 c , pressure tube , 4 h ; ( ii ) hcl , meoh , rt , 16 h ; ( iii )
hcl , etoh , microwave irradiation , 150 c , 0.5 h. next , 2-spiro-4-chromanones ( 7a c ) were synthesized by reacting 1e with an appropriate
cycloketone in a pressure tube at 150 c for 216 h in
the presence of pyrrolidine ( scheme 8) . the
following o - mom deprotection was performed in one
pot with excess concentrated hcl .
the spiro compounds 7a c were obtained in moderate to high yields ,
with 7c giving the lowest yield ( 53% ) probably due to
the steric hindrance of the seven - membered ring .
( i ) pyrrolidine , etoh , 150 c , pressure tube ,
216 h ; ( ii ) hcl , rt , overnight . to systematically investigate the sar of the chalcone and 4-chromanone
scaffolds on antibacterial activities , diverse aromatic aldehydes
were introduced to synthesize a series of 2-aryl chalcone and flavanone
derivatives ( scheme 9 ) .
accordingly , the claisen schmidt
aldol condensations were performed at room temperature with the addition
of 60% koh aqueous solution to the mixture of appropriate mom - protected
acetophenone and aldehyde in methanol .
subsequent removal of the mom - protecting group with concentrated
hcl afforded the chalcone derivatives 8a h .
chalcone 8f was synthesized as a comparison
under the same conditions to verify the potential effect of 2-hydroxy
group on antibacterial activity .
additionally , in comparison to 8a with the ortho - substituted allyloxy group , regioisomers 8 g and 8h ( with the allyloxy group at the meta-
and
para - position , respectively ) were next synthesized to investigate
the influence of the substitution at the r2 position in
the scaffold .
subsequent intramolecular conjugate additions of the
phenol on the ,-unsaturated system of 8a e were carried out under microwave irradiation
in the presence of catalytic amounts of concentrated hcl to yield
corresponding flavanones 8i m in
5075% yields .
reagents and conditions : ( i ) 60%
koh aq , meoh , rt , 60 h ; ( ii ) concentrated hcl , rt , overnight ; ( iii )
microwave , hcl , etoh , 150 c , 1.5 h. without 2-oh function for 8f .
all the synthesized compounds were characterized
by h and c nmr spectroscopy and high - resolution
mass spectrometry ( hrms ) , and purity was analyzed by reverse phase
hplc .
the structures of 3 g and 8a were confirmed
by x - ray crystallography , and their ortep drawings are shown in figure
s1 ( supporting information ) . all
the synthesized compounds were evaluated against mycobacterium
tuberculosis ( h37rv ) and a wide set of clinically relevant
gram - positive and -negative bacterial pathogens including enterococcus faecalis ( atcc 33186 ) , staphylococcus
aureus ( atcc 29213 and nrs 70 ) , escherichia coli ( k12 and tolc ) , klebsiella pneumoniae ( atcc 33495 ) , and pseudomonas aeruginosa ( pao1 ) .
a series , olympicin
a ( 2a ) and analogues ( 2b f ) showed weak antitubercular activity with mics of 100200
g / ml ( table 1 ) .
the observed weak antituberculosis activity may be attributed
to the general polar nature of this chemical series and decreased
membrane penetration .
in contrast , the olympicin derivatives with
geranyloxy ( 2a and 2b ) , n - hexyloxy ( 2d ) , and n - octyloxy ( 2e ) groups showed good to potent anti - gram - positive activity
against e. faecalis and s. aureus strains ( mic = 0.783.13 g / ml ) . however , the less
lipophilic olympicin derivatives 2c and 2f with a shorter allyloxy chain exhibited about 8- to 16-fold decrease
of antibacterial activity ( mic = 6.2512.5 g / ml ) . in
terms of stereochemistry effect ,
the racemic olympicin a ( 2b ) and allyloxy derivative ( 2c ) showed largely the same
antituberculosis and anti - gram - positive activity compared to their
corresponding chiral s - isomers 2a and 2f , respectively .
notably , the anti s. aureus activity ( 1.56 g / ml ) of our synthetic sample ( 2a ) of olympicin a is consistent with the previously reported anti s. aureus activity ( 0.51 g / ml ) of natural
olympicin a. in addition , none of these
olympicin analogues were active against gram - negative microorganisms
except for the reengineered e. coli strain ( tolc ) with deficient efflux activity .
no test compounds
were active ( > 200 g / ml ) against other gram - negative bacteria
including k. pneumonia ( atcc 33495 ) and p.
aeruginosa ( pao1 ) .
positive controls isoniazid and rifampin inhibited m. tuberculosis at 0.03 and 0.05 g / ml , respectively . in the 4-chromanone and chalcone chemical series
( tables 2 and 3 ) ,
the
2-propyl-4-chromanol 4a showed the most potent activity
in the entire series with a mic of 12.5 g / ml . the reduced
4-chromanol variants 4a and 4c ( 4-oh , 12.5
and 25 g / ml , respectively ) showed more potent antituberculosis
activity than their corresponding 4-chromanones 3a ( 200
g / ml ) and 3c ( 50 g / ml ) .
in addition , the
4-oximinochromane 6a ( = noh , 100 g / ml ) displayed
greater potency than 6b ( = nome , 200 g / ml )
and 6c ( = nobn , > 200 g / ml ) .
taken together ,
these results indicate that the small , polar , and hydrophilic groups
( e.g. , oh and = noh ) are more favorable at the 4-position
of the flavonoid scaffold for antituberculosis activity , suggesting
these polar groups may function as hydrogen bond donors when interacting
with potential biological cellular target .
different lengths
of the 2-alkyl side chains in the scaffold displayed an important
relationship with antituberculosis activity as well . compared to 3a ( three - carbon
, 200 g / ml ) , 3b ( six - carbon ,
50 g / ml ) , and 3c ( seven - carbon , 50 g / ml ) ,
compound 3d with a nine - carbon linear chain was inactive ,
suggesting the nine - carbon alkyl group is too long and bulky . to investigate
the impact of the substituent at the 5-position in the scaffold ,
these data showed that the compounds bearing 5,7-dihydroxy functionalities
( 5b , 5d , and 5f ) exhibited
similar mic values to the sole 7-hydroxychromanones 3a c .
however , 5h ( 5,7-di - oh , nine - carbon
chain , 100 g / ml ) was more potent than the corresponding 3d ( 7-oh , nine - carbon chain , > 200 g / ml ) .
in addition ,
the position of the sole hydroxy group in the scaffold also played
a notable role in their antituberculosis activity by comparing 3f ( 7-oh , 100 g / ml ) to 3k ( 6-oh , 200 g / ml )
and 3l ( 5-oh , > 200 g / ml ) , with 3f bearing the 7-hydroxy function being the most potent .
in general ,
2-aryl substituted compounds together with 2-spiro derivatives possessing
a cyclic ring system were less active against m. tuberculosis than 2-alkylated derivatives in the entire series . moreover , the
mom protected derivatives exhibited comparable or more potent antitubercular
activity than their corresponding free phenol parent molecules .
the
sar analysis above demonstrates that the 2-alkyl hydrophobic substituents
as well as the small and polar functionalities at the 4-position ( e.g. ,
hydrogen bond donor groups oh and = noh ) play important roles
in antituberculosis activities in the 4-chromanone scaffold .
no test compounds were active ( > 200 g / ml )
against other gram - negative bacteria including k. pneumonia ( atcc 33495 ) and p. aeruginosa ( pao1 ) .
the mic
values of control antibiotics used in this study are shown in table 1 .
in addition to antituberculosis evaluation , antimicrobial
assessment against representative clinical pathogens revealed that
the majority of compounds from these series exhibited notable anti - gram - positive
bacteria activities including against e. faecalis and s. aureus ( mssa and mrsa ) and poor activity
against gram - negative bacteria including e. coli , k. pneumoniae , and p. aeruginosa .
compared with the 4-chromanone flavonoid series , the chalcone series
generally exhibited more potent anti - gram - positive activity than their
corresponding cyclized derivatives . the 2,4-di - oh
chalcone compound 8a having an appended
2-allyloxy group
exhibited the best activity ( mic of 0.396.25 g / ml )
against mssa and mrsa , and the o - hydroxy group appeared
to have a beneficial effect on anti - gram - positive bacterial activity
by comparing 8a ( 2,4-di - oh , 2-allyloxy ,
0.3912.5 g / ml ) to 8f ( 4-oh , 2-allyloxy ,
6.25100 g / ml ) ( table 3 ) .
notably ,
this observation regarding the importance of the o - hydroxy group in the chalcone scaffold is also in agreement with
that found in the 4-chromanone flavonoid series , whereas the corresponding
hydroxy group at the 5-position of the 4-chromanone scaffold enhanced
the antibacterial activity .
however , the 2,4,6-tri - oh
chalcone compounds possessing an additional 6-hydroxy group 5 m
( 25 to > 200 g / ml ) and 8e ( 25 to
> 200 g / ml ) showed significantly decreased activities against
gram - positive microorganisms compared to the 2,4-di - oh
chalcones 3 g
( 1.563.13 g / ml ) and 8a ( 0.3912.5 g / ml ) , respectively .
the notable
decreased activity for trihydroxy compounds is likely due to increased
hydrophilicity and polarity properties and thus decreased bacterial
membrane penetration . taken together , these data suggest that two
free phenol hydroxy groups on the 4-chromanone and chalcone scaffolds
are optimal for gram - positive antibacterial activity . furthermore ,
in the chalcone series ( table 3 ) , the lipophilic o - alkyl substituent
at the 2-position of aromatic chalcones also had a great impact on
antibacterial activities , since the chalcones bearing diverse side
chains such as the allyloxy ( 8a ) , n - hexyloxy
( 8b ) , and n - octyloxy ( 8c ) exhibited notable differences in their activities ; compound 8b bearing the n - hexyloxy group showed optimal
antibacterial activity against e. faecalis , mssa ,
and mrsa ( 1.56 , 3.13 , and 0.78 g / ml , respectively ) .
compound 8a bearing the 2-allyloxy function demonstrated 2-fold more
potent activity against mrsa and an 8-fold reduction in activity against e. faecalis than 8b . in the flavonoid
series
, the length of 2-alkyl substitutions in the 4-chromanone scaffold
plays an important role in determining antibacterial activities .
the
5,7-dihydroxy-4-chromanones with long aliphatic alkyl chains 5d , 5f , 5h , and 5j ( six
to nine - carbon chain , 3.136.25 g / ml ) showed better
activity against mrsa than the shorter chain derivative 5b ( three - carbon chain , 100 g / ml ) , and notably , the 2-(2,6-dimethyl-5-heptenyl )
substituted 5j with a branched and unsaturated alkyl
chain displayed the best potency among these five 2-alkylated derivatives
against three gram - positive bacteria tested ( e. faecalis , mssa , and mrsa ; 6.25 , 3.13 , and 3.13 g / ml , respectively ) .
these results suggest that the branched unsaturated substitution in 5j may play an important role in enhancing interactions and
binding affinity with cellular biological target because of its favorable
lipophilicity and high conformational flexibility , as previously noted
for the prenylated derivatives .
we also observed that
the introduction of an additional 5-oh group to the 7-hydroxy-4-chromanones 5b ( 100 g / ml ) , 5d ( 6.25 g / ml ) , 5f ( 3.13 g / ml ) , 5h ( 3.13 g / ml ) ,
and 5n ( 6.25 g / ml ) significantly improved antibacterial
activity against mrsa , compared to their corresponding 7-oh-4-chromanones 3a d ( > 200 g / ml ) and 3j ( 200 g / ml ) except that 5j maintained anti - mrsa
activity ( 3.13 g / ml ) compared to 3f . these data
demonstrate the importance of the 5-oh group in the 7-oh-4-chromanone
scaffold for antibacterial activity .
in addition , the reduced
variants 4-chromanols 4a d ( in particular
2-n - heptyl-7-oh-4-chromanol 4c , 12.525
g / ml ; and 2-n - nonyl-7-oh-4-chromanol 4d , 2550 g / ml ) also displayed improved antibacterial
activities compared to their corresponding 4-chromanones 3a d , which were not active against gram - positive
bacteria tested .
in contrast , the 4-oximinochromanes ( 6a and 6d - f : = noh at the 4-position )
showed more potent activity against e. faecalis and
mssa and comparable activity against mrsa than their corresponding
4-chromanones ( 5h , 5b , 5d ,
and 5f ) , suggesting the free oxime = noh functionality
is preferred compared to the carbonyl group .
furthermore , by comparison
of 6a with the free 4-oxime functionality ( = noh ,
12.5 g / ml ) , compounds 6b ( = nome , 25100
g / ml ) and 6c ( = nobn , > 200 g / ml )
showed decreased antibacterial activity against s. aureus .
this observation is also consistent with the trend toward the antituberculosis
activity found in this series , indicating that the small , polar , and
hydrogen bond donor functionalities ( e.g. , oh and = noh
groups ) at the 4-position may be more favorable for antibacterial
properties , together with the results based upon 4-chromanols ( 4a d ) . to further evaluate the importance
of the 5- , 6- , and 7-oh functionality , a set of 4-chromanone
derivatives 3f ( 7-oh ) , 3k ( 6-oh ) , and 3l ( 5-oh )
were subsequently synthesized .
biological evaluation revealed
that the 6- or 7-hydroxy group also proved to be a determining factor
for antibacterial activities , since 3f ( 7-oh , 3.1312.5
g / ml ) and 3k ( 6-oh , 6.2512.5 g / ml )
demonstrated almost equally potent antibacterial activities against
gram - positive bacteria tested .
. the lack of antibacterial
activity of 3l may be due to the presence of intramolecular
hydrogen bonding between the carbonyl group at the 4-position and
the hydroxy group at the 5-position .
it should be noted that all the
mom protected derivatives ( 3h , 3i , 5a , 5c , 5e , 5 g , and 5i ) completely lost anti - gram - positive bacterial activities
against e. faecalis and s. aureus , demonstrating the importance of the free phenol hydroxy functionality
and its weakly acidic nature in the scaffold .
additionally ,
among the chemical series bearing a cyclic / bicyclic ring system at
the 2-position ( 5k , 2-cyclopentyl ; 5l , 2-cyclohexyl ; 5n , 2-myrtenyl ; and the 2-spiro compounds 7a c ) , compound 5n bearing the myrtenyl motif showed
relatively good antibacterial activity ( 6.2512.5 g / ml ) against gram - positive bacteria tested .
interestingly , its corresponding ring - opened
chalcone derivative 3 g demonstrated very good anti - gram - positive
activity ( 1.563.13 g / ml ) .
no test
compounds were active ( > 200 g / ml ) against other gram - negative
bacteria including k. pneumonia ( atcc 33495 ) and p. aeruginosa ( pao1 ) .
the mic values of control antibiotics
used in this study are shown in table 1 .
a detailed sar of the 4-chromanone
and chalcone series is summarized in figure 3 .
cytotoxicity against mammalian ( vero epithelial ) cells and solubility
in dulbecco s modified eagle medium ( dmem ) supplemented with
10% fetal bovine serum ( fbs ) were evaluated for a selected panel of
4-chromanone and chalcone lead compounds , and the results are shown
in table 4 .
overall , all the tested compounds
had good solubility ( 100 g / ml ) in the dmem / fbs medium
used in the cytotoxicity assay except for the 4-oxime derivative 6a ( 37.5 17.7 g / ml ) .
the selectivity indices
( si ) for the compounds were calculated as the ratio of the ic50 value of cytotoxicity against vero monkey kidney cell line
and the mic value against tested mrsa .
notably , 4-chromanone derivatives 5f ( si = 10.5 ) and 8j ( si = 15.7 ) and the chalcone
derivative 8a ( si = 54.4 ) possessed a more favorable
selectivity index ( si > 10 ) .
on the basis of these promising antibacterial
lead structures , advanced medicinal chemistry will be applied to produce
compounds with improved potency and decreased cytotoxicity .
dmem / fbs :
dulbecco s modified eagle medium ( dmem ) supplemented with 10%
fetal bovine serum ( fbs ) .
the clogp values of compounds were calculated using chembiooffice
ultra , version 12.0 , from cambridgesoft corporation .
the bactericidal activities
of compounds 3 g , 5j , 8a , and 8d were examined against s. aureus newman
( figure 4 ) .
the most effective compound was
the chalcone derivative 3 g , which killed more than 6
log of cells in just 2 h at 4 its mic , but at its mic ( 1.56
g / ml against s. aureus newman ) up to 24 h
was required to achieve a 3 log reduction in cells .
compound 8a ( mic = 6.25 g / ml ) was also rapidly bactericidal
at 4 its mic and achieved a 6 log reduction in 6 h. interestingly ,
compound 8d ( 6.25 g / ml ) was entirely bacteriostatic
and failed to kill more than 3 log of culture at 4 its mic ,
even up to 24 h of exposure . at concentrations between 1 and
4 their mics , spontaneous mutants of s. aureus newman could not be selected with 8a , 3 g , and 5j , but mutants arose to 8d at a
frequency of 10 .
the controls mupirocin and vancomycin
were either bacteriostatic or slowly bactericidal over a 24 h period ,
and mutants could only be selected with mupirocin at frequencies of
1010 .
several key biosynthetic processes were simultaneously
inhibited in s. aureus newman exposed to the compounds 2a , 5j , 8a , 3 g , and 8d ( figure 5 ) .
these effects are consistent
with the bacterial membrane being the primary target site of action ,
resulting in multiple nonspecific cellular effects .
surprisingly ,
the bacteriostatic compound 8d displayed the same time - dependent
effects on macromolecular synthesis as the bactericidal compounds .
to determine if the compounds dissipated the membrane potential of s. aureus , the fluorescent probe dioc2(3 ) was used .
compounds 2a , 5j , 3 g , and 8d all
dissipated the membrane potential of s. aureus newman
in a concentration - dependent manner .
maximum dissipation occurred
at 4 their mics and was similar to the control cccp ( carbonyl
cyanide m - chlorophenylhydrazone ) ( figure 6 ) ; as expected , vancomycin ( at 4 mic ) failed
to affect the membrane potential in s. aureus .
effects of 2a , 5j , 3 g , 8a , and 8d and indicated positive controls at 4 their mics on
macromolecular synthesis in s. aureus newman .
the
standard error of the mean ( sem ) is shown for three biological replicates .
ery = erythromycin ( mic = 0.78 g / ml ) ; rmp = rifampicin ( 0.12
g / ml ) ; cip = ciprofloxacin ( 0.25 g / ml ) .
dissipation of the staphylococcal membrane potential by 2a , 5j , 3 g , and 8d .
vancomycin
( mic = 0.8 g / ml ) and cccp ( mic = 6.25 g / ml ) were used
as negative and positive controls . clinically , dna gyrase and topo iv are validated and attractive antibacterial
targets for fluoroquinolone and novobiocin antibiotics . however , because
of the emergence of target - based bacterial resistance with fluoroquinolone
class and safety concerns of novobiocin , novel dna gyrase and topoisomerase
inhibitors are urgently needed for the treatment of pathogenic and
resistant bacterial infections .
thus ,
development of new chemotype bacterial topo inhibitors has attracted
great interest in the scientific community , and recent examples include
bisbenzimidazoles , anziaic acid , and
its analogues as bacterial topo ia inhibitors ,
and pyridylureas and pyrrolamides as topo ii inhibitors .
previously , flavonoids
have been identified as bacterial topoisomerase inhibitors , and we next tested to see if these promising antibacterial compounds
from olympicin a , 4-chromanone , and chalcone series inhibited e. coli topo i , topo iv , and dna gyrase .
the results are
shown in table 5 and figure s2 ( supporting information ) .
the e. coli topo i assay ( relaxation of negatively supercoiled plasmid dna )
was performed at both 0.5 and 5 mm magnesium chloride concentrations ,
and no significant inhibition was observed against topo i at 0.5 mm
compound concentration . the assay against e. coli gyrase ( supercoiling of relaxed plasmid dna ) and e. coli topo iv
( decatenation of catenated kinetoplast dna ) was subsequently
performed . again for dna gyrase , inhibition was not observed or was
weak with 8a , 3 g , and 2a ( mic
values of 0.396.25 g / ml against s. aureus ) exhibiting ic50 values of > 0.25 mm .
however , the e. coli topo iv showed more significant sensitivity toward 2a and 2e ( mic values of 0.781.56 g / ml
against e. faecalis and s. aureus ) with ic50 values of 3060 m ( table 5 and figure s2 , supporting information ) .
these results showed that the olympicin a ( 2a ) and
its analogue 2e may serve as a promising and novel scaffold
for topo iv inhibitors .
interestingly , olympicin a was also recently
reported as a moderate atp - dependent mycobacterium tuberculosis mure ligase inhibitor with an ic50 value of 75 m . studies to determine
if the olympicin a analogues 2c f inhibit the mure pathway in m. tuberculosis remain to be performed . finally , the antibacterial
mechanism of the 4-chromanone flavanone compounds 8k and 8j ( mic values of 1.5612.5 g / ml against s. aureus ) may not be likely to involve topoisomerase inhibition ,
as they were inactive in these topo enzyme inhibition assays ( table 5 ) .
collectively , no correlations between whole - cell - based
activity and topoisomerase inhibition were observed for selected compounds ,
suggesting that the membrane is likely the primary biological target
responsible for antibacterial activity and topo iv is a secondary
or alternative target .
further mechanistic studies are warranted to
define the exact mechanism of antibacterial action of these chemically
modified flavonoid and polyphenol compounds .
ic50 of known inhibitor for assay : anziaic
acid for topo i. ic50 of known inhibitor for assay : ciprofloxacin for dna gyrase and topo iv .
ic50 of known inhibitor for assay : nalidixic
acid for dna gyrase and topo iv .
in
summary , 58 olympicin a , 4-chromanone , and chalcone derivatives containing
various functionalities were synthesized and evaluated against mycobacterium tuberculosis and a panel of clinically relevant
gram - positive and -negative bacterial pathogens .
bacterial evaluation
showed that this class of compounds generally exhibited good activities
against gram - positive bacteria tested .
systematic sar study revealed
that the phenol hydroxy groups at the 5- and 7-position of the 4-chromanone
scaffold were essential for antibacterial activities . additionally ,
the hydrogen bond donor / acceptor functionality at the 4-position together
with the lipophilic 2-alkyl moiety in the scaffold also played important
roles in antibacterial activities .
the flavanone derivatives bearing
the lipophilic substituent on the 2-phenyl ring showed good antibacterial
properties as well . in the chalcone chemical series , both hydroxy groups
at 2- and 4-position , as well as the bicyclic myrtenyl
motif and the 2-alkyloxy substitution on the aromatic ring , favored
anti - gram - positive bacterial activities .
the selected compounds generally
possessed favorable solubility , and 5f , 8a , and 8j had more desirable selectivity indices ranging
from 10.5 to 54.4 .
in addition , compounds 2a , 5j , 3 g , and 8d were found to disrupt bacterial
membrane potential and have secondary inhibitory effect on macromolecular
biosynthesis of dna , rna , and protein .
further evaluation of selected
compounds against bacterial topoisomerases and dna gyrase revealed
that 2a and 2e inhibited topoisomerase iv
( ic50 = 3060 m ) .
taken together , the antibacterial
agents identified from this study provide chemically modified flavonoid
phytochemicals as promising antibacterial leads for further medicinal
chemistry optimization in an effort to identify advanced experimental
candidates with antimicrobial therapeutic potential .
solvents and reagents were supplied from aldrich , acros , or fisher
and used without further purification .
high - resolution mass spectra
were obtained on an agilent 6530 accurate mass q - tof lc / ms instrument .
reactions in pressure tube were carried out using a q - tube reactor
from q labtech .
compounds were purified by flash chromatography on silica gel on a
biotage isolera one system .
the purity of compounds was determined
by analytical hplc ( shimadzu lc-20a series ) using a gemini , 3 m ,
c18 , 110 column ( 50 mm 4.6 mm , phenomenex ) and flow
rate of 1 ml / min .
gradient conditions were the following : solvent
a ( 0.1% trifluoroacetic acid in water ) and solvent b ( acetonitrile ) ,
02.0 min 100% a , 2.07.0 min 0100% b ( linear
gradient ) , 7.08.0 min 100% b , uv detection at 254 and 220
nm . all the tested compounds were obtained with 95% purity
by hplc .
h nmr : cdcl3 , 7.26 ppm ; cd3od , 3.31 ppm ; dmso - d6 , 2.50 ppm .
c nmr : cdcl3 , 77.16
ppm ; cd3od , 49.00 ppm ; dmso - d6 , 39.52 ppm .
to
a solution of 1a ( 150 mg , 0.715 mmol ) in acetone ( 11
ml ) were added p - toluenesulfonic chloride ( 408 mg ,
2.14 mmol ) and k2co3 ( 845 mg , 6.15 mmol ) successively .
the resulting mixture was stirred under reflux for 1 h , and then acetone
was removed under reduced pressure .
the residue was diluted with water
and dcm , and the organic layer was washed with 1 m hcl aq , water ,
brine and dried over na2so4 .
the solvent was
removed under reduced pressure and the crude material was adsorbed
onto silica gel and subjected to silica gel chromatography with hexane / etoac
( first 85/15 , then 75/25 ) to give the product ( 350 mg , 0.52 mmol ,
73% ) as clear oil .
h nmr ( 400 mhz , cdcl3 ) :
( ppm ) 7.69 ( d , j = 8.3 hz , 2h ) , 7.62 ( d , j = 8.4 hz , 4h ) , 7.36 ( d , j = 8.2 hz , 2h ) ,
7.30 ( d , j = 8.3 hz , 4h ) , 7.0 ( s , 2h ) , 2.642.59
( m , 1h ) , 2.44 ( s , 9h ) , 1.561.50 ( m , 1h ) , 1.241.14
( m , 1h ) , 0.90 ( d , j = 7.0 hz , 3h ) , 0.76 ( t , j = 7.4 hz , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 201.2 , 149.8 , 146.8 , 146.5 , 146.4 , 131.7 , 131.3 ,
130.2 , 130.0 , 128.5 , 127.1 , 114.3 , 48.6 , 24.5 , 21.80 , 21.79 , 14.2 ,
11.2 .
hrms calculated for c32h32o10s3 ( m + h ) 673.1230 , found ( m + h ) 673.1229 .
hplc purity : 98.6% ( 254 nm ) , tr = 8.17 min ; 99.5% ( 220 nm ) , tr = 8.17
min . to a suspension of 1a ( 1.12 g , 5.33 mmol ) in dcm ( 11 ml ) at 0 c was added dipea
( 2.78 ml , 15.9 mmol ) carefully .
after stirring for 10 min , momcl ( 1.21
ml , 15.9 mmol ) was added to the solution dropwise .
the resulting mixture
was stirred for 1 h. afterward , the solution was poured into sat .
the solvent was removed under reduced pressure
and the crude material was adsorbed onto silica gel and subjected
to silica gel chromatography with hexane / etoac ( 90/10 ) to give the
product ( 1.02 g , 3.42 mmol , 64% ) as pale yellow solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 13.74 ( s , 1h ) , 6.27
( s , 2h ) , 5.24 ( s , 2h ) , 5.16 ( br s , 2h ) , 3.653.60 ( m , 1h ) ,
3.51 ( s , 3h ) , 3.46 ( s , 3h ) , 1.871.80 ( m , 1h ) , 1.431.36
( m , 1h ) , 1.16 ( d , j = 6.8 hz , 3h ) , 0.91 ( t , j = 7.4 hz , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 210.3 , 167.2 , 163.2 , 160.1 , 106.7 , 97.6 , 94.9 , 94.4 ,
94.1 , 56.9 , 56.6 , 46.6 , 27.1 , 16.7 , 12.2 . hrms calculated for c15h22o6 ( m + h ) 299.1489 ,
found ( m + h ) 299.1483 . hplc purity : 99.8% ( 254 nm ) , tr = 7.42 min ; 99.8% ( 220 nm ) , tr = 7.42 min .
h nmr ( 400 mhz , cdcl3 ) :
( ppm ) 13.74 ( s , 1h ) , 6.27 ( s , 2h ) , 5.24 ( s , 2h ) , 5.16 ( br
s , 2h ) , 3.653.60 ( m , 1h ) , 3.52 ( s , 3h ) , 3.46 ( s , 3h ) , 1.871.80
( m , 1h ) , 1.431.36 ( m , 1h ) , 1.16 ( d , j = 6.8
hz , 3h ) , 0.91 ( t , j = 7.4 hz , 3h ) .
c
nmr ( 100 mhz , cdcl3 ) : ( ppm ) 210.3 , 167.2 , 163.2 ,
160.1 , 106.7 , 97.6 , 94.9 , 94.4 , 94.1 , 56.8 , 56.6 , 46.6 , 27.1 , 16.7 ,
12.1 .
hrms calculated for c15h22o6 ( m + h ) 299.1489 , found ( m + h ) 299.1475 .
hplc purity : 99.9% ( 254 nm ) , tr = 7.38
min ; 100% ( 220 nm ) , tr = 7.38 min .
to a solution of 1b ( 410 mg , 0.61 mmol ) in dmf ( 4 ml )
at 0 c was added nah ( 49 mg , 1.21 mmol ) carefully . after stirring
for 30 min ,
geranyl bromide ( 198 mg , 0.91 mmol ) in dmf ( 1 ml ) was
added dropwise .
the resulting mixture was stirred at room temperature
for 1 h. afterward , the reaction was quenched with water and extracted
with etoac twice .
the solvent was removed under
reduced pressure , and the residue was dissolved in meoh ( 10 ml ) , followed
by the careful addition of sodium methoxide ( 659 mg , 12.2 mmol ) .
the
resulting mixture was stirred under reflux for 8 h , and then meoh
was removed .
the residue was diluted with 1 m hcl aq and extracted
with etoac twice .
the solvent was removed under
reduced pressure and the crude material was adsorbed onto silica gel
and subjected to silica gel chromatography with hexane / etoac to give
the product .
purified with hexane / etoac
( 90/10 ) to give the product ( 116 mg , 0.34 mmol , 55% , two - step overall
yield ) as pale yellow oil .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 5.98 ( d , j = 2.2 hz , 1h ) , 5.91
( d , j = 2.2 hz , 1h ) , 5.54 ( br , 1h ) , 5.525.49
( m , 1h ) , 5.115.09 ( m , 1h ) , 4.56 ( d , j = 6.6
hz , 2h ) , 3.673.63 ( m , 1h ) , 2.142.08 ( m , 4h ) , 1.811.78
( m , 1h ) , 1.74 ( s , 3h ) , 1.68 ( s , 3h ) , 1.61 ( s , 3h ) , 1.401.33
( m , 1h ) , 1.12 ( d , j = 6.7 hz , 3h ) , 0.89 ( t , j = 7.4 hz , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 210.8 , 167.3 , 163.1 , 162.8 , 142.6 , 132.1 , 123.7 ,
118.3 , 105.8 , 96.6 , 92.1 , 65.8 , 46.1 , 39.6 , 27.0 , 26.4 , 25.8 , 17.8 ,
16.73 , 16.67 , 12.0 . hrms calculated for c21h30o4 ( m + h ) 347.2217 , found ( m + h ) 347.2210 .
hplc purity : 99.7% ( 254 nm ) , tr = 8.18 min ; 99.6% ( 220 nm ) , tr = 8.18
min .
purified with hexane / etoac ( 90/10 ) to give
the product ( 110 mg , 0.32 mmol , 52% over two steps ) as pale yellow
oil .
h nmr ( 400 mhz , cdcl3 ) : ( ppm )
5.98 ( d , j = 2.2 hz , 1h ) , 5.91 ( d , j = 2.2 hz , 1h ) , 5.54 ( br , 1h ) , 5.525.49 ( m , 1h ) , 5.115.09
( m , 1h ) , 4.56 ( d , j = 6.6 hz , 2h ) , 3.673.63
( m , 1h ) , 2.142.08 ( m , 4h ) , 1.811.78 ( m , 1h ) , 1.74
( s , 3h ) , 1.68 ( s , 3h ) , 1.61 ( s , 3h ) , 1.401.33 ( m , 1h ) , 1.12
( d , j = 6.7 hz , 3h ) , 0.89 ( t , j =
7.4 hz , 3h ) .
c nmr ( 100 mhz , cdcl3 ) :
( ppm ) 210.8 , 167.3 , 163.1 , 162.8 , 142.6 , 132.1 , 123.7 , 118.3 , 105.8 ,
96.6 , 92.1 , 65.8 , 46.1 , 39.6 , 27.0 , 26.4 , 25.8 , 17.8 , 16.74 , 16.68 ,
12.0 .
hrms calculated for c21h30o4 ( m + h ) 347.2217 , found ( m + h ) 347.2214 .
hplc purity : 99.7% ( 254 nm ) , tr = 8.17
min ; 99.6% ( 220 nm ) , tr = 8.17 min .
to a solution of 1c ( 200 mg , 0.67
mmol ) in dmf ( 4 ml ) at 0 c was added nah ( 54 mg , 1.34 mmol )
carefully . after stirring for 30 min , appropriate alkyl bromide ( 1
mmol ) in dmf ( 1 ml )
the resulting mixture was
stirred at room temperature until the complete consumption of 1c ( 17 h ) .
the
solvent was removed under reduced pressure , and the residue was dissolved
in meoh ( 10 ml ) , followed by the addition of concentrated hcl ( 510
l , 6 mmol ) carefully .
the resulting mixture was stirred at
room temperature overnight , and the solvent was removed under reduced
pressure .
the crude material was adsorbed onto silica gel and subjected
to silica gel chromatography with hexane / etoac to give the product .
purified with hexane / etoac ( 85/15 ) to give
the product ( 157 mg , 0.63 mmol , 93% over two steps ) as pale yellow
solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm )
6.116.02 ( m , 1h ) , 6.00 ( d , j = 2.1 hz , 1h ) ,
5.91 ( d , j = 2.1 hz , 1h ) , 5.86 ( br , 1h ) , 5.42 ( d , j = 17.2 hz , 1h ) , 5.35 ( d , j = 10.4 hz ,
1h ) , 4.57 ( d , j = 5.6 hz , 2h ) , 3.693.64 ( m ,
1h ) , 1.841.79 ( m , 1h ) , 1.421.35 ( m , 1h ) , 1.13 ( d , j = 6.7 hz , 3h ) , 0.89 ( t , j = 7.4 hz , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 210.9 , 167.2 ,
163.1 , 162.3 , 132.1 , 119.2 , 105.7 , 96.9 , 92.3 , 70.0 , 46.1 , 27.0 , 16.7 ,
11.9 .
hrms calculated for c14h18o4 ( m h ) 249.1132 , found ( m h ) 249.1102 .
hplc purity : 99.7% ( 254 nm ) , tr = 7.16 min ; 99.9% ( 220 nm ) , tr = 7.16 min .
purified with reverse phase c18 silica
gel chromatography with h2o / mecn ( 45/55 ) to give the product
( 130 mg , 0.44 mmol , 66% over two steps ) as pale solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 6.01 ( s , 1h ) , 5.92
( s , 1h ) , 3.96 ( t , j = 6.5 hz , 2h ) , 3.743.69
( m , 1h ) , 1.851.75 ( m , 3h ) , 1.461.33 ( m , 7h ) , 1.14
( d , j = 6.8 hz , 3h ) , 0.920.87 ( m , 6h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 210.8 , 167.3 ,
163.2 , 163.0 , 105.6 , 96.6 , 91.9 , 69.2 , 46.0 , 31.6 , 29.1 , 26.8 , 26.1 ,
22.7 , 17.0 , 14.1 , 11.9 .
hrms calculated for c17h26o4 ( m h ) 293.1758 , found ( m
h ) 293.1713 .
hplc purity : 99.2% ( 254 nm ) , tr = 7.93 min ; 99.9% ( 220 nm ) , tr = 7.92 min . purified with reverse phase c18 silica
gel chromatography with h2o / mecn ( 40/60 ) to give the product
( 151 mg , 0.47 mmol , 70% over two steps ) as pale yellow solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 7.33 ( br ,
1h ) , 6.01 ( d , j = 1.5 hz , 1h ) , 5.91 ( d , j = 1.5 hz , 1h ) , 3.97 ( t , j = 6.5 hz , 2h ) , 3.743.69
( m , 1h ) , 1.851.77 ( m , 3h ) , 1.461.28 ( m , 11h ) , 1.14
( d , j = 6.8 hz , 3h ) , 0.900.87 ( m , 6h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 210.7 , 167.3 ,
163.2 , 163.0 , 105.6 , 96.6 , 91.9 , 69.2 , 46.1 , 31.9 , 29.4 , 29.3 , 29.1 ,
26.8 , 26.4 , 22.8 , 17.0 , 14.2 , 11.9 .
hrms calculated for c19h30o4 ( m + h ) 323.2217 , found ( m
+ h ) 323.2213 .
hplc purity : 98.8% ( 254 nm ) , tr = 8.31 min ; 99.9% ( 220 nm ) , tr = 8.31 min .
purified with hexane / etoac ( 85/15 ) to give
the product ( 152 mg , 0.61 mmol , 90% over two steps ) as white solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 6.116.02
( m , 1h ) , 6.00 ( d , j = 2.1 hz , 1h ) , 5.91 ( d , j = 2.1 hz , 1h ) , 5.86 ( br , 1h ) , 5.42 ( d , j = 17.2 hz , 1h ) , 5.35 ( d , j = 10.4 hz , 1h ) , 4.57
( d , j = 5.6 hz , 2h ) , 3.693.64 ( m , 1h ) , 1.841.79
( m , 1h ) , 1.421.35 ( m , 1h ) , 1.13 ( d , j = 6.7
hz , 3h ) , 0.89 ( t , j = 7.4 hz , 3h ) .
c
nmr ( 100 mhz , cdcl3 ) : ( ppm ) 210.8 , 167.3 , 163.0 ,
162.3 , 132.1 , 119.3 , 105.7 , 96.9 , 92.3 , 70.1 , 46.2 , 27.0 , 16.7 , 11.9 .
hrms calculated for c14h18o4 ( m
h ) 249.1132 , found ( m h ) 249.1104 .
hplc purity : 99.1% ( 254 nm ) , tr = 7.17 min ; 99.6% ( 220 nm ) , tr = 7.17
min .
to a solution of 1d ( 152 mg , 1 mmol ) in ethanol ( 2.5 ml ) were added pyrrolidine ( 220
mg , 3.1 mmol ) and corresponding aldehyde ( 6 mmol ) successively .
the
resulting mixture was stirred at 150 c in a pressure tube for
1 h. afterward , the solution was diluted with ethyl acetate and the
organic layer was washed with 10% hcl , water , brine and dried over
na2so4 .
the solvent was removed under reduced
pressure and the crude material was adsorbed onto silica gel and subjected
to silica gel chromatography with hexane / etoac to give the product .
purified with hexane / etoac ( 87/13 ) to give
the product ( 85 mg , 0.41 mmol , 41% ) as light brown solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 8.13 ( br , 1h ) , 7.79
( d , j = 8.6 hz , 1h ) , 6.55 ( d , j =
8.4 hz , 1h ) , 6.43 ( s , 1h ) , 4.42 ( br , 1h ) , 2.672.63 ( m , 2h ) ,
1.851.80 ( m , 1h ) , 1.681.44 ( m , 3h ) , 0.990.95
( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm )
193.0 , 164.32 , 164.29 , 129.5 , 114.6 , 110.8 , 103.4 , 78.0 , 42.6 , 37.1 ,
18.3 , 14.0 .
hrms calculated for c12h14o3 ( m h ) 205.0870 , found ( m
h ) 205.0863 .
hplc purity : 97.3% ( 254 nm ) , tr = 6.31 min ; 98.6% ( 220 nm ) , tr = 6.31 min .
purified with hexane / etoac ( 90/10 ) to give the product
( 92 mg , 0.37 mmol , 37% ) as light brown solid .
h nmr ( 400
mhz , cdcl3 ) : ( ppm ) 7.78 ( d , j =
8.7 hz , 1h ) , 6.55 ( dd , j = 8.6 , 1.7 hz , 1h ) , 6.44
( d , j = 1.7 hz , 1h ) , 4.434.39 ( m , 1h ) , 2.662.63
( m , 2h ) , 1.871.82 ( m , 1h ) , 1.671.64 ( m , 1h ) , 1.531.30
( m , 8h ) , 0.900.87 ( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 193.1 , 164.34 , 164.30 , 129.4 , 114.6 , 110.8 ,
103.4 , 78.3 , 42.6 , 35.0 , 31.8 , 29.2 , 25.0 , 22.7 , 14.2 . hrms calculated
for c15h20o3 ( m h ) 247.1340 , found ( m h ) 247.1331 .
hplc
purity : 98.4% ( 254 nm ) , tr = 7.06 min ;
99.1% ( 220 nm ) , tr = 7.06 min .
purified with hexane / etoac ( 90/10 ) to give
the product ( 91 mg , 0.35 mmol , 35% ) as light brown solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 7.78 ( d , j = 8.7 hz , 1h ) , 6.55 ( dd , j = 8.7 , 2.3
hz , 1h ) , 6.43 ( d , j = 2.2 hz , 1h ) , 4.434.39
( m , 1h ) , 2.692.60 ( m , 2h ) , 1.881.80 ( m , 1h ) , 1.701.63
( m , 1h ) , 1.531.25 ( m , 10h ) , 0.890.86 ( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 193.0 , 164.4 ,
164.3 , 129.4 , 114.6 , 110.9 , 103.4 , 78.3 , 42.6 , 35.0 , 31.9 , 29.5 , 29.3 ,
25.0 , 22.8 , 14.2 .
hrms calculated for c16h22o3 ( m h ) 261.1496 , found ( m
h ) 261.1479 .
hplc purity : 95.0% ( 254 nm ) , tr = 7.28 min ; 96.1% ( 220 nm ) , tr = 7.28 min .
purified with hexane / etoac ( 90/10 ) to give the product
( 98 mg , 0.33 mmol , 33% ) as light brown solid .
h nmr ( 400
mhz , cdcl3 ) : ( ppm ) 8.23 ( br , 1h ) , 7.79 ( d , j = 8.7 hz , 1h ) , 6.56 ( dd , j = 8.7 , 2.1
hz , 1h ) , 6.43 ( d , j = 2.1 hz , 1h ) , 4.454.38
( m , 1h ) , 2.702.61 ( m , 2h ) , 1.881.80 ( m , 1h ) , 1.701.63
( m , 1h ) , 1.551.25 ( m , 14h ) , 0.890.86 ( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 193.1 , 164.4 ,
129.5 , 114.6 , 110.9 , 103.4 , 78.3 , 42.5 , 35.0 , 32.0 , 29.7 , 29.6 , 29.5 ,
29.4 , 25.0 , 22.8 , 14.2 . hrms calculated for c18h26o3 ( m h ) 289.1809 , found ( m
h ) 289.1787 .
hplc purity : 99.1% ( 254 nm ) , tr = 7.71 min ; 99.3% ( 220 nm ) , tr = 7.71 min .
purified with reverse phase c18 silica gel chromatography
with h2o / mecn ( 45/55 ) to give the product ( 54 mg , 0.20
mmol , 20% ) as white solid .
h nmr ( 400 mhz ,
cdcl3 ) : ( ppm ) 7.79 ( d , j = 8.6
hz , 1h ) , 7.277.25 ( m , 2h ) , 7.207.16 ( m , 3h ) , 6.53
( dd , j = 8.7 , 1.8 hz , 1h ) , 6.45 ( d , j = 1.7 hz , 1h ) , 4.434.37 ( m , 1h ) , 2.912.76 ( m , 2h ) ,
2.712.59 ( m , 2h ) , 2.222.14 ( m , 1h ) , 2.011.94
( m , 1h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm )
192.7 , 164.3 , 164.2 , 141.0 , 129.5 , 128.7 , 128.6 , 126.3 , 114.6 , 111.0 ,
103.4 , 77.1 , 42.6 , 36.6 , 31.2 .
hrms calculated for c17h16o3 ( m h ) 267.1027 ,
found ( m h ) 267.1012 .
hplc purity : 100%
( 254 nm ) , tr = 6.69 min ; 99.5% ( 220 nm ) , tr = 6.69 min .
to a solution of corresponding mom - protected acetophenone
( 196 mg , 1 mmol ) in ethanol ( 2.5 ml ) was added dea ( 154 mg , 2.1 mmol )
and ( )-citronellal ( 309 mg , 2 mmol ) successively .
the resulting
mixture was stirred at 150 c in a pressure tube for 1 h. the
resulting solution was cooled to room temperature and diluted with
etoac . the organic layer was washed with 10% hcl aq , water , brine
and dried over na2so4 . the solvent was removed
under reduced pressure and the residue was dissolved in methanol ( 14
ml ) , followed by the careful addition of concentrated hcl ( 340 l ,
4 mmol ) , and the resulting mixture was stirred at room temperature
overnight .
afterward , the solution was concentrated and the crude
material was adsorbed onto silica gel and subjected to silica gel
chromatography with hexane / etoac to give the product .
purified with hexane / etoac ( 90/10 ) to obtain
a mixture of two diastereomers ( 167 mg , 0.58 mmol , 58% over two steps )
as white solid .
h nmr ( 400 mhz , cdcl3 ) :
( ppm ) 7.79 ( d , j = 8.6 hz , 2h ) , 6.55 ( d , j = 8.7 hz , 2h ) , 6.43 ( s , 2h ) , 5.98 ( br , 2h ) , 5.115.08
( m , 2h ) , 4.554.50 ( m , 2h ) , 2.692.56 ( m , 4h ) , 2.041.90
( m , 6h ) , 1.821.69 ( m , 2h ) , 1.68 ( s , 6h ) , 1.60 ( s , 6h ) , 1.441.32
( m , 4h ) , 1.261.19 ( m , 2h ) , 0.970.94 ( m , 6h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 192.95 ,
192.86 , 164.4 , 164.32 , 164.28 , 131.7 , 131.6 , 129.4 , 124.6 , 124.5 ,
114.6 , 110.9 , 103.4 , 76.2 , 43.2 , 42.9 , 42.3 , 42.2 , 37.5 , 36.9 , 28.9 ,
28.5 , 25.9 , 25.5 , 25.4 , 20.0 , 19.4 , 17.8 .
hrms calculated for c18h24o3 ( m h ) 287.1653 , found ( m h ) 287.1632 .
hplc
purity : 97.8% ( 254 nm ) , tr = 7.32 min ;
98.0% ( 220 nm ) , tr = 7.32 min .
purified with hexane / etoac ( 92/8 ) to obtain
a mixture of two diastereomers ( 216 mg , 0.75 mmol , 75% over two steps )
as yellow oil .
h nmr ( 400 mhz , cdcl3 ) :
( ppm ) 7.40 ( d , j = 3.1 hz , 2h ) , 7.07 ( dd , j = 8.9 , 3.1 hz , 2h ) , 6.91 ( br , 2h ) , 6.87 ( dd , j = 8.9 , 2.6 hz , 2h ) , 5.115.08 ( m , 2h ) , 4.514.45 ( m ,
2h ) , 2.712.58 ( m , 4h ) , 2.041.72 ( m , 8h ) , 1.68 ( s ,
6h ) , 1.60 ( s , 6h ) , 1.451.17 ( m , 6h ) , 0.970.94 ( m ,
6h ) . c nmr ( 100 mhz , cdcl3 ) : ( ppm )
194.2 , 194.1 , 156.44 , 156.38 , 150.5 , 131.61 , 131.56 , 125.3 , 124.61 ,
124.56 , 121.0 , 119.4 , 119.3 , 111.1 , 76.6 , 76.1 , 43.7 , 43.4 , 42.30 ,
42.26 , 37.5 , 36.9 , 28.9 , 28.6 , 25.8 , 25.5 , 25.4 , 20.0 , 19.4 , 17.8 .
hrms calculated for c18h24o3 ( m
h ) 287.1653 , found ( m h ) 287.1613 .
hplc purity : 99.8% ( 254 nm ) , tr = 7.40 min ; 99.7% ( 220 nm ) , tr = 7.38
min . purified by reverse phase c18 silica gel chromatography
with h2o / mecn ( 30/70 ) to obtain a mixture of two diastereomers
( 170 mg , 0.59 mmol , 59% over two steps ) as pale yellow oil .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 11.69 ( s , 2h ) , 7.33
( t , j = 8.3 hz , 2h ) , 6.48 ( dd , j = 8.3 , 0.8 hz , 2h ) , 6.41 ( ddd , j = 8.3 , 2.2 , 0.8
hz , 2h ) , 5.115.07 ( m , 2h ) , 4.524.48 ( m , 2h ) , 2.772.62
( m , 4h ) , 2.071.63 ( m , 8h ) , 1.68 ( s , 6h ) , 1.61 ( s , 6h ) , 1.471.18
( m , 6h ) , 0.980.95 ( m , 6h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 198.8 , 198.7 , 162.2 , 161.84 , 161.79 , 138.24 ,
138.23 , 131.7 , 131.6 , 124.54 , 124.48 , 109.2 , 108.4 , 107.48 , 107.47 ,
76.2 , 75.6 , 43.0 , 42.7 , 42.21 , 42.15 , 37.5 , 36.8 , 28.9 , 28.6 , 25.9 ,
25.5 , 25.4 , 20.0 , 19.4 , 17.8 .
hrms calculated for c18h24o3 ( m h ) 287.1653 ,
found ( m h ) 287.1604 .
hplc purity : 99.9%
( 254 nm ) , tr = 8.00 min ; 100% ( 220 nm ) , tr = 7.99 min .
to a solution of 1e ( 196 mg ,
1 mmol ) in ethanol ( 2.5 ml ) were added pyrrolidine ( 149 mg , 2.1 mmol )
and ( )-myrtenal ( 300 mg , 2 mmol ) successively .
the resulting
mixture was stirred at 75 c in a pressure tube for 1 h. afterward ,
the solution was diluted with ethyl acetate , and the organic layer
was washed with 10% hcl , water , brine and dried over na2so4 .
the solvent was removed under reduced pressure and
the crude material was adsorbed onto silica gel and subjected to silica
gel chromatography with hexane / etoac ( 97/3 ) to give compound 3h ( 160 mg , 0.48 mmol , 48% ) as yellow oil .
h nmr
( 400 mhz , cdcl3 ) : ( ppm ) 13.37 ( s , 1h ) , 7.75 ( d , j = 9.0 hz , 1h ) , 7.52 ( d , j = 15.1 hz ,
1h ) , 6.88 ( d , j = 15.1 hz , 1h ) , 6.61 ( d , j = 2.4 hz , 1h ) , 6.54 ( dd , j = 8.9 , 2.4
hz , 1h ) , 6.21 ( m , 1h ) , 5.20 ( s , 2h ) , 3.47 ( s , 3h ) , 2.682.67
( m , 1h ) , 2.552.41 ( m , 3h ) , 2.192.18 ( m , 1h ) , 1.39
( s , 3h ) , 1.18 ( d , j = 9.0 hz , 1h ) , 0.80 ( s , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 192.9 , 166.2 ,
163.5 , 146.5 , 145.6 , 137.3 , 131.3 , 116.7 , 115.2 , 108.1 , 104.0 , 94.2 ,
56.5 , 41.6 , 40.8 , 38.1 , 33.1 , 31.3 , 26.3 , 21.0 .
hrms calculated for
c20h24o4 ( m + h ) 329.1747 ,
found ( m + h ) 329.1735 .
hplc purity : 98.8% ( 254 nm ) , tr = 7.98 min ; 98.5% ( 220 nm ) , tr = 7.98 min .
to a solution of 3h ( 130 mg ,
0.396 mmol ) in methanol ( 6 ml ) was added concentrated hcl ( 154 l ,
1.78 mmol ) dropwise .
the resulting mixture was stirred at room temperature
for 24 h , after which the solvent was removed .
the crude material
was adsorbed onto silica gel and subjected to silica gel chromatography
with hexane / etoac ( 90/10 ) to obtain compound 3 g ( 100
mg , 0.35 mmol , 89% ) as yellow solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 13.56 ( s , 1h ) , 7.72 ( d , j = 9.5 hz , 1h ) , 7.51 ( d , j = 15.1 hz , 1h ) , 6.87
( d , j = 15.2 hz , 1h ) , 6.436.41 ( m , 2h ) , 6.20
( m , 1h ) , 2.67 ( t , j = 5.4 hz , 1h ) , 2.542.41
( m , 3h ) , 2.18 ( br , 1h ) , 1.38 ( s , 3h ) , 1.18 ( d , j =
9.0 hz , 1h ) , 0.79 ( s , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 193.0 , 166.2 , 163.1 , 146.5 , 145.8 , 137.5 , 132.1 ,
116.6 , 114.5 , 108.0 , 103.8 , 41.5 , 40.8 , 38.1 , 33.1 , 31.3 , 26.3 , 21.0 .
hrms calculated for c18h20o3 ( m
h ) 283.1340 , found ( m h ) 283.1313 .
hplc purity : 99.3% ( 254 nm ) , tr = 7.48 min ; 99.2% ( 220 nm ) , tr = 7.48
min .
to a solution of 3h ( 60 mg ,
0.183 mmol ) in ethanol ( 3 ml ) was added sodium acetate ( 300 mg , 3.6
mmol ) .
the resulting mixture was refluxed for 24 h , after which the
solvent was removed .
the residue was dissolved in ethyl acetate , and
the organic layer was washed with water , brine and dried over na2so4 .
the solvent was removed under reduced pressure
and the crude material was adsorbed onto silica gel and subjected
to silica gel chromatography with hexane / etoac ( 95/5 ) to obtain a
mixture of two diastereomers 3i ( 28 mg , 0.085 mmol , 47% )
as clear oil .
h nmr ( 400 mhz , cdcl3 ) :
( ppm ) 7.827.79 ( m , 2h ) , 6.666.62 ( m , 2h ) , 6.61 ( s ,
2h ) , 5.675.64 ( m , 2h ) , 5.19 ( s , 2h ) , 5.18 ( s , 2h ) , 4.884.77
( m , 2h ) , 3.47 ( s , 3h ) , 3.46 ( s , 3h ) , 2.822.72 ( m , 2h ) , 2.662.53
( m , 2h ) , 2.512.38 ( m , 3h ) , 2.342.23 ( m , 5h ) , 2.12
( br , 2h ) , 1.321.30 ( m , 6h ) , 1.281.14 ( m , 2h ) , 0.87
( s , 3h ) , 0.74 ( s , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 191.6 , 191.5 , 163.59 , 163.58 , 163.50 , 163.48 , 145.4 ,
145.3 , 128.72 , 128.67 , 122.1 , 120.7 , 115.9 , 115.8 , 111.0 , 103.63 ,
103.58 , 94.15 , 94.14 , 80.3 , 79.8 , 77.4 , 56.5 , 56.4 , 42.6 , 42.2 , 41.0 ,
40.9 , 40.8 , 38.2 , 38.0 , 31.8 , 31.7 , 31.38 , 31.36 , 26.24 . 26.20 , 21.40 ,
21.35 .
hrms calculated for c20h24o4 ( m + h ) 329.1747 , found ( m + h ) 329.1736 .
hplc purity : 99.6% ( 49.0% + 50.6% ) ( 254 nm ) , tr = 7.66 and 7.68 min ; 98.8% ( 220 nm ) , tr = 7.66 min .
the split hplc product peaks further supported
the product is a mixture of two diastereomers ( see supporting information for the details of hplc trace ) . to a solution of 3i ( 38 mg ,
0.116 mmol ) in methanol ( 2 ml ) was added concentrated hcl ( 45 l ,
0.52 mmol ) carefully .
the resulting mixture was stirred at room temperature
for 24 h , after which the solvent was removed .
the crude material
was adsorbed onto silica gel and subjected to silica gel chromatography
with hexane / etoac ( 85/15 ) to obtain a mixture of two diastereomers 3j ( 30 mg , 0.106 mmol , 90% ) as white solid . h
nmr ( 400 mhz , cdcl3 ) : ( ppm ) 7.797.76 ( m ,
2h ) , 7.67 ( br , 2h ) , 6.546.51 ( m , 2h ) , 6.436.42 ( m ,
2h ) , 5.655.64 ( m , 2h ) , 4.874.77 ( m , 2h ) , 2.842.75
( m , 2h ) , 2.672.54 ( m , 2h ) , 2.492.22 ( m , 8h ) , 2.11
( br , 2h ) , 2.00 ( br , 2h ) , 1.311.29 ( m , 6h ) , 1.261.12
( m , 2h ) , 0.85 ( s , 3h ) , 0.73 ( s , 3h ) . c nmr ( 100 mhz ,
cdcl3 ) : ( ppm ) 192.39 , 192.36 , 164.0 , 163.7 , 145.3 ,
145.2 , 129.4 , 129.3 , 122.2 , 120.9 , 114.89 , 114.86 , 110.62 , 110.61 ,
103.5 , 80.1 , 79.6 , 77.4 , 77.1 , 42.6 , 42.2 , 40.9 , 40.83 , 40.79 , 40.7 ,
38.2 , 38.0 , 31.8 , 31.7 , 31.39 , 31.36 , 26.24 , 26.20 , 21.38 , 21.36 .
hrms calculated for c18h20o3 ( m
h ) 283.1340 , found ( m h ) 283.1310 .
hplc purity : 99.4% ( 49.7% + 49.7% ) ( 254 nm ) , tr = 7.09 and 7.11 min ; 99.6% ( 50.6% + 49.0% ) ( 220 nm ) , tr = 7.09 and 7.11 min .
the split hplc product
peaks further supported the product is a mixture of two diastereomers
( see supporting information for the details
of hplc trace ) . to a solution of appropriate
4-chromanone 3a d ( 0.22 mmol ) in
methanol ( 3 ml )
was added sodium borohydride ( 16.6 mg , 0.44 mmol )
every 1.5 h for a total of 9 h. the resulting mixture was allowed
to stir at room temperature overnight .
the mixture was cooled to 0
c , quenched with saturated nh4cl aq carefully , and
extracted with etoac twice .
the combined organic layer was washed
with water , brine and dried over na2so4 .
the
solvent was removed under reduced pressure and the crude material
was adsorbed onto silica gel and subjected to silica gel chromatography
with hexane / etoac to give the product .
purified with hexane / etoac ( 85/15 ) to give
the product ( 29 mg , 0.14 mmol , 64% ) as light brown oil .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 7.19 ( d , j = 8.4 hz , 1h ) , 6.64 ( br , 1h ) , 6.34 ( dd , j = 8.4 , 2.4 hz , 1h ) , 6.24 ( d , j = 2.4 hz , 1h ) , 4.834.79
( m , 1h ) , 4.044.98 ( m , 1h ) , 2.68 ( br , 1h ) , 2.33 ( br , 1h ) , 2.232.17
( m , 1h ) , 1.741.62 ( m , 2h ) , 1.591.39 ( m , 3h ) , 0.94
( t , j = 7.2 hz , 3h ) .
c nmr ( 100 mhz ,
cdcl3 ) : ( ppm ) 156.6 , 155.8 , 128.3 , 118.3 , 108.6 ,
103.1 , 75.2 , 65.5 , 38.0 , 37.6 , 18.4 , 14.1 .
hrms calculated for c12h16o3 ( m h2o +
h ) 191.1067 , found ( m h2o +
purified with hexane / etoac ( 85/15 ) to give the product ( 42 mg ,
0.17 mmol , 77% ) as light brown oil .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 7.18 ( d , j = 8.4 hz , 1h ) ,
6.72 ( br , 1h ) , 6.34 ( dd , j = 8.4 , 2.4 hz , 1h ) , 6.25
( d , j = 2.4 hz , 1h ) , 4.824.80 ( m , 1h ) , 4.033.97
( m , 1h ) , 2.752.73 ( m , 1h ) , 2.43 ( br , 1h ) , 2.242.19
( m , 1h ) , 1.761.52 ( m , 3h ) , 1.501.30 ( m , 7h ) , 0.900.87
( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm )
156.5 , 155.8 , 128.3 , 118.3 , 108.6 , 103.1 , 75.5 , 65.6 , 38.0 , 35.5 ,
31.9 , 29.3 , 25.2 , 22.7 , 14.2 .
hrms calculated for c15h22o3 ( m h2o + h ) 233.1536 , found ( m h2o + h ) 233.1534 .
purified
with hexane / etoac ( 85/15 ) to give the product ( 39 mg , 0.15 mmol , 68% )
as light brown oil .
h nmr ( 400 mhz , cdcl3 ) :
( ppm ) 7.25 ( d , j = 8.4 hz , 1h ) , 6.39 ( dd , j = 8.4 , 2.5 hz , 1h ) , 6.26 ( d , j = 2.4
hz , 1h ) , 5.82 ( br , 1h ) , 4.884.82 ( m , 1h ) , 4.074.01
( m , 1h ) , 2.292.23 ( m , 1h ) , 2.112.09 ( m , 1h ) , 1.92
( br , 1h ) , 1.781.38 ( m , 5h ) , 1.331.28 ( m , 9h ) , 0.900.87
( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm )
156.6 , 155.9 , 128.3 , 118.5 , 108.5 , 103.1 , 75.5 , 65.6 , 38.2 , 35.6 ,
32.0 , 29.7 , 29.4 , 25.2 , 22.8 , 14.2 .
hrms calculated for c16h24o3 ( m h ) 263.1653 ,
found ( m h ) 263.1632 .
purified with hexane / etoac ( 85/15 ) to give
the product ( 52 mg , 0.18 mmol , 81% ) as light brown oil .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 7.19 ( d , j = 8.4 hz , 1h ) , 6.54 ( br , 1h ) , 6.34 ( dd , j = 8.4 , 2.4 hz , 1h ) , 6.25 ( d , j = 2.4 hz , 1h ) , 4.834.81
( m , 1h ) , 4.023.99 ( m , 1h ) , 2.612.59 ( m , 1h ) , 2.32
( br , 1h ) , 2.252.20 ( m , 1h ) , 1.751.53 ( m , 2h ) , 1.491.27
( m , 14h ) , 0.900.87 ( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 156.5 , 155.8 , 128.3 , 118.3 , 108.6 , 103.1 ,
75.5 , 65.6 , 38.1 , 35.5 , 32.0 , 29.72 , 29.70 , 29.5 , 25.2 , 22.8 , 14.2 .
hrms calculated for c18h28o3 ( m
h ) 291.1966 , found ( m h ) 291.1926 .
to a solution of 1h ( 256 mg , 1 mmol ) in ethanol ( 2.5 ml ) were added dea ( 154 mg , 2.1
mmol ) and corresponding aldehyde ( 2 mmol ) successively .
the resulting
mixture was stirred at 150 c in a pressure tube for 1 h. afterward ,
the solution was diluted with ethyl acetate and the organic layer
was washed with 10% hcl , water , brine and dried over na2so4 .
the solvent was removed under reduced pressure and
the crude material was adsorbed onto silica gel and subjected to silica
gel chromatography with hexane / etoac to give the mom - protected product . to a solution of appropriate mom - protected compound ( 0.22 mmol )
in methanol
( 4 ml ) was added concentrated hcl ( 172 l , 1.98
mmol ) at room temperature , and the resulting mixture was stirred overnight .
the solvent was removed under reduced pressure and the crude material
was adsorbed onto silica gel and subjected to silica gel chromatography
with hexane / etoac to give the corresponding deprotected product .
purified with hexane / etoac ( 87/13 ) to give
the product ( 195 mg , 0.63 mmol , 63% ) as clear oil .
h nmr
( 400 mhz , cdcl3 ) : ( ppm ) 6.37 ( s , 1h ) , 6.29 ( s ,
1h ) , 5.24 ( s , 2h ) , 5.16 ( s , 2h ) , 4.394.35 ( m , 1h ) , 3.51 ( s ,
3h ) , 3.46 ( s , 3h ) , 2.642.53 ( m , 2h ) , 1.831.79 ( m ,
1h ) , 1.661.43 ( m , 3h ) , 0.96 ( t , j = 7.1 hz ,
3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm )
190.1 , 164.8 , 163.2 , 159.5 , 107.5 , 97.8 , 97.2 , 95.1 , 94.1 , 77.3 , 56.64 ,
56.57 , 44.3 , 37.0 , 18.3 , 14.0 .
hrms calculated for c16h22o6 ( m + h ) 311.1489 , found ( m + h ) 311.1481 .
hplc purity : 98.0% ( 254 nm ) , tr = 6.78 min ; 96.3% ( 220 nm ) , tr = 6.78 min .
purified with hexane / etoac ( 85/15 ) to give the
product ( 46 mg , 0.207 mmol , 94% ) as white solid .
h nmr
( 400 mhz , cdcl3 ) : ( ppm ) 12.03 ( s , 1h ) , 7.24 ( br ,
1h ) , 5.97 ( s , 1h ) , 5.93 ( s , 1h ) , 4.414.36 ( m , 1h ) , 2.732.57
( m , 2h ) , 1.861.79 ( m , 1h ) , 1.691.42 ( m , 3h ) , 0.97
( t , j = 7.2 hz , 3h ) .
c nmr ( 100 mhz ,
cdcl3 ) : ( ppm ) 197.0 , 165.3 , 164.2 , 163.7 , 103.2 ,
96.5 , 95.5 , 41.6 , 36.9 , 18.2 , 14.0 .
hrms calculated for c12h14o4 ( m h ) 221.0819 ,
found ( m h ) 221.0802 .
hplc purity : 96.7%
( 254 nm ) , tr = 6.54 min ; 100% ( 220 nm ) , tr = 6.54 min .
purified with hexane / etoac ( 90/10 ) to give
the product ( 220 mg , 0.63 mmol , 63% ) as clear oil .
h nmr
( 400 mhz , cdcl3 ) : ( ppm ) 6.37 ( s , 1h ) , 6.30 ( s ,
1h ) , 5.24 ( s , 2h ) , 5.16 ( s , 2h ) , 4.394.32 ( m , 1h ) , 3.51 ( s ,
3h ) , 3.47 ( s , 3h ) , 2.652.53 ( m , 2h ) , 1.841.77 ( m ,
1h ) , 1.671.60 ( m , 1h ) , 1.551.30 ( m , 8h ) , 0.900.87
( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm )
190.0 , 164.8 , 163.2 , 159.5 , 107.5 , 97.8 , 97.3 , 95.1 , 94.1 , 77.6 , 56.6 ,
56.5 , 44.3 , 34.9 , 31.8 , 29.2 , 24.9 , 22.7 , 14.2 .
hrms calculated for
c19h28o6 ( m + h ) 353.1959 ,
found ( m + h ) 353.1954 .
hplc purity : 99.5% ( 254 nm ) , tr = 7.49 min ; 99.3% ( 220 nm ) , tr = 7.49 min .
purified with hexane / etoac ( 85/15 ) to give the
product ( 44 mg , 0.165 mmol , 75% ) as white solid .
h nmr
( 400 mhz , cdcl3 ) : ( ppm ) 12.02 ( s , 1h ) , 6.99 ( br ,
1h ) , 5.96 ( d , j = 1.9 hz , 1h ) , 5.93 ( d , j = 1.9 hz , 1h ) , 4.404.33 ( m , 1h ) , 2.722.57 ( m , 2h ) ,
1.861.78 ( m , 1h ) , 1.691.62 ( m , 1h ) , 1.541.30
( m , 8h ) , 0.900.87 ( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 197.0 , 165.3 , 164.2 , 163.7 , 103.2 , 96.5 ,
95.5 , 77.7 , 41.6 , 34.9 , 31.8 , 29.1 , 24.9 , 22.7 , 14.2 .
hrms calculated
for c15h20o4 ( m h ) 263.1289 , found ( m h ) 263.1264 .
hplc
purity : 97.9% ( 254 nm ) , tr = 7.26 min ;
99.1% ( 220 nm ) , tr = 7.26 min .
purified with hexane / etoac ( 90/10 ) to give
the product ( 220 mg , 0.60 mmol , 60% ) as clear oil .
h nmr
( 400 mhz , cdcl3 ) : ( ppm ) 6.37 ( s , 1h ) , 6.29 ( s ,
1h ) , 5.24 ( s , 2h ) , 5.16 ( s , 2h ) , 4.384.31 ( m , 1h ) , 3.51 ( s ,
3h ) , 3.46 ( s , 3h ) , 2.642.52 ( m , 2h ) , 1.851.76 ( m ,
1h ) , 1.681.59 ( m , 1h ) , 1.541.27 ( m , 10h ) , 0.890.86
( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm )
190.0 , 164.8 , 163.2 , 159.6 , 107.5 , 97.8 , 97.3 , 95.1 , 94.2 , 77.6 , 56.64 ,
56.57 , 44.3 , 34.9 , 31.9 , 29.5 , 29.3 , 25.0 , 22.8 , 14.2 .
hrms calculated
for c20h30o6 ( m + h ) 367.2115 ,
found ( m + h ) 367.2114 .
hplc purity : 99.6% ( 254 nm ) , tr = 7.69 min ; 98.8% ( 220 nm ) , tr = 7.69 min .
purified with hexane / etoac ( 90/10 ) to give the
product ( 49 mg , 0.176 mmol , 80% ) as white solid .
h nmr
( 400 mhz , cdcl3 ) : ( ppm ) 12.03 ( s , 1h ) , 6.57 ( br ,
1h ) , 5.96 ( s , 1h ) , 5.93 ( s , 1h ) , 4.394.34 ( m , 1h ) , 2.722.57
( m , 2h ) , 1.861.79 ( m , 1h ) , 1.691.62 ( m , 1h ) , 1.541.26
( m , 10h ) , 0.900.87 ( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 196.9 , 165.0 , 164.3 , 163.6 , 103.3 , 96.5 ,
95.4 , 77.8 , 41.7 , 34.9 , 31.9 , 29.4 , 29.3 , 25.0 , 22.8 , 14.2 .
hrms calculated
for c16h22o4 ( m h ) 277.1445 , found ( m h ) 277.1420 .
hplc
purity : 98.6% ( 254 nm ) , tr = 7.47 min ;
98.8% ( 220 nm ) , tr = 7.47 min .
purified with hexane / etoac ( 90/10 ) to give
the product ( 218 mg , 0.55 mmol , 55% ) as clear oil .
h nmr
( 400 mhz , cdcl3 ) : ( ppm ) 6.37 ( s , 1h ) , 6.29 ( s ,
1h ) , 5.24 ( s , 2h ) , 5.16 ( s , 2h ) , 4.374.31 ( m , 1h ) , 3.51 ( s ,
3h ) , 3.47 ( s , 3h ) , 2.642.53 ( m , 2h ) , 1.811.76 ( m ,
1h ) , 1.671.59 ( m , 1h ) , 1.541.26 ( m , 14h ) , 0.890.85
( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm )
190.1 , 164.8 , 163.2 , 159.6 , 107.5 , 97.8 , 97.3 , 95.1 , 94.2 , 77.6 , 56.64 ,
56.57 , 44.3 , 34.9 , 32.0 , 29.63 , 29.63 , 29.5 , 29.4 , 25.0 , 22.8 , 14.2 .
hrms calculated for c22h34o6 ( m +
h ) 395.2428 , found ( m + h ) 395.2407 .
hplc
purity : 99.9% ( 254 nm ) , tr = 8.09 min ;
99.5% ( 220 nm ) , tr = 8.09 min .
purified with hexane / etoac ( 90/10 ) to give
the product ( 55 mg , 0.18 mmol , 82% ) as white solid . h
nmr ( 400 mhz , cdcl3 ) : ( ppm ) 12.05 ( s , 1h ) , 5.95
( s , 1h ) , 5.92 ( s , 1h ) , 5.44 ( br , 1h ) , 4.404.35 ( m , 1h ) , 2.722.58
( m , 2h ) , 1.861.80 ( m , 1h ) , 1.691.61 ( m , 1h ) , 1.541.26
( m , 14h ) , 0.900.88 ( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 197.1 , 165.4 , 164.2 , 163.7 , 103.2 , 96.5 ,
95.5 , 77.7 , 41.6 , 34.8 , 32.0 , 29.62 , 29.58 , 29.5 , 29.4 , 24.9 , 22.8 ,
14.2 .
hrms calculated for c18h26o4 ( m h ) 305.1758 , found ( m h ) 305.1719 .
hplc purity : 99.7% ( 254 nm ) , tr = 7.87 min ; 99.2% ( 220 nm ) , tr = 7.87 min .
purified with hexane / etoac ( 90/10 ) to obtain
a mixture of two diastereomers ( 275 mg , 0.70 mmol , 70% ) as clear oil .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 6.35 ( s ,
2h ) , 6.27 ( s , 2h ) , 5.22 ( s , 4h ) , 5.14 ( s , 4h ) , 5.075.05 ( m ,
2h ) , 4.464.41 ( m , 2h ) , 3.49 ( s , 6h ) , 3.44 ( s , 6h ) , 2.612.45
( m , 4h ) , 1.991.68 ( m , 8h ) , 1.65 ( s , 6h ) , 1.57 ( s , 6h ) , 1.411.14
( m , 6h ) , 0.930.91 ( m , 6h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 189.9 , 189.8 , 164.72 , 164.67 , 163.1 , 159.49 ,
159.48 , 131.5 , 131.4 , 124.54 , 124.48 , 107.5 , 97.8 , 97.22 , 97.21 , 95.0 ,
94.1 , 76.1 , 75.5 , 56.53 , 56.46 , 44.9 , 44.5 , 42.11 , 42.06 , 37.4 , 36.8 ,
28.7 , 28.4 , 25.8 , 25.4 , 25.3 , 19.9 , 19.4 , 17.7 .
hrms calculated for
c22h32o6 ( m + h ) 393.2272 ,
found ( m + h ) 393.2263 .
hplc purity : 98.8% ( 254 nm ) , tr = 7.71 min ; 98.4% ( 220 nm ) , tr = 7.71 min .
purified with hexane / etoac ( 90/10 ) to obtain
a mixture of two diastereomers ( 54 mg , 0.176 mmol , 80% ) as white solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 12.02 ( s ,
2h ) , 7.25 ( br , 2h ) , 5.97 ( s , 2h ) , 5.94 ( s , 2h ) , 5.095.08 ( m ,
2h ) , 4.514.46 ( m , 2h ) , 2.732.56 ( m , 4h ) , 2.041.70
( m , 8h ) , 1.68 ( s , 6h ) , 1.60 ( s , 6h ) , 1.531.32 ( m , 4h ) , 1.251.18
( m , 2h ) , 0.980.94 ( m , 6h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 197.1 , 197.0 , 165.4 , 164.2 , 163.67 , 163.65 ,
131.72 , 131.67 , 124.54 , 124.48 , 103.2 , 96.6 , 95.62 , 95.60 , 76.3 , 75.7 ,
42.3 , 42.14 , 42.08 , 41.9 , 37.5 , 36.8 , 28.9 , 28.5 , 25.8 , 25.5 , 25.4 ,
20.0 , 19.4 , 17.8 .
hrms calculated for c18h24o4 ( m h ) 303.1602 , found ( m
h ) 303.1564 .
hplc purity : 98.4% ( 254 nm ) , tr = 7.50 min ; 98.4% ( 220 nm ) , tr = 7.50 min .
purified with hexane / etoac ( 85/15 ) to give
the product ( 174 mg , 0.70 mmol , 70% over two steps ) as white solid .
h nmr ( 400 mhz , dmso - d6 ) :
( ppm ) 12.12 ( s , 1h ) , 10.73 ( s , 1h ) , 5.83 ( s , 2h ) , 4.264.20
( m , 1h ) , 2.802.73 ( m , 1h ) , 2.612.56 ( m , 1h ) , 2.182.12
( m , 1h ) , 1.841.78 ( m , 1h ) , 1.721.42 ( m , 6h ) , 1.321.27
( m , 1h ) .
c nmr ( 100 mhz , dmso - d6 ) : ( ppm ) 196.4 , 166.5 , 163.4 , 163.0 , 101.8 , 95.6 ,
94.8 , 80.7 , 43.3 , 40.1 , 28.3 , 27.7 , 25.0 , 24.9 .
hrms calculated for
c14h16o4 ( m h ) 247.0976 , found ( m h ) 247.0954 .
hplc
purity : 99.6% ( 254 nm ) , tr = 6.84 min ;
99.6% ( 220 nm ) , tr = 6.84 min .
purified with hexane / etoac ( 85/15 ) to give
the product ( 168 mg , 0.64 mmol , 64% over two steps ) as white solid .
h nmr ( 400 mhz , dmso - d6 ) :
( ppm ) 12.12 ( s , 1h ) , 10.74 ( s , 1h ) , 5.84 ( s , 2h ) , 4.244.18
( m , 1h ) , 2.852.77 ( m , 1h ) , 2.552.51 ( m , 1h ) , 1.911.88
( m , 1h ) , 1.751.63 ( m , 5h ) , 1.281.01 ( m , 5h ) .
c nmr ( 100 mhz , dmso - d6 ) :
( ppm ) 196.7 , 166.5 , 163.4 , 163.0 , 101.8 , 95.6 , 94.7 , 80.9 , 40.9 , 38.3 ,
27.58 , 27.56 , 25.9 , 25.43 , 25.36 .
hrms calculated for c15h18o4 ( m h ) 261.1132 ,
found ( m h ) 261.1106 .
hplc purity : 99.1%
( 254 nm ) , tr = 7.05 min ; 99.5% ( 220 nm ) , tr = 7.05 min .
to a solution of 1h ( 256 mg ,
1 mmol ) in ethanol ( 2.5 ml ) were added dea ( 154 mg , 2.1 mmol ) and
( )-myrtenal ( 300 mg , 2 mmol ) successively . the resulting mixture
was stirred at 150 c in a pressure tube for 4 h. afterward ,
the solution was diluted with ethyl acetate and the organic layer
was washed with 10% hcl , water , brine and dried over na2so4 .
the solvent was removed under reduced pressure , and
the residue was dissolved in methanol ( 15 ml ) , followed by the addition
of concentrated hcl ( 765 l , 9 mmol ) dropwise .
the resulting
mixture was stirred at room temperature for 16 h , after which the
solvent was removed .
the crude material was adsorbed onto silica gel
and subjected to silica gel chromatography with hexane / etoac ( 75/25 )
to obtain compound 5 m ( 102 mg , 0.34 mmol , 34% ) as yellow
solid .
h nmr ( 400 mhz , cd3od ) : ( ppm )
7.55 ( d , j = 15.4 hz , 1h ) , 7.38 ( d , j = 15.4 hz , 1h ) , 6.11 ( s , 1h ) , 5.81 ( s , 2h ) , 2.652.64 ( m ,
1h ) , 2.572.47 ( m , 3h ) , 2.182.17 ( m , 1h ) , 1.38 ( s ,
3h ) , 1.18 ( d , j = 9.0 hz , 1h ) , 0.82 ( s , 3h ) .
c nmr ( 100 mhz , cd3od ) : ( ppm ) 194.6 , 166.2 ,
165.9 , 148.3 , 144.2 , 135.5 , 125.5 , 105.9 , 96.0 , 42.9 , 42.0 , 38.7 ,
33.7 , 32.0 , 26.6 , 21.2 .
hrms calculated for c18h20o4 ( m h ) 299.1289 , found ( m
h ) 299.1240 .
hplc purity : 99.6% ( 254 nm ) , tr = 7.29 min ; 99.9% ( 220 nm ) , tr = 7.29 min . to a suspension of 5 m ( 57
mg , 0.19 mmol ) in ethanol ( 2.5 ml )
the resulting mixture was stirred at 150 c under microwave
irradiation for 30 min .
the solvent was removed under reduced pressure
and the crude material was adsorbed onto silica gel and subjected
to silica gel chromatography with hexane / etoac ( 75/25 ) to obtain a
mixture of two diastereomers 5n ( 41 mg , 0.136 mmol , 72% )
as pale yellow solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 12.05 ( br , 2h ) , 5.985.94 ( m , 4h ) , 5.685.67
( m , 2h ) , 4.864.75 ( m , 2h ) , 2.892.80 ( m , 2h ) , 2.692.55
( m , 2h ) , 2.532.45 ( m , 2h ) , 2.432.26 ( m , 6h ) , 2.162.15
( m , 2h ) , 1.341.33 ( m , 6h ) , 1.291.16 ( m , 2h ) , 0.88
( s , 3h ) , 0.78 ( s , 3h ) . c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 196.82 , 196.80 , 165.2 , 164.2 , 163.5 , 145.0 , 144.8 ,
122.4 , 121.2 , 103.21 , 103.18 , 96.55 , 96.54 , 95.7 , 79.5 , 79.0 , 42.5 ,
42.2 , 40.9 , 40.8 , 39.8 , 39.7 , 38.2 , 38.0 , 31.7 , 31.6 , 31.4 , 31.3 ,
26.20 , 26.16 , 21.4 , 21.3 .
hrms calculated for c18h20o4 ( m h ) 299.1289 ,
found ( m h ) 299.1247 .
hplc purity : 99.7%
( 254 nm ) , tr = 7.53 min ; 99.9% ( 220 nm ) , tr = 7.52 min . to a suspension
of corresponding hydroxyamine ( 0.8 mmol ) in ethanol ( 1 ml
) was added
pyridine ( 64 mg , 0.8 mmol ) . after stirring at room temperature for
15 min , the solution of appropriate 4-chromanone ( 0.1 mmol ) in ethanol
( 2 ml ) was added .
the resulting mixture was stirred for 2672
h at room temperature , after which the solvent was removed .
etoac
was added to the residue , and the organic layer was washed with water ,
brine and dried over na2so4 .
the solvent was
removed under reduced pressure and the crude material was adsorbed
onto silica gel and subjected to silica gel chromatography with hexane / etoac
to give oxime compound .
purified with hexane / etoac ( 85/15 ) to give
the product ( 29 mg , 0.09 mmol , 90% ) as white solid .
h
nmr ( 400 mhz , cd3od ) : ( ppm ) 5.89 ( d , j = 2.3 hz , 1h ) , 5.85 ( d , j = 2.3 hz , 1h ) , 3.993.93
( m , 1h ) , 3.24 ( dd , j = 17.1 , 3.5 hz , 1h ) , 2.32 ( dd , j = 17.1 , 11.4 hz , 1h ) , 1.791.70 ( m , 1h ) , 1.671.59
( m , 1h ) , 1.571.30 ( m , 14h ) , 0.920.88 ( m , 3h ) .
c nmr ( 100 mhz , cd3od ) : ( ppm ) 161.5 , 160.7 ,
159.5 , 154.7 , 98.8 , 97.3 , 96.2 , 76.2 , 36.1 , 33.1 , 30.69 , 30.68 , 30.62 ,
30.5 , 29.0 , 26.2 , 23.7 , 14.5 .
hrms calculated for c18h27no4 ( m h ) 320.1867 ,
found ( m h ) 320.1818 .
hplc purity : 99.9%
( 254 nm ) , tr = 7.62 min ; 99.5% ( 220 nm ) , tr = 7.62 min .
purified with hexane / etoac
( 90/10 ) to give the product ( 27 mg , 0.081 mmol , 81% ) as white solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 10.96 ( s ,
1h ) , 6.04 ( d , j = 2.3 hz , 1h ) , 5.96 ( d , j = 2.3 hz , 1h ) , 5.60 ( br , 1h ) , 4.033.98 ( m , 1h ) , 3.94 ( s ,
3h ) , 3.18 ( dd , j = 17.2 , 3.0 hz , 1h ) , 2.36 ( dd , j = 17.2 , 11.6 hz , 1h ) , 1.821.73 ( m , 1h ) , 1.661.57
( m , 1h ) , 1.541.27 ( m , 14h ) , 0.900.86 ( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 159.7 , 159.1 ,
158.7 , 154.1 , 98.3 , 97.0 , 95.8 , 75.1 , 62.5 , 35.0 , 32.0 , 29.67 , 29.66 ,
29.59 , 29.5 , 28.6 , 25.2 , 22.8 , 14.3 .
hrms calculated for c19h29no4 ( m h ) 334.2024 ,
found ( m h ) 334.1977 .
hplc purity : 99.8%
( 254 nm ) , tr = 8.13 min ; 99.1% ( 220 nm ) , tr = 8.13 min .
purified with hexane / etoac
( 92/8 ) to give the product ( 34 mg , 0.083 mmol , 83% ) as white solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 10.89 ( s ,
1h ) , 7.397.31 ( m , 5h ) , 6.01 ( d , j = 2.4 hz ,
1h ) , 5.94 ( d , j = 2.3 hz , 1h ) , 5.45 ( br , 1h ) , 5.12
( s , 2h ) , 4.023.96 ( m , 1h ) , 3.22 ( dd , j =
17.2 , 3.0 hz , 1h ) , 2.40 ( dd , j = 17.2 , 11.6 hz , 1h ) ,
1.801.72 ( m , 1h ) , 1.651.57 ( m , 1h ) , 1.541.27
( m , 14h ) , 0.910.87 ( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 159.7 , 159.1 , 158.7 , 154.5 , 137.0 , 128.72 ,
128.68 , 128.5 , 98.4 , 96.9 , 95.8 , 76.7 , 75.0 , 35.0 , 32.0 , 29.67 , 29.65 ,
29.58 , 29.4 , 28.9 , 25.1 , 22.8 , 14.3 .
hrms calculated for c25h33no4 ( m + h ) 412.2482 , found
( m + h ) 412.2472 .
hplc purity : 99.1% ( 254 nm ) , tr = 8.36 min ; 98.7% ( 220 nm ) , tr = 8.37 min .
purified with hexane / etoac ( 83/17 ) to give
the product ( 20 mg , 0.084 mmol , 84% ) as white solid .
h
nmr ( 400 mhz , cd3od ) : ( ppm ) 5.90 ( s , 1h ) , 5.85
( s , 1h ) , 3.98 ( br , 1h ) , 3.24 ( d , j = 17.0 , 1h ) , 2.33
( dd , j = 17.0 , 11.4 hz , 1h ) , 1.751.72 ( m ,
1h ) , 1.631.47 ( m , 3h ) , 1.00.96 ( m , 3h ) .
c nmr ( 100 mhz , cd3od ) : ( ppm ) 161.5 , 160.7 , 159.5 ,
154.8 , 98.8 , 97.3 , 96.2 , 76.0 , 38.2 , 28.0 , 19.4 , 14.3 .
hrms calculated
for c12h15no4 ( m h ) 236.0928 , found ( m h ) 236.0908 .
hplc purity : 99.9% ( 254 nm ) , tr = 6.35
min ; 100% ( 220 nm ) , tr = 6.34 min .
purified with hexane / etoac ( 86/14 )
to give the product ( 22 mg , 0.08 mmol , 80% ) as white solid .
h nmr ( 400 mhz , cd3od ) : ( ppm ) 5.90 ( d , j = 2.3 hz , 1h ) , 5.85 ( d , j = 2.3 hz , 1h ) ,
3.973.91 ( m , 1h ) , 3.24 ( dd , j = 17.1 , 3.1
hz , 1h ) , 2.32 ( dd , j = 17.1 , 11.4 hz , 1h ) , 1.781.69
( m , 1h ) , 1.651.49 ( m , 2h ) , 1.451.32 ( m , 7h ) , 0.920.89
( m , 3h ) .
c nmr ( 100 mhz , cd3od ) : ( ppm )
161.4 , 160.6 , 159.5 , 154.7 , 98.8 , 97.3 , 96.2 , 76.2 , 36.0 , 32.9 , 30.3 ,
29.0 , 26.2 , 23.6 , 14.4 .
hrms calculated for c15h21no4 ( m h ) 278.1398 , found
( m h ) 278.1354 .
hplc purity : 99.8% ( 254
nm ) , tr = 7.02 min ; 99.9% ( 220 nm ) , tr = 7.01 min .
purified with hexane / etoac ( 90/10 )
to give the product ( 25 mg , 0.085 mmol , 85% ) as white solid .
h nmr ( 400 mhz , cd3od ) : ( ppm ) 5.90 ( s ,
1h ) , 5.85 ( s , 1h ) , 3.95 ( br , 1h ) , 3.24 ( d , j = 17.0
hz , 1h ) , 2.32 ( dd , j = 17.0 , 11.4 hz , 1h ) , 1.751.73
( m , 1h ) , 1.631.33 ( m , 11h ) , 0.90 ( br , 3h ) . c
nmr ( 100 mhz , cd3od ) : ( ppm ) 161.5 , 160.7 , 159.5 ,
154.7 , 98.8 , 97.3 , 96.2 , 76.2 , 36.0 , 33.0 , 30.6 , 30.3 , 29.0 , 26.2 ,
23.7 , 14.4 .
hrms calculated for c16h23no4 ( m h ) 292.1554 , found ( m
h ) 292.1512 .
hplc purity : 99.9% ( 254 nm ) , tr = 7.22 min ; 99.8% ( 220 nm ) , tr = 7.22 min .
to a solution
of 1e ( 196 mg , 1 mmol ) in ethanol ( 2.5 ml ) were added
pyrrolidine ( 149 mg , 2.1 mmol ) and corresponding cycloketone ( 2 mmol )
successively .
the resulting mixture was stirred at 150 c in
a pressure tube for 216 h. the resulting solution was cooled
to room temperature , and concentrated hcl ( 1.02 ml , 12 mmol ) was added .
afterward , the solution was diluted with etoac , and the organic layer
was washed with water , brine and dried over na2so4 .
the solvent was removed under reduced pressure and the crude material
was adsorbed onto silica gel and subjected to silica gel chromatography
with hexane / etoac to give the product .
purified with hexane / etoac ( 90/10 ) to give
the product ( 170 mg , 0.78 mmol , 78% over two steps ) as white solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 7.78 ( d , j = 8.6 hz , 1h ) , 7.12 ( br , 1h ) , 6.49 ( dd , j = 8.6 , 2.3 hz , 1h ) , 6.36 ( d , j = 2.3 hz , 1h ) , 2.78
( s , 2h ) , 2.092.04 ( m , 2h ) , 1.871.83 ( m , 2h ) , 1.721.59
( m , 4h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm )
192.5 , 163.7 , 162.8 , 129.2 , 114.9 , 110.1 , 104.0 , 90.5 , 46.8 , 37.7 ,
24.0 .
hrms calculated for c13h14o3 ( m h ) 217.0870 , found ( m h ) 217.0854 .
hplc purity : 99.1% ( 254 nm ) , tr = 6.26 min ; 98.7% ( 220 nm ) , tr = 6.26 min .
purified with hexane / etoac ( 90/10 ) to give
the product ( 207 mg , 0.89 mmol , 89% over two steps ) as white solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 7.77 ( d , j = 8.6 hz , 1h ) , 7.45 ( br , 1h ) , 6.50 ( dd , j = 8.6 , 2.2 hz , 1h ) , 6.42 ( d , j = 2.2 hz , 1h ) , 2.66
( s , 2h ) , 1.991.96 ( m , 2h ) , 1.721.59 ( m , 3h ) , 1.501.44
( m , 4h ) , 1.341.25 ( m , 1h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 192.6 , 164.0 , 162.2 , 129.0 , 114.6 , 110.1 ,
103.9 , 80.5 , 47.9 , 35.0 , 25.3 , 21.6 .
hrms calculated for c14h16o3 ( m h ) 231.1027 ,
found ( m h ) 231.1007 .
hplc purity : 98.2%
( 254 nm ) , tr = 6.47 min ; 98.8% ( 220 nm ) , tr = 6.47 min . purified by reverse phase c18 silica gel
chromatography with h2o / mecn ( 65/35 ) to give the product
( 130 mg , 0.53 mmol , 53% over two steps ) as white solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 8.26 ( br , 1h ) , 7.75
( d , j = 8.6 hz , 1h ) , 6.51 ( dd , j = 8.6 , 2.2 hz , 1h ) , 6.40 ( d , j = 2.2 hz , 1h ) , 2.70
( s , 2h ) , 2.092.03 ( m , 2h ) , 1.771.61 ( m , 6h ) , 1.571.50
( m , 2h ) , 1.431.36 ( m , 2h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 193.1 , 164.6 , 162.5 , 128.9 , 114.3 , 110.2 ,
103.9 , 84.7 , 48.5 , 38.4 , 29.4 , 22.1 .
hrms calculated for c15h18o3 ( m h ) 245.1183 ,
found ( m h ) 245.1154 .
hplc purity : 97.4%
( 254 nm ) , tr = 6.67 min ; 97.0% ( 220 nm ) , tr = 6.67 min .
to a solution
of corresponding acetophenone ( 1 mmol ) and appropriate benzaldehyde
( 1.5 mmol ) in methanol ( 10 ml ) was added 60% koh aqueous solution
( 1.5 ml ) dropwise at room temperature .
the resulting solution was
stirred for 60 h at room temperature , after which the reaction mixture
was neutralized with 10% hcl aq and extracted with ethyl acetate twice .
the solvent was removed under reduced pressure ,
and the residue was dissolved in methanol ( 14 ml ) , followed by the
careful addition of concentrated hcl ( 340 l , 4 mmol ) .
the obtained
mixture was stirred at room temperature until the mom - protected chalcone
was gone , and then the mixture was concentrated .
the crude material
was adsorbed onto silica gel and subjected to silica gel chromatography
with hexane / etoac to afford the chalcones .
purified with hexane / etoac ( 90/10 ) to give
the product ( 175 mg , 0.59 mmol , 59% over two steps ) as yellow solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 13.49 ( s ,
1h ) , 8.18 ( d , j = 15.6 hz , 1h ) , 7.81 ( d , j = 9.4 hz , 1h ) , 7.74 ( d , j = 15.6 hz ,
1h ) , 7.62 ( d , j = 7.6 hz , 1h ) , 7.36 ( t , j = 8.4 hz , 1h ) , 7.0 ( t , j = 7.5 hz , 1h ) , 6.94 ( d , j = 8.4 hz , 1h ) , 6.436.41 ( m , 2h ) , 6.22 ( s , 1h ) ,
6.166.09 ( m , 1h ) , 5.47 ( d , j = 17.2 hz , 1h ) ,
5.35 ( d , j = 10.6 hz , 1h ) , 4.65 ( d , j = 5.3 hz , 2h ) .
c nmr ( 100 mhz , cdcl3 ) :
( ppm ) 192.8 , 166.5 , 162.9 , 158.1 , 140.5 , 133.0 , 132.2 , 132.0 , 130.1 ,
124.2 , 121.4 , 121.2 , 118.4 , 114.8 , 112.8 , 107.9 , 103.9 , 69.5 .
hrms
calculated for c18h16o4 ( m
h ) 295.0976 , found ( m h ) 295.0955 .
hplc purity : 100% ( 254 nm ) , tr = 7.20 min ; 99.9% ( 220 nm ) , tr = 7.20
min . purified by reverse phase c18 silica gel
chromatography with h2o / mecn ( 43/57 ) to give the product
( 170 mg , 0.50 mmol , 50% over two steps ) as yellow solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 13.61 ( s , 1h ) , 8.11
( d , j = 15.6 hz , 1h ) , 7.817.77 ( m , 2h ) , 7.57
( dd , j = 7.6 , 1.2 hz , 1h ) , 7.35 ( t , j = 7.9 hz , 1h ) , 6.996.92 ( m , 3h ) , 6.456.43 ( m , 2h ) ,
4.084.04 ( m , 2h ) , 1.931.86 ( m , 2h ) , 1.561.49
( m , 2h ) , 1.391.32 ( m , 4h ) , 0.920.88 ( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 193.0 , 166.4 ,
163.2 , 158.8 , 141.1 , 132.14 , 132.06 , 130.7 , 123.8 , 121.3 , 120.7 , 114.6 ,
112.3 , 108.1 , 103.8 , 68.7 , 31.7 , 29.4 , 26.1 , 22.7 , 14.1 .
hrms calculated
for c21h24o4 ( m h ) 339.1602 , found ( m h ) 339.1550 .
hplc
purity : 99.6% ( 254 nm ) , tr = 8.00 min ;
98.9% ( 220 nm ) , tr = 8.01 min . purified by reverse phase c18 silica gel
chromatography with h2o / mecn ( 45/55 ) to give the product
( 195 mg , 0.53 mmol , 53% over two steps ) as yellow solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 13.64 ( s , 1h ) , 8.12
( d , j = 15.6 hz , 1h ) , 7.80 ( s , 1h ) , 7.77 ( d , j = 6.2 hz , 1h ) , 7.57 ( d , j = 7.5 hz , 1h ) ,
7.35 ( t , j = 8.2 hz , 1h ) , 7.14 ( br , 1h ) , 6.97 ( t , j = 7.5 hz , 1h ) , 6.92 ( d , j = 8.3 hz , 1h ) ,
6.466.44 ( m , 2h ) , 4.064.03 ( m , 2h ) , 1.921.85
( m , 2h ) , 1.551.48 ( m , 2h ) , 1.391.27 ( m , 8h ) , 0.880.85
( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm )
193.0 , 166.3 , 163.3 , 158.8 , 141.1 , 132.2 , 132.1 , 130.6 , 123.8 , 121.2 ,
120.7 , 114.6 , 112.3 , 108.2 , 103.8 , 68.7 , 31.9 , 29.5 , 29.4 , 29.3 , 26.4 ,
22.8 , 14.2 .
hrms calculated for c23h28o4 ( m + h ) 369.2060 , found ( m + h ) 369.2057 .
hplc purity : 99.5% ( 254 nm ) , tr = 8.36
min ; 99.4% ( 220 nm ) , tr = 8.36 min .
the crude solid was washed
with small amount of methanol three times to give the product ( 210
mg , 0.65 mmol , 65% over two steps ) as yellow solid . h
nmr ( 400 mhz , dmso - d6 ) : ( ppm )
8.19 ( d , j = 9.0 hz , 1h ) , 7.987.92 ( m , 3h ) ,
7.77 ( d , j = 15.4 hz , 1h ) , 7.67 ( br , 2h ) , 6.45 ( dd , j = 8.9 , 2.2 hz , 1h ) , 6.33 ( d , j = 2.2
hz , 1h ) , 3.493.46 ( m , 4h ) , 1.88 ( br , 4h ) , 1.64 ( br , 2h ) .
c nmr ( 100 mhz , dmso - d6 ) :
( ppm ) 191.7 , 166.3 , 165.8 , 133.5 , 131.0 , 113.5 , 108.8 , 103.1 , 24.0 .
hrms calculated for c20h21no3 ( m
h ) 322.1449 , found ( m h ) 322.1407 .
hplc purity : 99.0% ( 254 nm ) , tr = 5.99 min ; 98.8% ( 220 nm ) , tr = 5.98 min .
purified with hexane / etoac ( 70/30 ) to give
the product ( 106 mg , 0.34 mmol , 34% over two steps ) as yellow solid .
h nmr ( 400 mhz , cd3od ) : ( ppm ) 8.25 ( d , j = 15.8 hz , 1h ) , 8.10 ( d , j = 15.8 hz ,
1h ) , 7.61 ( dd , j = 7.7 , 1.3 hz , 1h ) , 7.347.30
( m , 1h ) , 7.06.94 ( m , 2h ) , 6.166.09 ( m , 1h ) , 5.86 ( s ,
2h ) , 5.45 ( dd , j = 17.3 , 1.6 hz , 1h ) , 5.29 ( dd , j = 10.6 , 1.4 hz , 1h ) , 4.63 ( d , j = 5.2
hz , 2h ) .
c nmr ( 100 mhz , cd3od ) : ( ppm )
194.5 , 166.4 , 166.1 , 158.9 , 138.2 , 134.6 , 132.4 , 129.5 , 129.1 , 126.0 ,
122.0 , 117.8 , 113.9 , 106.0 , 96.0 , 70.3 .
hrms calculated for c18h16o5 ( m h ) 311.0925 , found ( m h ) 311.0877 .
hplc
purity : 97.5% ( 254 nm ) , tr = 6.93 min ;
97.2% ( 220 nm ) , tr = 6.93 min .
purified with hexane / etoac ( 80/20 ) to give
the product ( 205 mg , 0.73 mmol , 73% over two steps ) as pale yellow
solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm )
8.42 ( br , 1h ) , 8.16 ( d , j = 15.8 hz , 1h ) , 8.017.99
( m , 2h ) , 7.70 ( d , j = 15.8 hz , 1h ) , 7.61 ( dd , j = 7.7 , 1.4 hz , 1h ) , 7.367.31 ( m , 1h ) , 7.036.96
( m , 3h ) , 6.91 ( d , j = 8.3 hz , 1h ) , 6.116.02
( m , 1h ) , 5.43 ( dd , j = 17.2 , 1.4 hz , 1h ) , 5.29 ( dd , j = 10.6 , 1.3 hz , 1h ) , 4.614.59 ( m , 2h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 190.8 , 161.6 , 158.0 ,
140.6 , 132.9 , 131.8 , 131.5 , 130.5 , 129.6 , 124.3 , 122.8 , 121.1 , 118.1 ,
115.9 , 112.7 , 69.3 .
hrms calculated for c18h16o3 ( m h ) 279.1027 , found ( m
h ) 279.0988 .
hplc purity : 99.6% ( 254 nm ) , tr = 6.99 min ; 99.8% ( 220 nm ) , tr = 6.99 min .
purified with hexane / etoac ( 90/10 ) to give
the product ( 113 mg , 0.38 mmol , 38% over two steps ) as yellow solid .
h nmr ( 400 mhz , dmso - d6 ) :
( ppm ) 13.40 ( s , 1h ) , 10.77 ( br , 1h ) , 8.23 ( d , j =
9.0 hz , 1h ) , 7.98 ( d , j = 15.4 hz , 1h ) , 7.76 ( d , j = 15.4 hz , 1h ) , 7.53 ( s , 1h ) , 7.43 ( d , j = 7.6 hz , 1h ) , 7.37 ( t , j = 7.7 hz , 1h ) , 7.05 ( dd , j = 8.0 , 2.0 hz , 1h ) , 6.43 ( dd , j = 8.9 ,
2.3 hz , 1h ) , 6.30 ( d , j = 2.2 hz , 1h ) , 6.116.03
( m , 1h ) , 5.44 ( dd , j = 17.3 , 1.4 hz , 1h ) , 5.29 ( d , j = 10.5 hz , 1h ) , 4.65 ( d , j = 5.2 hz ,
2h ) .
c nmr ( 100 mhz , dmso - d6 ) : ( ppm ) 191.5 , 165.9 , 165.3 , 158.6 , 143.7 , 136.0 , 133.6 ,
133.3 , 130.0 , 122.2 , 121.5 , 117.7 , 117.4 , 114.1 , 113.0 , 108.3 , 102.6 ,
68.4 .
hrms calculated for c18h16o4 ( m + h ) 297.1121 , found ( m + h ) 297.1107 .
hplc purity : 99.7% ( 254 nm ) , tr = 7.22
min ; 99.6% ( 220 nm ) , tr = 7.22 min .
purified with hexane / etoac ( 90/10 ) to give
the product ( 130 mg , 0.44 mmol , 44% over two steps ) as yellow solid .
h nmr ( 400 mhz , dmso - d6 ) : ( ppm ) 13.54 ( s , 1h ) , 10.70 ( br , 1h ) , 8.19 ( d , j = 9.0 hz , 1h ) , 7.877.75 ( m , 4h ) , 7.04 ( d , j = 8.7 hz , 2h ) , 6.41 ( dd , j = 8.9 , 2.3
hz , 1h ) , 6.29 ( d , j = 2.3 hz , 1h ) , 6.106.01
( m , 1h ) , 5.42 ( dd , j = 17.3 , 1.4 hz , 1h ) , 5.28 ( d , j = 10.5 hz , 1h ) , 4.65 ( d , j = 5.2 hz ,
2h ) .
c nmr ( 100 mhz , dmso - d6 ) : ( ppm ) 191.5 , 165.8 , 165.1 , 160.4 , 143.7 , 133.4 , 133.0 ,
131.0 , 127.4 , 118.6 , 117.8 , 115.1 , 113.0 , 108.2 , 102.6 , 68.4 .
hrms
calculated for c18h16o4 ( m + h ) 297.1121 , found ( m + h ) 297.1108 .
hplc purity :
99.8% ( 254 nm ) , tr = 7.18 min ; 99.6% ( 220
nm ) , tr = 7.18 min .
the obtained appropriate chalcone ( 0.2 mmol ) was dissolved in ethanol
( 2.5 ml ) with a catalytic amount of concentrated hcl and then heated
at 150 c under microwave irradiation for 1.5 h. the solvent
was removed under reduced pressure and the crude material was adsorbed
onto silica gel and subjected to silica gel chromatography with hexane / etoac
to afford the corresponding flavanones .
purified with hexane / etoac ( 90/10 ) to give
the product ( 30 mg , 0.1 mmol , 50% ) as pale yellow solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 7.85 ( d , j = 8.7 hz , 1h ) , 7.60 ( d , j = 7.6 hz , 1h ) ,
7.54 ( br , 1h ) , 7.30 ( t , j = 8.5 hz , 1h ) , 7.04 ( t , j = 7.5 hz , 1h ) , 6.89 ( d , j = 8.3 hz , 1h ) ,
6.58 ( dd , j = 8.7 , 2.2 hz , 1h ) , 6.51 ( d , j = 2.1 hz , 1h ) , 6.035.95 ( m , 1h ) , 5.87 ( dd , j = 11.3 , 5.0 hz , 1h ) , 5.34 ( d , j = 17.2
hz , 1h ) , 5.24 ( d , j = 10.6 hz , 1h ) , 4.614.51
( m , 2h ) , 2.972.86 ( m , 2h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm ) 192.6 , 164.5 , 163.9 , 154.9 , 133.0 , 129.6 ,
129.5 , 127.8 , 126.7 , 121.2 , 117.8 , 114.8 , 112.0 , 111.0 , 103.6 , 75.0 ,
69.0 , 43.4 .
hrms calculated for c18h16o4 ( m h ) 295.0976 , found ( m
h ) 295.0949 .
hplc purity : 98.0% ( 254 nm ) , tr = 6.76 min ; 99.0% ( 220 nm ) , tr = 6.76 min . purified by reverse phase c18 silica gel
chromatography with h2o / mecn ( 50/50 ) to give the product
( 35 mg , 0.1 mmol , 52% ) as pale yellow solid .
h nmr ( 400
mhz , cdcl3 ) : ( ppm ) 7.86 ( d , j =
8.7 hz , 1h ) , 7.58 ( d , j = 7.6 hz , 1h ) , 7.31 ( t , j = 8.5 hz , 1h ) , 7.02 ( t , j = 7.5 hz , 1h ) ,
6.89 ( d , j = 8.2 hz , 1h ) , 6.59 ( dd , j = 8.7 , 2.2 hz , 1h ) , 6.52 ( d , j = 2.1 hz , 1h ) , 5.865.82
( m , 1h ) , 4.033.93 ( m , 2h ) , 2.962.87 ( m , 2h ) , 1.791.72
( m , 2h ) , 1.451.37 ( m , 2h ) , 1.311.27 ( m , 4h ) , 0.870.84
( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm )
192.8 , 164.5 , 164.1 , 155.5 , 129.52 , 129.50 , 127.5 , 126.5 , 120.7 , 114.7 ,
111.5 , 111.0 , 103.6 , 75.1 , 68.3 , 43.3 , 31.6 , 29.2 , 25.9 , 22.6 , 14.1 .
hrms calculated for c21h24o4 ( m
h ) 339.1602 , found ( m h ) 339.1563 .
hplc purity : 99.9% ( 254 nm ) , tr = 7.65 min ; 99.6% ( 220 nm ) , tr = 7.65
min . purified by reverse phase c18 silica gel chromatography
with h2o / mecn ( 42/58 ) to give the product ( 37 mg , 0.1 mmol ,
50% ) as pale yellow solid .
h nmr ( 400 mhz , cdcl3 ) : ( ppm ) 7.86 ( d , j = 8.7 hz , 1h ) , 7.58
( dd , j = 7.5 , 1.0 hz , 1h ) , 7.31 ( t , j = 7.8 hz , 1h ) , 7.02 ( t , j = 7.5 hz , 1h ) , 6.89 ( d , j = 8.2 hz , 1h ) , 6.60 ( dd , j = 8.7 , 2.2
hz , 1h ) , 6.53 ( d , j = 2.2 hz , 1h ) , 5.865.82
( m , 1h ) , 4.033.93 ( m , 2h ) , 2.972.87 ( m , 2h ) , 1.791.72
( m , 2h ) , 1.441.37 ( m , 2h ) , 1.321.24 ( m , 8h ) , 0.870.83
( m , 3h ) .
c nmr ( 100 mhz , cdcl3 ) : ( ppm )
192.9 , 164.6 , 164.2 , 155.5 , 129.53 , 129.49 , 127.5 , 126.5 , 120.7 , 114.6 ,
111.5 , 111.0 , 103.6 , 75.1 , 68.3 , 43.3 , 31.9 , 29.4 , 29.3 , 29.2 , 26.2 ,
22.7 , 14.2 .
hrms calculated for c23h28o4 ( m + h ) 369.2060 , found ( m + h ) 369.2056 .
hplc purity : 99.9% ( 254 nm ) , tr = 8.05
min ; 99.9% ( 220 nm ) , tr = 8.05 min .
purified with hexane / etoac ( 84/16 ) to give the product
( 37 mg , 0.11 mmol , 57% ) as pale yellow solid .
h nmr ( 400
mhz , cd3od ) : ( ppm ) 7.73 ( d , j =
8.7 hz , 1h ) , 7.377.35 ( m , 2h ) , 7.026.99 ( m , 2h ) , 6.50
( dd , j = 8.7 , 2.2 hz , 1h ) , 6.36 ( d , j = 2.2 hz , 1h ) , 5.39 ( dd , j = 12.9 , 2.9 hz , 1h ) ,
3.193.16 ( m , 4h ) , 3.06 ( dd , j = 16.9 , 12.9
hz , 1h ) , 2.70 ( dd , j = 16.9 , 3.0 hz , 1h ) , 1.751.69
( m , 4h ) , 1.631.59 ( m , 2h ) .
c nmr ( 100 mhz , cd3od ) : ( ppm ) 193.6 , 166.8 , 165.6 , 153.8 , 131.2 , 129.9 ,
128.5 , 117.7 , 115.1 , 115.0 , 111.7 , 103.8 , 81.0 , 51.9 , 44.8 , 26.8 ,
25.4 .
hrms calculated for c20h21no3 ( m h ) 322.1449 , found ( m h ) 322.1401 .
hplc purity : 97.4% ( 254 nm ) , tr = 5.22 min ; 98.7% ( 220 nm ) , tr = 5.22 min .
purified with hexane / etoac ( 85/15 ) to give
the product ( 47 mg , 0.15 mmol , 75% ) as white solid .
h
nmr ( 400 mhz , cd3od ) : ( ppm ) 7.54 ( d , j = 7.6 hz , 1h ) , 7.30 ( td , j = 7.9 , 1.6 hz , 1h ) ,
7.036.99 ( m , 2h ) , 6.116.01 ( m , 1h ) , 5.95 ( d , j = 2.1 hz , 1h ) , 5.90 ( d , j = 2.1 hz , 1h ) ,
5.73 ( dd , j = 12.7 , 3.2 hz , 1h ) , 5.38 ( dd , j = 17.3 , 1.6 hz , 1h ) , 5.25 ( dd , j = 10.6 ,
1.4 hz , 1h ) , 4.654.56 ( m , 2h ) , 2.992.91 ( m , 1h ) , 2.832.78
( m , 1h ) .
c nmr ( 100 mhz , cd3od ) : ( ppm )
197.7 , 168.3 , 165.5 , 165.0 , 156.4 , 134.6 , 130.5 , 128.8 , 127.5 , 122.0 ,
117.6 , 113.2 , 103.3 , 97.2 , 96.2 , 75.7 , 70.0 , 43.1 .
hrms calculated
for c18h16o5 ( m h ) 311.0925 , found ( m h ) 311.0877 .
hplc
purity : 99.8% ( 254 nm ) , tr = 7.14 min ;
99.6% ( 220 nm ) , tr = 7.14 min .
mic values were determined against m. tuberculosis ( h37rv ) and other bacteria using the standard
microbroth dilution method exactly as previously described , which is based on the methods by the clinical
and laboratory standards institute .
cytotoxicity was assessed in vitro using vero cells ( kidney epithelial
cells , atcc ccl-81 ) as described previously . in brief , monolayers of cells cultured in dulbecco s modified
eagle medium ( dmem)/10% fetal bovine serum ( fbs ) were trypsinized ,
seeded at approximately 10% confluence in white - walled 96-well plates ,
and incubated overnight to allow adherence .
medium was replaced with
dmem / fbs containing 2-fold serial dilutions of test compounds .
detection
was performed using mtt ( celltiter96 , promega ) with overnight solubilization
according to the manufacturer s instructions .
the 2-fold serial dilutions
in clear , round - bottom 96-well plates were prepared in dmem with 5%
fbs .
the highest compound
concentration that did not result in visible precipitation of compound
was used to approximate the solubility limit in cell culture medium .
overnight cultures were diluted 1:25 in fresh
mueller hinton broth and grown to od600 nm
0.3 before being exposed to compounds at various increments of their
mics .
the effects of compounds on key
macromolecular processes were determined as described , using radiolabeled precursors from american
radiolabeled chemicals , inc .
: [ methyl - h]thymidine , [ 5,6-h]uridine , and [ 4,5-h]leucine for dna , rna , and
protein , respectively .
experiments were performed on three independent
mid - logarithmic cultures ( od600 nm 0.3 ) .
the antibiotics
ciprofloxacin ( dna , from sigma - aldrich ) , rifampicin ( rna , from tci
america ) , and erythromycin ( protein , from calbiochem ) were used as
positive controls .
the effects of compounds on the membrane potential of s.
aureus were evaluated by flow cytometry using the fluorescent
probe diethyloxacarbocyanine dye dioc2(3 ) .
the emission
of red fluorescence of dioc2(3 ) from cells is dependent
on the membrane potential , while green fluorescence emission is independent
of the membrane potential .
therefore , the ratio of red to green fluorescence
provides a measure of the effects of compounds on the membrane potential .
these experiments were performed as previously described , using s. aureus newman grown
to od600 nm 0.3 in mueller
samples
were analyzed using bd lsr ii flow cytometer and the effects of compounds
on the membrane potential evaluated using the software flowjo x 10.0.7
as described .
carbonyl cyanide m - chlorophenylhydrazone ( cccp ; sigma - aldrich ) and vancomycin
were used as positive and negative controls , respectively .
cscl
gradient purified plasmid dna ( 160 ng ) was added to relaxation reaction
buffer containing 10 mm tris - hcl , ph 8.0 , 50 mm nacl , 0.1 mg / ml gelatin ,
and 0.5 mm mgcl2 .
the resulting solution was divided into
9.5 l aliquots , to which 0.5 l of the 20 mm compounds
dissolved in dmso was added for final compound concentrations of 500
m .
ectopi
( 20 ng ) in 10 l of the relaxation reaction buffer was then
added to each dna / compound reaction mixture .
the reaction mixtures
were then incubated at 37 c for 30 min before the reaction was
terminated , and the mixtures were loaded onto a 1% agarose gel for
electrophoretic analysis in tae buffer ( 40 mm tris acetate ,
ph 8.1 , 2 mm edta ) as described previously .
the e. coli dna gyrase supercoiling assay was performed according
to the manufacturer s protocol .
briefly , 1.25 u of e. coli dna gyrase ( new england biolabs ) was added to 20
l of dna gyrase reaction mixture ( 35 mm tris - hcl , ph 7.5 , 24
mm kcl , 4 mm mgcl2 , 2 mm dtt , 1.75 mm atp , 5 mm spermidine ,
0.1 mg / ml bsa , 6.5% glycerol ) containing 300 ng of relaxed plasmid
dna substrate ( new england biolabs ) in the presence of indicated concentration
of compound .
after incubation at 37 c for 30 min , the reactions
were stopped and analyzed by agarose gel electrophoresis similarly
as the topoisomerase i relaxation assay .
ic50 values ( compound concentrations at which only 50%
of the input dna was converted to supercoiled form ) were calculated
by spot densitometry analysis with alphaview , alphaimager mini ( protein
simple ) .
the ic50 values represent the average from at
least two experiments performed separately . for the assay of decatenation
activity of topoisomerase iv , 0.25 u
of e. coli topoisomerase iv ( topogen )
was added to
20 l of decatenation reaction mixture ( 40 mm hepes - koh , ph
8.0 , 100 mm potassium glutamate , 10 mm magnesium acetate , 10 mm dithiothreitol ,
50 g of bsa / ml ) containing 290 ng of kinetoplast dna substrate
( topogen ) and 1 mm atp in the presence of indicated concentration
of compound .
after incubation at 37 c for 30 min , the reactions
were stopped by the addition of stop buffer ( 50 mm edta , 50% glycerol ,
and 0.5% ( v / v ) bromophenol blue ) .
the dna samples were electrophoresed
in a 1% agarose gel containing 0.5 g / ml ethidium bromide in
tae buffer also containing 0.5 g / ml ethidium bromide . visualization
of the bands was carried out by exposure to uv light .
ic50 values ( compound concentrations at which only 50% of kinetoplast
dna was converted into monomeric products ) were calculated by spot
densitometry analysis with alphaview , alphaimager mini ( protein simple ) .
Output:
| on
the basis of recently reported abyssinone ii and olympicin a , a series
of chemically modified flavonoid phytochemicals were synthesized and
evaluated against mycobacterium tuberculosis and
a panel of gram - positive and -negative bacterial pathogens .
some of
the synthesized compounds exhibited good antibacterial activities
against gram - positive pathogens including methicillin resistant staphylococcus aureus with minimum inhibitory concentration
as low as 0.39 g / ml . sar analysis revealed that the 2-hydrophobic
substituent and the 4-hydrogen bond donor / acceptor of the 4-chromanone
scaffold together with the hydroxy groups at 5- and 7-positions enhanced
antibacterial activities ; the 2,4-dihydroxylated a
ring and the lipophilic substituted b ring of chalcone derivatives
were pharmacophoric elements for antibacterial activities . mode of
action studies performed on selected compounds revealed that they
dissipated the bacterial membrane potential , resulting in the inhibition
of macromolecular biosynthesis ; further studies showed that selected
compounds inhibited dna topoisomerase iv , suggesting complex mechanisms
of actions for compounds in this series . |
PubmedSumm118583 | ***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: three cases of single - port vats were performed for lung cancer in haeundae paik hospital .
preoperatively , needle biopsy was performed in all of the patients , and lung cancer was confirmed by microscopic examination . under general anesthesia ,
the patient was placed in a lateral decubitus position and one lung ventilation was performed .
a 3- to 4-cm incision was made in the 6th intercostal space on the anterior axillary line .
the soft tissue and intercostal muscles were retracted with an x - small alexis ( applied medical , rancho santa margarita , ca , usa ) wound retractor for securing the intercostal space ( fig .
30 thoracoscope ( karl storz endoscope ; karl storz , tuttlingen , germany ) was used in all of the patients .
the pulmonary vessels and bronchus were dissected with a 5-mm endoscopic grasper , spatula - shaped electrocautery , and 5-mm endoscopic harmonic scalpel ( harmonic ace ; ethicon endo - surgery , cincinnati , oh , usa ) .
first , the pulmonary veins were divided , and then branches of the pulmonary artery and bronchus were divided .
the pulmonary veins and bronchus were divided with endoscopic flexible linear staplers ( ethicon echelon flex ; ethicon endo - surgery ) in all cases .
the branches of pulmonary artery were also divided with endoscopic linear staplers in two left lower lobe cases . in a left upper lobe case , the segmental arteries were divided at the level of the proximal portion with endoscopic scissors after clipping with hemoclips ( hem - o - lok ; teleflex medical co. , westmeath , ireland ) because optimal angulation could not be achieved for stapling with endoscopic linear staplers . in the patients with incomplete fissure
after lobectomy , the resected lobe was removed using a protective bag in all cases .
routine systematic mediastinal and hilar lymph node dissection was performed with a harmonic scalpel in all cases .
the lymph nodes , including perinodal tissue , were removed . in all of the cases , the lower paratracheal ( no .
5 ) , paraaortic ( no . 6 ) , subcarinal ( no . 7 ) , lower paraesophageal ( no .
a 24-french chest tube was placed in the posterior part of the single incision ( fig .
the mean duration of the chest tube drainage was 3.71.2 days and mean amount of chest tube drainage for the initial 24 hours was 32392.4 ml .
vats is a minimally invasive technique that has advantages with regard to postoperative pain and respiratory function when compared with conventional thoracotomy . as the technique of vats evolved , minimally invasive major pulmonary resection , such as lobectomy and pneumonectomy , became possible .
generally , most surgeons have performed vats pulmonary resection with three or more incisions . recently ,
some authors have reported that one of advantages of single - port vats was less postoperative pain because only one intercostal space was involved .
reported that there was less postoperative pain and fewer cases of paresthesia in patients who underwent single - port vats than who underwent the traditional three - port vats .
however , most cases of single - port vats have been limited to diagnostic purposes or minor pulmonary resection .
gonzalez et al . first reported the outcomes of single - port vats lobectomy in 2010 .
the resected lobe was removed through this incision , and a single chest tube was placed in the posterior part of the incision .
they reported that there was no difference in postoperative results or operation time between single - port vats lobectomy and three - port vats lobectomy .
they also reported that a systematic lymph node dissection was possible . in haeundae paik hospital , three single - port vats lobectomies for lung cancer have been performed .
systematic lymph node dissection was possible to perform similarly to three - port vats lobectomy .
the mean operation time was 206.7 minutes . compared with the mean operation time of the three - port vats lobectomy for lung cancer in haeundae paik hospital ( 190.0 minutes ) , there was no significant difference .
however , there was no statistical significance because the number of patients who underwent single - port vats lobectomy was very small . with the accumulation of experience
some authors have reported that vats left upper lobectomy is the most difficult and challenging major pulmonary resection because of the branching pattern of the pulmonary artery .
gonzalez - rivas et al . reported that single - port vats left upper lobectomy was the most difficult .
they recommended using hemoclips to divide the pulmonary vessels . in our left upper lobectomy case , optimal angulation for stapling the vessels
we were able to perform the left upper lobectomy using hemoclips . when we performed the single - port lobectomies , the most difficult aspect of the procedure was optimal lung exposure and stapling the pulmonary vessels .
using a 30 thoracoscope , flexible stapler , and hemoclips would be helpful in solving these problems .
we prefer to make a single port in the 6th intercostal space on the anterior axillary line .
if the single port is made above the 6th intercostal space , investigating the lower lobe might be difficult .
if the single port is made below the 6th intercostal space , endoscopic instruments might not be able to reach the pulmonary apex .
the intercostal space on the anterior axillary line is wider than the space on the mid- or posterior axillary line , which could make the surgical procedure easier . in our cases
, there was less postoperative pain in the patients with a single - port on the anterior axillary line than in the patients with a port on the mid- or posterior axillary line . through more experience , determination of the appropriate location for the single incision for each lobe will be important . in conclusion
, we successfully used single - port vats to treat lung cancer in three patients . nevertheless , to evaluate the feasibility and advantages of single - port vats lobectomy for lung cancer , more experience , including right side lobectomies , will be required in well selected patients .
Output:
| video - assisted thoracic surgery ( vats ) is a minimally invasive technique that has many advantages in postoperative pain and recovery time . because of its advantages ,
vats is one of the surgical techniques widely used in patients with lung cancer .
most surgeons perform vats for lung cancer with three or more incisions .
as the technique of vats has evolved , single - port vats for lung cancer has been attempted and its advantages have been reported .
we describe our experiences of vats for lung cancer with a single incision in this report . |
PubmedSumm118584 | ***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 most clinicians are aware , clozapine is clearly superior in the management of treatment - resistant schizophrenia . unlike classic neuroleptic agents ,
clozapine does not cause parkinsonism , dystonia,1 or tardive dyskinesia , nor does it elevate prolactin levels.2 a meta - analysis3 confirmed the efficacy of clozapine over conventional neuroleptics in reducing symptoms of patients with both treatment - resistant and nonresistant schizophrenia .
however there is reluctance regarding its usage due to its side effects , and more recently , in some clinicians opinions , in terms of its metabolic profile .
the use of clozapine has been limited in view of the risk of agranulocytosis , despite clear evidence of its efficacy over other antipsychotics.4 wheeler estimated that the mean duration between year of first contact with a clinician and starting clozapine in 2,796 individuals was 9.7 years , and taylor et al calculated that the mean delay in using clozapine was 5 years in individuals admitted to london hospitals.5,6 clozapine was superior to risperidone and quetiapine for patients who discontinued a second - generation antipsychotic in phase i.5 the risk of neutropenia / agranulocytosis is about 0.38% with monitoring and 2.5% without it.6 clozapine has been shown to substantially reduce the risk of suicide , such that the benefit gained in the reduction in all - cause mortality far outweighs the risk of death from agranulocytosis.6,7 the mechanisms implicated are immunologically mediated , and there are at least three of them .
immune complexes may selectively adhere to granulocytes or their immature precursor cells , the drug may bind to the granulocytes as carriers of the immunogenic drug , and finally the drug may induce antibodies directed to granulocyte - specific structures.8,9 there was some suggestion that a metabolite could be responsible for clozapine - induced agranulocytosis , either by direct toxicity or through an immune - mediated mechanism .
it has been found that several drugs associated with a relatively high incidence of drug - induced agranulocytosis are metabolized by activated neutrophils to chemically reactive metabolites . in preliminary experiments with clozapine , it was found that it was metabolized by neutrophils.10,11 there have been attempts to identify genetic links in this area , eg , in a study carried out to examine the human leukocyte antigen - encoded genetic susceptibility to clozapine - induced agranulocytosis .
the antigens did not reveal any relation to this hematotoxic reaction.12 in view of the speculations that agranulocytosis is possibly caused by the clozapine - mediated stimulation of cytokines and soluble cytokine receptors release , followed by induction of granulocyte proliferation and induction of myeloperoxidase ( mpo ) and nadph - oxidase as nadph - oxidase / mpo which may oxidize clozapine to highly reactive nitrenium ions , the authors in a research project investigated the role of hereditary polymorphisms in the nadph oxidase / myeloperoxidase system in agranulocytosis patients who received clozapine ( n = 49 ) , ticlopidine ( n = 11 ) , and other drugs prior to the event .
sequencing the entire coding region of the nadph subunit cytochrome b245 , beta polypeptide ( cybb ; gps1 phase ) disclosed that cybb is a highly conserved gene , which does not represent a risk factor for clozapine - induced agranulocytosis .
the impact of polymorphic myeloperoxidase , however , needs further verification to predict a patient s risk to develop drug - induced agranulocytosis.13 despite manufacturing companies advertised willingness to allow a continued supply of medication on compassionate grounds for individuals undergoing chemotherapy , there are notable cases in which clozapine has been stopped when proper liaison had not been carried out between the services .
this can lead to disastrous consequences , with the patient becoming so unwell that the actual cancer treatment can not be carried out .
the following case report is of a similar nature , where a patient who had been stable for 15 years was taken off clozapine by the community psychiatrist following chemotherapy for lymphoma , which caused the white blood cells and neutrophils to fall , even though this was a predictable consequence of r - chop ( rituximab with cyclophosphamide , hydroxydaunorubicin , oncovin , and prednisolone ) chemotherapy .
there have been few case reports or expert reviews on this topic , although a recent case report was published in 2012.14 a manuscript in the british journal of psychiatry serves as good guidance for clinicians embarking on rechallenging patients on clozapine.15 patients were required to have a break for at least a week in order to qualify as a rechallenge patient .
in addition , communication with the monitoring division of the company is extremely important in order to obtain permission on compassionate grounds .
as there are other stakeholders involved in such cases ( ie , the oncology / hematology team administering the treatment ) , they would also have to be on board with it .
in the next part of this document , we discuss the case of ce , a 58-year - old male with chronic paranoid schizophrenia . institutional research ethics board approval ( psiy-380 - 12 ) and
ce had been placed on clozapine after several trials of other antipsychotics in 1998 , following a prolonged admission at a chronic care facility .
he had been stable from that time onwards with clozapine at 500 mg in divided doses , and was residing at a group home under the care of the local assertive community team ( act ) .
acts are multidisciplinary mental health teams that manage individuals with severe mental illness in the community .
they originated in north america in the 1980s as part of the planning to deinstitutionalize the chronic inpatient population and transition them in the community .
it is an intense form of support in the community in most places in north america to manage severely mentally ill patients with multiple needs who would otherwise be unable to stay outside tertiary care hospitals
. this community mental health team offers support in various domains , like medication compliance , maintenance of accommodation , employment , adhering to probation if required , managing addictions , and offering interventions to improve physical health . at some point
, the team was considering discharging him to a step - down service in the community .
he developed a swelling in the jaw ( 4 cm mass in the right preauricular region extending down into the submandibular region ) and a right axillary mass ( 6 cm ) , which was on examination a lymph - node swelling as noted by the family physician .
in addition to this , there were bilateral posterior sternocleidomastoid nodes ( measuring 12 cm ) .
this prompted a referral to an ear , nose , and throat specialist , who diagnosed him with a large b - cell lymphoma .
this being a treatable form of lymphoma , the hematologist started the chop therapy with additional rituximab , now popularly known as the r - chop therapy , used for b - cell lymphomas .
the first chemotherapy cycle was well tolerated by the patient , and showed a good response in shrinking of the mass .
however , his white cell and neutrophil count went quite low ( 1.1 and 0.8 , respectively ) on the 13th day of the cycle , though this was as predicted .
the local lab alerted the community psychiatrist when ce went for his monitoring blood work .
as a consequence of being in the red zone , the clozapine monitoring network was promptly informed and a discontinuation protocol initiated .
this had an adverse effect on his mental state : he became extremely agitated and restless , and was unable to sleep for days .
this proved to be inadequate , and he relapsed ; his usual relapse signature symptoms of religious delusions exacerbated , and he seemed to be clearly responding to auditory hallucinations .
unfortunately , this meant the hematology team could not give him his second treatment of the r - chop cycle .
this led to various issues between the act service , the hematology team , and the family , who were extremely unhappy with the situation .
he ended up in the acute psychiatric unit in view of his psychotic relapse . in an attempt to stabilize him ,
later on , aripiprazole was added to the regimen , which was titrated to 15 mg once daily .
he was much calmer and able to sleep , though still tormented by his active psychotic symptoms ( ie , religious delusions and auditory hallucinations ) .
the chemotherapy was resumed with the cover of filgrastim ( granulocyte colony - stimulating factor ) by the heme oncology team .
as his psychotic symptoms persisted a decision was made to reinitiate him on clozapine , and the clozapine support network was contacted .
the directive given by them was as follows : patient is deemed to be capable of consenting and signs the consent form .
letter to be submitted by the prescribing physician outlining the details of the treatment with chemotherapy regimen . monitoring criteria to be set by the prescribing physician in consensus with the hematologist .
the consultant hematologist would review the submissions and if in agreement , the patient would be registered with the novartis special program on a compassionate basis .
the monitoring service would be informed of the start and end dates of the chemotherapy . if the chemotherapy had ended the regular monitoring protocols would be put in place upon informing the monitoring service .
he continued to stay as an inpatient , and received all six cycles of the r - chop therapy with filgrastim cover .
his white blood cell counts remained within the range of 3.511.6 , with his neutrophils in the vicinity of 35 .
his lymphoma went onto clinical remission ; there was one remaining 2.5 cm right axillary node that was attributed to fibrotic tissue .
the patient s mental state gradually improved with upward titration of clozapine to achieve a suitable therapeutic response at 375 mg daily in divided doses . the achievement of adequate efficacy at a lower dose than previously was attributable to his substantial reduction in smoking while an inpatient .
his religious delusions went into the background and the auditory hallucinations lessened in intensity and frequency to a great extent .
he was finally discharged to the care of the act after being an inpatient for approximately 4 months .
the monitoring service was subsequently informed a few months later after review by the cancer ( heme oncology ) specialists that his treatment for the malignant lymphoma had been completed .
in this case , liaison between the cancer team , inpatient , and the community mental health team was successful in achieving a good outcome eventually , though unfortunately the patient suffered for a prolonged length of time . however , in hindsight this could have been done in a more effective and less painful manner .
such events might possibly become actionable in the future , as in this case there was a clearly identifiable cause for the agranulocytosis . in a published case report in the british journal of psychiatry ,
a patient was continued on clozapine despite a red - alert status ; this was an individual who required chemotherapy for a testicular carcinoma with pulmonary metastases .
it probably needs to be mentioned , though , that the treatment was initially delayed due to refusal to consent.14 in a manuscript published in the american journal of psychiatry,15 a comment was :
discontinuation of clozapine in a treatment resistant patient often results in relapse , and this may be prevented if the clinician is able to identify a causative agent other than clozapine .
the authors proposed that polypharmacy may have contributed to the initial episode of neutropenia as well as the failed rechallenge .
there are other similar case reports in which the patients were taking additional psychotropic medications that carry a risk for blood dyscrasia , namely valproic acid , haloperidol , or risperidone.16,17 in a letter to the editor in the american journal of psychiatry , the authors gave their opinion on drug interactions : benign ethnic neutropenia and medical comorbidity can often contribute to clozapine - induced agranulocytosis.17 most patients who develop neutropenia and agranulocytosis do not restart clozapine after its discontinuation.18 in terms of the risk of clozapine - induced agranulocytosis , there is reduced incidence after the first 6 months ; moreover , it is higher in women and increases with age.19 in the future , we might be able to identify individuals at higher risk of developing agranulocytosis / neutropenia by genetic linkage and hereditary polymorphism .
the risk of clozapine - induced leucopenia or agranulocytosis decreases exponentially over time , and after 1 year of treatment the incidence is nearly equivalent to that observed in phenothiazines.20 a systematic review published in 2012 examined patients who were rechallenged with clozapine after potentially life - threatening adverse events .
it showed that the rechallenge was successful in 69.6% patients and none of them died .
this systematic review in addition to the dunk et al15 study can possibly serve as some assurance and guidance to clinicians who are considering the possibility of a rechallenge .
these research papers have reliable data that indicates that rechallenges for neutropenia are successful in two - thirds of cases.15,2123 a high level of commitment on the part of the treating team is crucial to implementation of clozapine treatment in these circumstances , and after the treatment begins , the team must be able to contain their own and everybody else s anxiety .
in conclusion , this was an event that could have been avoided with some due diligence and close liaison between the various services with planning for the actual chemotherapy
. it would be beneficial if there were more data available in this area to guide clinicians in weighing the risks and benefits in making a decision as to whether to rechallenge patients on clozapine or with respect to how to avoid such a scenario arising by being prepared for the situation
. it could be worth suggesting that a descriptive column be added in the form from the clozapine - monitoring service to the discontinuation section in order to obtain useful clinical data .
as we are well aware with the patient population with schizophrenia , malignancy is not an uncommon occurrence .
in fact , it is a leading cause of death in addition to cardiac diseases in such patients . in a recent study in western australia ,
the findings were that more than 77% of excess deaths were attributed to physical health conditions , including cardiovascular diseases ( 29.9% ) and cancer ( 13.5% ) , and 13.9% of excess deaths were attributed to suicide.25
Output:
| we describe a case of a patient whose clozapine was discontinued after a red result following r - chop ( rituximab with cyclophosphamide , hydroxydaunorubicin , oncovin , and prednisolone ) chemotherapy for large b - cell lymphoma . in some cases , manufacturers grant permission , on compassionate grounds , for clozapine to be continued or reinitiated following assessment by their consultant hematologist .
other than a recent case report , there is not much literature surrounding this medical issue .
however , since the two leading causes of mortality in schizophrenia are cancer and cardiac disease , this is not an uncommon occurrence .
clinicians are reluctant to prescribe clozapine in view of its side - effect profile , despite its proven efficacy for managing treatment - resistant schizophrenia .
the alternative is to prescribe two antipsychotics to manage symptoms .
this approach may be associated with increased side effects , and evidence for actual benefits is scant .
the consequences were disastrous in this case , as the individual not only relapsed following clozapine discontinuation , but the therapy for this treatable form of lymphoma had to be delayed .
he was eventually admitted to an inpatient unit after having been stable for 15 years .
we managed to stabilize him with olanzapine and aripiprazole which enabled the heme - oncology group to resume r - chop therapy with filgrastim ( granulocyte colony - stimulating factor ) .
even so , he continued to exhibit severe psychotic symptoms , with religious delusions and auditory hallucinations .
we therefore applied for permission to rechallenge him on clozapine .
permission was granted when protocol conditions were met , and reinitiation went without any adverse events .
the patient s symptoms showed improvement within a few weeks , and the other antipsychotics were discontinued once clozapine was titrated up to 300 mg .
the decision to reinitiate clozapine following a red result is not to be taken lightly , but needs to be considered in terms of the risks versus benefits . more literature surrounding this issue would be of great benefit to clinicians , patients , and their families . |
PubmedSumm118585 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
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the output is the summary of an input biomedical literature in six sentences
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Input: the diagnosis and treatment of this disorder stands out as one of the most rapidly evolving area in medicine .
experience has shown that majority of pelvic pathology in infertile women is frequently not well appreciated by routine pelvic examinations and the usual diagnostic procedures . the ability to see and manipulate the uterus , fallopian tubes , and ovaries during laparoscopy
similarly , visualising the uterine cavity and identifying the possible pathology has made hysteroscopy an equally important tool in infertility evaluation .
the question of tubal morphology and patency , ovarian morphology , any unsuspected pelvic pathology , and uterine cavity abnormalities can all be resolved with accuracy at one session .
additionally , hysteroscopic guided biopsy and therapeutic procedures like polypectomy , myomectomy , septal resection , and adhesiolysis can be done in the same sitting .
this study was undertaken to evaluate the role of diagnostic hystero - laparoscopy ( dhl ) in the comprehensive work up of infertility , which would help in planning appropriate management .
this retrospective study was conducted at two tertiary care centres ( the infertility clinics of sriram chandra bhanj medical college and prachi hospital at cuttack , odisha ) from january to december in 2008 .
patients between 20 and 40 years of age with either primary or secondary infertility of more than 1 year duration were included in the study .
primary infertility patients were those who had never conceived before , while secondary infertile patients had at least one prior conception , irrespective of the outcome .
hormonal abnormalities known to cause anovulation like thyroid dysfunction , hyperprolactinemia , and polycystic ovarian syndrome were excluded .
the student 's t - test was used for comparison of continuous variables and chi - square test for proportions .
out of 300 patients , 206 ( 69% ) women had primary infertility and the rest ( 31% ) had secondary infertility .
the patients in secondary infertility group were slightly elder compared to primary group ( 28.8 3.7 vs. 31.1 4.5 years , p < 0.0001 ) .
but there was no difference in duration of infertility in two groups ( 4.8 3.2 vs. 4.5 2.9 years ) .
in primary infertility group , laparoscopic abnormalites were more common [ table 1 ] than hysteroscopy ( 35% vs. 17% , p < 0.0001 ) .
endometriosis and adnexal adhesions were the most common abnormalities detected in laparoscopy in primary and secondary infertility groups respectively [ table 2 ] .
the most common intrauterine pathology in both the groups was uterine septum [ table 3 ] .
the septum was extending upto the internal os of the cervix or beyond in complete septum .
out of 29 patients having septate uterus , only one had complete septum in primary infertility group .
multiple abnormalities were also detected ; laparoscopically in 17 patients and hysteroscopically in 6 patients .
the prevalence of unilateral and bilateral tubal block was equal in both the groups [ table 4 ] .
other than mild abdominal pain , there was no major surgical or anesthetic complication in any of our patients .
prevalence of hysteroscopy and laparoscopy abnormalities hysteroscopy findings prevalence of complete tubal block ( chromopertubation test )
tubal and peritoneal pathology account for the primary diagnosis in approximately 30 to 35% of infertile couples .
the gold standard technique for diagnosing these disorders is laparoscopy , which is a better predictor of future spontaneous pregnancy in infertile couples with unexplained infertility .
in addition , endometriosis and adnexal adhesions were the two major abnormalities found among infertile patients in different studies similar to our findings .
in contrast to the study by godinjak et al . , we got equal prevalence of tubal block in both groups of infertility patients .
uterine pathologies are the cause of infertility in as many as 15% of couples seeking treatment and are diagnosed in as many as 50% of infertile patients .
developmental uterine anomalies have long been associated with pregnancy loss and obstetric complications , but the ability to conceive is generally not affected .
septate uterus was the most common intrauterine abnormality in our study , which was undiagnosed by prior ultrasonography .
the pooled data suggest that the prevalence of septate uterus is similar in infertile and fertile women ( approximately 1% ) , but is significantly higher in women with recurrent pregnancy loss ( approximately 3.5% ) . among all congenital uterine abnormalities ,
although a diagnosis of septate uterus per se is not an indication for septoplasty , the reproductive performance of women with an uncorrected septum is rather poor ( 80% pregnancy loss , 10% preterm delivery , 10% term delivery ) with most losses occurring in the first trimester ( approximately 65% ) .
pregnancy outcomes dramatically improved after surgical correction ( 80% term delivery , 5% preterm delivery , 15% pregnancy loss ) .
previously , surgical correction of septate uterus was requiring an abdominal metroplasty , which was associated with increased morbidity and future pregnancy complications due to scarred uterus .
currently , the modern operative hysteroscopic techniques have made it a relatively easy and brief day care procedure with low morbidity and prompt recovery .
other than septate uterus , the major hysteroscopy abnormalities in our study were myomas and polyps similar to another study .
the evidence to suggest that uterine myomas decrease fertility is inferential and relatively weak ; the bulk of it is derived from studies that had compared the prevalence of myomas in fertile and infertile women or the reproductive performance of women with otherwise unexplained infertility before and after myomectomy .
proposed mechanisms by which myomas might adversely affect fertility include cornual myomas that involve or compress the interstitial segment of the tube , dysfunctional uterine contractility interfering with ovum or sperm transport or embryo implantation , and poor regional blood flow resulting in focal endometrial attenuation or ulceration . the incidence of asymptomatic endometrial polyps in women with infertility has been reported to range from 10% to 32% . a prospective study of 224 infertile women who underwent hysteroscopy observed a 50% pregnancy rate after polypectomy .
other than mild abdominal pain , there were no major surgical or anesthetic complications in any of our patients .
diagnostic hysterolaparoscopy is an effective and safe tool in comprehensive evaluation of infertility , particularly for detecting peritoneal endometriosis , adnexal adhesions , and septum in the uterus .
these are correctable abnormalities that are unfortunately missed by routine pelvic examination and usual imaging procedures .
needless to emphasize that , it is a very useful tool that can detect various structural abnormalities in multiple sites like pelvis , tubes , and the uterus in the same sitting in patients with normal ovulation and seminogram . when done by experienced hands and with proper selection of patients ,
hystero - laparoscopy can be considered as a definitive investigative daycare procedure for evaluation of female infertility .
Output:
| objective : to determine the role of diagnostic hysterolaparoscopy in the evaluation of infertility in tertiary care centres.materials and methods : this retrospective study was conducted at two tertiary care centres ( the infertility clinics of sriram chandra bhanj medical college and prachi hospital at cuttack , odisha ) throughout the year in 2008 .
women aged 20 - 40 years with normal hormone profile without male factor infertility were included.results:out of 300 cases , 206 ( 69% ) patients had primary infertility . while laparoscopy detected abnormalities in 34% of the cases , significant hysteroscopy findings were noted in 18% of cases .
together , diagnostic hysterolaparoscopy detected abnormalities in 26% of the infertile patients in both groups . while the most common laparoscopic abnormality was endometriosis ( 14% ) and adnexal adhesion ( 12% ) in primary and secondary infertile patients ,
respectively , hysteroscopy found intrauterine septum as the most common abnormality in both groups.conclusions:hysterolaparoscopy is an effective diagnostic tool for evaluation of certain significant and correctable tubo - peritoneal and intrauterine pathologies like peritoneal endometriosis , adnexal adhesions , and subseptate uterus , which are usually missed by other imaging modalities . |
PubmedSumm118586 | ***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: gold - based nanomaterials have been focused on in diverse biomedical applications due to their unique surface chemistry and optical properties.1,2 because of their strong and size - tunable surface plasmon resonance , fluorescence , and easy surface functionalization , gold - based nanomaterials have been widely used in biosensors , cancer cell imaging , photothermal therapy , and drug delivery.39 recently , gold nanoparticles have been suggested as a novel radiosensitizer technique in radiotherapy , because their strong photoelectric absorption and secondary electron caused by gamma or x - ray irradiation can accelerate dna strand breakage.1012 therefore , it was necessary to investigate the toxicity of these materials .
the toxicity of gold - based nanomaterials has been reported in recent years.1318 in general , their toxicity depends on particle size and surface coating .
gold was used in vivo in the 1950s , but functionalized gold particles showed obvious cytotoxicity.19 recently , the cytotoxicity of gold nanoparticles in human cells was studied in detail , and the results showed that these nanoparticles were nontoxic up to 250 mm , while ionic gold showed obvious cytotoxicity at 25 mm.20 similar results were also reported recently using gold nanoparticles in radiotherapy experiments in vitro.2128 however , in vitro systems can not replicate the complexity of an in vivo system or provide meaningful data about the response of a physiological system to an agent . a case in point
is carbon nanotubes.29 manna et al29 found them to be toxic in vitro , whereas schipper et al found no significant toxicity in vivo.30 similarly , sayes et al found that in vivo toxicology results for fullerenes were very different from in vitro data.31 therefore , the in vivo toxicity of gold nanoparticles is important . very recently
, size - dependent organ distribution of gold nanoparticles has been investigated , and the results showed that small gold nanoparticles of 515 nm had a wider organ distribution than that of larger gold nanoparticles of 50100 nm , with the liver and spleen being the dominant targeted organs.3237 meanwhile , it has been found that gold nanoparticles with a long blood circulation time can accumulate in the liver and spleen , and have obvious effects on gene expression.3840 furthermore , the toxicity and biodistribution of polyethylene glycol ( peg)-coated gold nanoparticles have also been investigated , and the results showed that 20 nm gold nanoparticles coated with ta - terminated peg5000 were the most stable , and had the lowest toxicity among the 20 , 40 , and 80 nm gold nanoparticles coated with ta - terminated peg5000.36,38,41,42 however , the peg - coated gold nanoparticles had a very low zeta potential which was significantly different from that of naked gold nanoparticles .
for example , it has been reported that 13.5 nm peg - coated gold nanoparticles can damage the liver and that 100 nm particles can be cleared partially.36,38 therefore , it is desirable to clarify what size of peg - coated gold particle is safe . in previous work , we evaluated the in vitro and in vivo toxicity of naked gold nanoparticles.43,44 here , we investigate the in vivo toxicity of 5 , 10 , 30 , and 60 nm peg - coated gold nanoparticles by evaluating biodistribution , blood chemistry , biochemistry , and characteristics on transmission electron microscopy . the outcome of this research will determine which size would be suitable for photothermal therapy and radiotherapy .
the gold nanoparticles were fabricated following the classical method devised by turkevich et al.45 a 100 ml aliquot of 0.01% chloroauric acid ( haucl44h2o ) solution was refluxed , and 0.8 , 1.3 , and 5 ml of 1% sodium citrate solution was then added to the boiling solution .
reduction of gold ions by the citrate ions was complete after 5 minutes , and the solution was then boiled for a further 30 minutes and left to cool to room temperature .
this method yielded spherical particles with an average diameter of about 10 , 30 , and 60 nm .
subsequently , peg - sh ( sigma - aldrich , st louis , mo ) 1 mg was mixed with the gold nanoparticles and stirred for 1 hour to modify the surface of the gold nanoparticles covalently with peg .
the resulting peg - coated gold nanoparticles were collected by centrifugation at 16,000 rpm for 30 minutes and washed twice with distilled water .
the peg - coated gold nanoparticle solution was stored at 4c in order to prevent aggregation .
although the mean size varied slightly for each preparation , the size distribution was always found to be less than 20% of the standard deviation shown in figure 1 .
the zeta potential for the gold nanoparticles was determined using a nano zetasizer particle analyzer ( malvern instruments , worcestershire , uk ) .
data in the phase analysis were acquired in the light scattering mode at 25c , and sample solutions were prepared by diluting the gold nanoparticles in 10 mm phosphate - buffered saline solution ( ph 7.0 ) .
the zeta potential of the 5 , 10 , 30 , and 60 nm naked gold particles was 22.1 , 28.23 , 26.7 , and 12.27 mv , respectively .
due to citric acid coating and the negative surface charge , peg - sh coating decreased the zeta potential to 2.96 , 1.55 , 1.97 , and 1.65 mv , respectively .
the size and morphology of the gold nanoparticles were analyzed by transmission electron microscopy using a hitachi hf-2000 field emission high - resolution transmission electron microscope operating at 200 kv .
the optical absorption spectra in a wavelength range of 200850 nm was measured in a 5 ml glass cuvette using a du800 spectrometer .
the animals are purchased , maintained , and handled according to protocols approved by the institute of radiation medicine , chinese academy of medical sciences .
male mice were obtained from the institute of radiation medicine laboratory at 11 weeks of age and were housed on a 12-hour light/12-hour dark cycle , and had access to food and water ad libitum . in the size - dependent toxicology experiment ,
30 mice were randomly divided into five groups ( six mice in each group ) comprising one control group and four experimental groups for administration of different sizes of gold nanoparticles .
the mice received an intraperitoneal injection of approximately 200 l of gold nanoparticle solution at a dose of 4000 g / kg , based on the previously identified toxic dose in vivo.44 the mice were weighed following injection and assessed for behavioral changes every day for 28 days . using a standard blood collection technique ,
blood was drawn from the saphenous vein into a potassium ethylenediamine tetra - acetic acid collection tube for hematology analysis .
, the mice were sacrificed by isoflurane anesthetic and exsanguinated with phosphate - buffered saline using an angiocatheter .
the liver , kidneys , spleen , heart , lungs , thyroid , lymph nodes , and bone marrow were then collected and weighed .
the spleen and thymus indices ( sx ) can be expressed as : bone marrow and blood cells were obtained after 28 days of administration of a nanoparticle dose of 4000 g / kg . for the transmission electron microscopy analysis ,
the solution was centrifuged and the pellet fixed with 2.5% glutaraldehyde in 0.03 m potassium phosphate buffer ( ph 7.4 ) .
the cells were postfixed with 1% osmium tetroxide in 0.1 m sodium cacodylate buffer , and 0.5% uranyl acetate in 0.05 m maleate buffer .
cells are then dehydrated in a graded series of ethanol and embedded in epon resin .
ultrathin sections were cut and transferred onto 200 mesh uncoated copper grids , stained with uranyl acetate , counterstained with lead citrate , and observed using an hitachi hf-2000 field emission high - resolution transmission electron microscope operating at 200 kv .
the gold nanoparticles were fabricated following the classical method devised by turkevich et al.45 a 100 ml aliquot of 0.01% chloroauric acid ( haucl44h2o ) solution was refluxed , and 0.8 , 1.3 , and 5 ml of 1% sodium citrate solution was then added to the boiling solution .
reduction of gold ions by the citrate ions was complete after 5 minutes , and the solution was then boiled for a further 30 minutes and left to cool to room temperature .
this method yielded spherical particles with an average diameter of about 10 , 30 , and 60 nm .
subsequently , peg - sh ( sigma - aldrich , st louis , mo ) 1 mg was mixed with the gold nanoparticles and stirred for 1 hour to modify the surface of the gold nanoparticles covalently with peg .
the resulting peg - coated gold nanoparticles were collected by centrifugation at 16,000 rpm for 30 minutes and washed twice with distilled water .
the peg - coated gold nanoparticle solution was stored at 4c in order to prevent aggregation .
although the mean size varied slightly for each preparation , the size distribution was always found to be less than 20% of the standard deviation shown in figure 1 .
the zeta potential for the gold nanoparticles was determined using a nano zetasizer particle analyzer ( malvern instruments , worcestershire , uk ) .
data in the phase analysis were acquired in the light scattering mode at 25c , and sample solutions were prepared by diluting the gold nanoparticles in 10 mm phosphate - buffered saline solution ( ph 7.0 ) .
the zeta potential of the 5 , 10 , 30 , and 60 nm naked gold particles was 22.1 , 28.23 , 26.7 , and 12.27 mv , respectively .
due to citric acid coating and the negative surface charge , peg - sh coating decreased the zeta potential to 2.96 , 1.55 , 1.97 , and 1.65 mv , respectively .
the size and morphology of the gold nanoparticles were analyzed by transmission electron microscopy using a hitachi hf-2000 field emission high - resolution transmission electron microscope operating at 200 kv .
the optical absorption spectra in a wavelength range of 200850 nm was measured in a 5 ml glass cuvette using a du800 spectrometer .
the animals are purchased , maintained , and handled according to protocols approved by the institute of radiation medicine , chinese academy of medical sciences .
male mice were obtained from the institute of radiation medicine laboratory at 11 weeks of age and were housed on a 12-hour light/12-hour dark cycle , and had access to food and water ad libitum . in the size - dependent toxicology experiment ,
30 mice were randomly divided into five groups ( six mice in each group ) comprising one control group and four experimental groups for administration of different sizes of gold nanoparticles .
the mice received an intraperitoneal injection of approximately 200 l of gold nanoparticle solution at a dose of 4000 g / kg , based on the previously identified toxic dose in vivo.44 the mice were weighed following injection and assessed for behavioral changes every day for 28 days .
using a standard blood collection technique , blood was drawn from the saphenous vein into a potassium ethylenediamine tetra - acetic acid collection tube for hematology analysis .
, the mice were sacrificed by isoflurane anesthetic and exsanguinated with phosphate - buffered saline using an angiocatheter .
the liver , kidneys , spleen , heart , lungs , thyroid , lymph nodes , and bone marrow were then collected and weighed .
bone marrow and blood cells were obtained after 28 days of administration of a nanoparticle dose of 4000 g / kg . for the transmission electron microscopy analysis ,
the solution was centrifuged and the pellet fixed with 2.5% glutaraldehyde in 0.03 m potassium phosphate buffer ( ph 7.4 ) .
the cells were postfixed with 1% osmium tetroxide in 0.1 m sodium cacodylate buffer , and 0.5% uranyl acetate in 0.05 m maleate buffer .
cells are then dehydrated in a graded series of ethanol and embedded in epon resin .
ultrathin sections were cut and transferred onto 200 mesh uncoated copper grids , stained with uranyl acetate , counterstained with lead citrate , and observed using an hitachi hf-2000 field emission high - resolution transmission electron microscope operating at 200 kv .
figure 2 shows the variations in body weight of mice treated with different - sized gold nanoparticles .
it can be seen that peg - coated nanoparticles at a dose of 4000 g / kg did not cause any deaths , and that body weight was slightly higher than in the control group during a 1-day observation period . the body weight of mice which received the 5 nm particles was slightly different from the other groups . during the study period ,
treatment with gold nanoparticles for 28 days did not cause obvious adverse effects on growth because no statistically significant differences in weight gain were observed between the gold nanoparticle - treated mice and the control mice .
furthermore , no abnormal clinical signs or behaviors were detected in either the controls and treated groups .
considered overall , treatment with gold nanoparticles did not induce any apparent toxicity in the mice .
necropsy at the end of the experiment did not show any macroscopic changes in the organs in any of the four treatment groups . to demonstrate the biodistribution of the peg - coated gold nanoparticles , gold concentrations in the heart , liver , spleen , and kidney after 28 days are shown in figure 3 .
it can be seen that concentrations of the 5 , 10 , 30 , and 60 nm particles in the heart were 214 , 18 , 8.6 , and 37 g / kg , respectively , with the 5 nm particles showing the highest concentration .
these gold concentrations are markedly higher than previous biodistribution results.42 for the liver , the gold concentrations achieved by the 5 , 10 , 30 , and 60 nm particles were 1797 , 2898 , 21 , and 432 g / kg , respectively .
it was found that the 5 nm and 10 nm particles had a very high concentration in the liver , which is in good agreement with previous work.42 for the spleen , the gold concentrations achieved by the 5 , 10 , 30 , and 60 nm particles were 628 , 138 , 3363 , and 721 g / kg , respectively , with the 30 nm peg - coated gold particles showing the highest gold concentration .
finally , we showed that the gold concentrations achieved by 5 , 10 , 30 , and 60 nm particles in the kidney were 390 , 48 , 151 , and 14 g / kg , respectively , with the 5 nm particles showing the highest gold concentration . the 5 nm particles had the widest distribution , and the 60 nm particles showed the lowest concentration in all organs examined .
it is well known that the size and surface - capping of gold nanoparticles play an important role in their biodistribution in mice.3641 it has been shown that naked gold can accumulate in the liver and spleen , and that the spleen and liver are the dominant target organs.32,33 small - sized particles have a wider distribution , and larger - sized particles preferentially accumulate in the liver and spleen.34,35 furthermore , the different surface charge on gold nanoparticles can influence their distribution .
peg - coated gold nanoparticles have a neutral charge , so their dynamic behavior in mice should be different from that of naked and alternatively coated gold nanoparticles.3638 therefore , we can conclude that the liver is the dominant target organ for 5 nm and 10 nm peg - coated gold particles , and that the spleen is the dominant target organ for the 30 nm particles .
the 60 nm peg - coated gold particles , similar to previously reported 100 nm gold particles , have a low distribution in all organs,36 and our results show that 60 nm gold particles can be metabolized partially by the liver and kidney .
however , the smaller - sized 5 nm and 10 nm gold nanoparticles showed high accumulation and were difficult to metabolize .
indeed , previous biodistribution and pharmacokinetic studies of pegylated gold nanoparticles have demonstrated high colloidal stability , nonaggregation , and nontoxicity for 20 nm peg - coated gold nanoparticles.41 other recent work carried out by cho et al showed that 13 nm peg - coated gold nanoparticles could induce acute inflammation and apoptosis in the liver , and were found to accumulate in the liver and spleen for up to 7 days after tail vein injection and to have a long blood circulation time.38 the results reported by cho et al demonstrated organ micropathology , indicating that gold nanoparticles potentially induce long - term organ damage and toxicity.38 figure 4 shows transmission electron microscopic images of 5 , 10 , 30 , and 60 nm gold particles in blood and bone marrow cells after intraperitoneal injection at a dose of 4000 g / kg for 28 days .
the 5 nm particles were found in bone marrow cells , with no significant decrease in size , demonstrating that the small particles did not undergo any obvious breakdown .
the 10 , 30 , and 60 nm particles could be found easily in both the intracellular and extracellular environment , which indicates that these gold particles have a long time retention in the bone marrow , and is in good agreement with previous work.36,38 however , in the blood cells , the morphology of the gold particles is different from that in bone marrow cells .
the 5 nm nanoparticles showed good aggregation and hybridization with macromolecules , and could form 1020 nm compounds .
a similar phenomenon was observed for the 10 and 60 nm gold particles but not the 30 nm particles .
the gold nanoparticles could be found in the blood cells easily , because of surface chemistry and endocytosis .
it is noteworthy that the gold nanoparticles could still be found in the blood cells 28 days after administration , which indicates that the gold nanoparticles have a long blood circulation time , and is again in good agreement with previous reports.3840 it has been suggested that interaction between protein and the gold nanoparticles may be closely related to the toxicity of the latter.27 the surface of a peg - coated gold nanoparticle probably has a low zeta potential , and cellular uptake of these nanoparticles is different from that of naked gold nanoparticles .
the peg - coated gold nanoparticles can also interact with the cell by endocytosis and a conformational change in the protein , although peg - coated gold particles have a low charge in the surface .
endocytosis plays an important role in the interaction between gold nanoparticles and cells , and the peg - coated gold nanoparticles are different from naked gold nanoparticles .
recent quantitative evaluation revealed that the surface coating on gold nanoparticles could modulate endocytotic uptake pathways and cellular trafficking of the nanoparticles .
the naked gold nanoparticles were shown to be taken up by macropinocytosis as well as by clathrin - mediated and caveolin - mediated endocytosis.4648 the difference is due to interactions with different proteins or lipids , related to mechanisms of uptake and endocytosis . increased transcytosis of peg - coated gold nanoparticles has been observed and a significant number of peg - coated gold nanoparticles were measured.49 thus , further study is necessary to understand how the mechanism of endocytosis and the protein adsorption process changes the protein conformation and the tendency of 5 nm and 60 nm peg - coated gold particles to aggregate .
table 1 gives the organ weights of mice for the different nanoparticle sizes , and illustrates the effect of the peg - coated gold nanoparticles on the organs .
it can be seen that the weights of the heart , liver , spleen , lung , and kidneys showed no obvious variation at the dose of 4000 g / kg . however , the weight of the thymus increased with increasing particle size , but no statistically significant differences were found in these data . to demonstrate the immune reaction in the organs further , the organ indices for the thymus and spleen are shown in figure 5
. the average values of the thymus and spleen indices in the control group were 2.3 and 3.3 , respectively .
the spleen indices of the mice treated with the 5 , 10 , 30 , and 60 nm particles changed to 3.7 , 4.1 , 3.3 , and 4.3 , respectively , at a gold nanoparticle dose of 4000 g / kg .
the thymus indices for the mice treated with the 5 , 10 , 30 , and 60 nm particles changed to 2.2 , 2.7 , 3.3 , and 2.5 , respectively , at a gold nanoparticle dose of 4000 g / kg . there were still no statistically significant differences between the treated groups and the control group , showing that injections of peg - coated gold nanoparticles of different sizes do not cause obvious immune effects in either the thymus or spleen .
the spleen index increased for all particle sizes . combining the variations of body weight and biodistribution
, it can be seen that the peg - coated gold nanoparticles had only a slight influence on the mice compared with the naked gold nanoparticles .
moreover , the results imply that the spleen is one of the target organs for peg - coated gold nanoparticles , which is in good agreement with previous work.3242,50 the liver and spleen have been described as the two dominant organs for biodistribution and metabolism of gold nanoparticles.3242 to quantify the toxicity of the peg - coated gold nanoparticles , the next important step is assessment of standard hematology and biochemistry , which is very useful for toxicity.5053 we selected standard hematology markers for analysis , ie , platelets , hematocrit , hemoglobin , red blood cells , white blood cells , mean corpuscular volume , mean corpuscular hemoglobin , and mean corpuscular hemoglobin concentration .
the white blood cells in mice treated with 5 nm and 30 nm particles decreased significantly , while white blood cells from mice treated with 10 nm particles increased at a dose of 4000 g / kg .
similarly , red blood cells from mice treated with 5 and 30 nm particles decreased significantly , while the red blood cells from mice treated with 10 nm and 60 nm particles increased .
in addition , platelets , hematocrit , and hemoglobin from mice treated with 5 and 10 nm particles also increased , but this does not indicate a size - dependent trend associated with treatment . the mean corpuscular volume , platelets ,
mean corpuscular hemoglobin , and mean corpuscular hemoglobin concentration changed , but no statistically significant difference was found .
the rise in white blood cells seen in mice treated with 10 and 60 nm particles indicate an inflammatory response , and the decrease in white blood cells seen in mice treated with 5 nm and 30 nm particles may be associated with infection .
red blood cells are derived from hemopoietic stem cells in the bone marrow . following a series of maturation steps , and directed largely by the hormone erythropoietin ,
thus , any variation in red blood cell levels can be related to the hematopoietic system .
the increase in red blood cells found in mice treated with 10 and 60 nm particles indicates that particles of this size have an effect on the hematopoietic system .
the four sizes of gold nanoparticles used in this study could cause different reactions in the mice .
the 10 and 60 nm particles caused a more serious toxic response than the 5 nm and 30 nm particles .
finally , we investigated the biochemical effects of 5 , 10 , 30 , and 60 nm peg - coated particles , as shown in figure 7 , including for alanine transaminase , aspartate transaminase , blood urea nitrogen , globulin , creatinine , total protein , albumin , and total bilirubin .
it was found that alanine transaminase and aspartate transaminase in mice treated with the 10 and 60 nm particles increased significantly , and globulin is decreased , indicating that the liver was damaged after injection of the nanoparticles .
creatinine levels in mice treated with the 60 nm particles decreased sharply , indicating kidney damage in the mice .
total protein and albumin in mice treated with the 10 and 60 nm particles also decreased after peg - coated gold injection , while total bilirubin and blood urea nitrogen showed no significant change for any size of particles .
these results show clearly that the 10 nm particles are highly toxic to the liver and that the 60 nm particles are toxic to both the kidney and liver .
however , the 5 nm and 30 nm particles did not cause any significant liver and kidney damage .
alanine transaminase and aspartate transaminase are mainly distributed in liver cells , and their levels rise with necrosis of liver cells .
the levels of these enzymes correspond well with the extent of liver cell damage , and are commonly used indicators of liver function .
alanine transaminase mainly exists in the cytoplasm of liver cells , whereas aspartate transaminase mainly exists in the cytoplasm and mitochondria of liver cells .
therefore , the increase in alanine transaminase in our mice treated with 10 and 60 nm gold nanoparticles indicates damage to liver cells .
however , their biodistribution shows that the concentration reached by 60 nm gold particles in the liver was not as high as that reached by 10 nm particles , indicate that the liver damage caused by the 60 nm particles was due to metabolism of the gold nanoparticles .
in contrast , the 5 nm particles also reached high concentrations in the liver , but liver function was not significantly affected , showing that the 5 nm particles did not caused direct damage to the liver .
the 5 nm particles are promising for the treatment of liver cancer without liver damage , which is very important for further work .
, creatine mainly generates creatinine slowly through nonenzymatic dehydration , which is then released into the blood , with excretion in the urine .
however , serum creatinine is not entirely consistent with the creatinine clearance rate , and creatinine clearance is more sensitive than serum creatinine . in early renal dysfunction ( decompensated ) , creatinine clearance rate and serum creatinine are normal . when the glomerular filtration rate rises to above 50% of normal , serum creatinine begins to rise rapidly .
therefore , when the serum creatinine is significantly higher than normal , kidney function is seriously damaged .
the decrease in creatinine seen in mice treated with the 60 nm particles is closely related to kidney function , although the kidney is not the main target organ for gold distribution .
the 5 nm particles did not induce any kidney damage , but the 10 nm particles caused some damage by decreasing total protein and globulin . in summary , the 60 nm particles induced serious toxicity and damage to the liver and kidney , but had a relatively low distribution in the liver , spleen , and kidney .
it is proposed that this toxicity may be due to the metabolism of peg - coated gold particles , which is similar to that previously reported for 100 nm peg - coated gold particles.36 the toxicity of the 10 nm particles was also high , due to liver and kidney damage , as well as an inflammatory response , and large amounts of gold can accumulate in the liver .
the present results are in good agreement with the results of cho et al , showing that 13.5 nm peg - coated gold particles can induce serious toxicity.36,38 our 5 nm and 30 nm particles showed low toxicity , although accumulation of 5 nm particles did occur in the liver and kidneys , and the 30 nm particles preferentially remained in the spleen .
therefore , we suggest that 10 nm peg - coated gold particles are not sufficiently safe to be administered at a concentration of 4000 g / kg . if we want to use these particles to encapsulate drugs for use in the clinical setting , metabolism must be considered
the most important finding for the size - dependent toxicity of peg - coated gold nanoparticles are that the 5 nm and 30 nm particles are safe , but the 10 nm and 60 nm particles are toxic , which is not consistent with previous in vitro findings , ie , the smaller the particle , the greater the toxicity .
figure 2 shows the variations in body weight of mice treated with different - sized gold nanoparticles .
it can be seen that peg - coated nanoparticles at a dose of 4000 g / kg did not cause any deaths , and that body weight was slightly higher than in the control group during a 1-day observation period . the body weight of mice which received the 5 nm particles was slightly different from the other groups . during the study period ,
treatment with gold nanoparticles for 28 days did not cause obvious adverse effects on growth because no statistically significant differences in weight gain were observed between the gold nanoparticle - treated mice and the control mice .
furthermore , no abnormal clinical signs or behaviors were detected in either the controls and treated groups .
considered overall , treatment with gold nanoparticles did not induce any apparent toxicity in the mice .
necropsy at the end of the experiment did not show any macroscopic changes in the organs in any of the four treatment groups . to demonstrate the biodistribution of the peg - coated gold nanoparticles , gold concentrations in the heart , liver , spleen , and kidney after 28 days are shown in figure 3 .
it can be seen that concentrations of the 5 , 10 , 30 , and 60 nm particles in the heart were 214 , 18 , 8.6 , and 37 g / kg , respectively , with the 5 nm particles showing the highest concentration .
these gold concentrations are markedly higher than previous biodistribution results.42 for the liver , the gold concentrations achieved by the 5 , 10 , 30 , and 60 nm particles were 1797 , 2898 , 21 , and 432 g / kg , respectively .
it was found that the 5 nm and 10 nm particles had a very high concentration in the liver , which is in good agreement with previous work.42 for the spleen , the gold concentrations achieved by the 5 , 10 , 30 , and 60 nm particles were 628 , 138 , 3363 , and 721 g / kg , respectively , with the 30 nm peg - coated gold particles showing the highest gold concentration .
finally , we showed that the gold concentrations achieved by 5 , 10 , 30 , and 60 nm particles in the kidney were 390 , 48 , 151 , and 14 g / kg , respectively , with the 5 nm particles showing the highest gold concentration . the 5 nm particles had the widest distribution , and the 60 nm particles showed the lowest concentration in all organs examined .
it is well known that the size and surface - capping of gold nanoparticles play an important role in their biodistribution in mice.3641 it has been shown that naked gold can accumulate in the liver and spleen , and that the spleen and liver are the dominant target organs.32,33 small - sized particles have a wider distribution , and larger - sized particles preferentially accumulate in the liver and spleen.34,35 furthermore , the different surface charge on gold nanoparticles can influence their distribution .
peg - coated gold nanoparticles have a neutral charge , so their dynamic behavior in mice should be different from that of naked and alternatively coated gold nanoparticles.3638 therefore , we can conclude that the liver is the dominant target organ for 5 nm and 10 nm peg - coated gold particles , and that the spleen is the dominant target organ for the 30 nm particles .
the 60 nm peg - coated gold particles , similar to previously reported 100 nm gold particles , have a low distribution in all organs,36 and our results show that 60 nm gold particles can be metabolized partially by the liver and kidney .
however , the smaller - sized 5 nm and 10 nm gold nanoparticles showed high accumulation and were difficult to metabolize .
indeed , previous biodistribution and pharmacokinetic studies of pegylated gold nanoparticles have demonstrated high colloidal stability , nonaggregation , and nontoxicity for 20 nm peg - coated gold nanoparticles.41 other recent work carried out by cho et al showed that 13 nm peg - coated gold nanoparticles could induce acute inflammation and apoptosis in the liver , and were found to accumulate in the liver and spleen for up to 7 days after tail vein injection and to have a long blood circulation time.38 the results reported by cho et al demonstrated organ micropathology , indicating that gold nanoparticles potentially induce long - term organ damage and toxicity.38
figure 4 shows transmission electron microscopic images of 5 , 10 , 30 , and 60 nm gold particles in blood and bone marrow cells after intraperitoneal injection at a dose of 4000 g / kg for 28 days .
the 5 nm particles were found in bone marrow cells , with no significant decrease in size , demonstrating that the small particles did not undergo any obvious breakdown .
the 10 , 30 , and 60 nm particles could be found easily in both the intracellular and extracellular environment , which indicates that these gold particles have a long time retention in the bone marrow , and is in good agreement with previous work.36,38 however , in the blood cells , the morphology of the gold particles is different from that in bone marrow cells .
the 5 nm nanoparticles showed good aggregation and hybridization with macromolecules , and could form 1020 nm compounds .
a similar phenomenon was observed for the 10 and 60 nm gold particles but not the 30 nm particles .
the gold nanoparticles could be found in the blood cells easily , because of surface chemistry and endocytosis .
it is noteworthy that the gold nanoparticles could still be found in the blood cells 28 days after administration , which indicates that the gold nanoparticles have a long blood circulation time , and is again in good agreement with previous reports.3840 it has been suggested that interaction between protein and the gold nanoparticles may be closely related to the toxicity of the latter.27 the surface of a peg - coated gold nanoparticle probably has a low zeta potential , and cellular uptake of these nanoparticles is different from that of naked gold nanoparticles .
the peg - coated gold nanoparticles can also interact with the cell by endocytosis and a conformational change in the protein , although peg - coated gold particles have a low charge in the surface .
endocytosis plays an important role in the interaction between gold nanoparticles and cells , and the peg - coated gold nanoparticles are different from naked gold nanoparticles .
recent quantitative evaluation revealed that the surface coating on gold nanoparticles could modulate endocytotic uptake pathways and cellular trafficking of the nanoparticles .
the naked gold nanoparticles were shown to be taken up by macropinocytosis as well as by clathrin - mediated and caveolin - mediated endocytosis.4648 the difference is due to interactions with different proteins or lipids , related to mechanisms of uptake and endocytosis
. increased transcytosis of peg - coated gold nanoparticles has been observed and a significant number of peg - coated gold nanoparticles were measured.49 thus , further study is necessary to understand how the mechanism of endocytosis and the protein adsorption process changes the protein conformation and the tendency of 5 nm and 60 nm peg - coated gold particles to aggregate .
table 1 gives the organ weights of mice for the different nanoparticle sizes , and illustrates the effect of the peg - coated gold nanoparticles on the organs .
it can be seen that the weights of the heart , liver , spleen , lung , and kidneys showed no obvious variation at the dose of 4000 g / kg . however , the weight of the thymus increased with increasing particle size , but no statistically significant differences were found in these data . to demonstrate the immune reaction in the organs further , the organ indices for the thymus and spleen are shown in figure 5 .
the average values of the thymus and spleen indices in the control group were 2.3 and 3.3 , respectively .
the spleen indices of the mice treated with the 5 , 10 , 30 , and 60 nm particles changed to 3.7 , 4.1 , 3.3 , and 4.3 , respectively , at a gold nanoparticle dose of 4000 g / kg . the thymus indices for the mice treated with the 5 , 10 , 30 , and 60 nm particles changed to 2.2 , 2.7 , 3.3 , and 2.5 , respectively , at a gold nanoparticle dose of 4000 g / kg . there were still no statistically significant differences between the treated groups and the control group , showing that injections of peg - coated gold nanoparticles of different sizes do not cause obvious immune effects in either the thymus or spleen .
the spleen index increased for all particle sizes . combining the variations of body weight and biodistribution
, it can be seen that the peg - coated gold nanoparticles had only a slight influence on the mice compared with the naked gold nanoparticles .
moreover , the results imply that the spleen is one of the target organs for peg - coated gold nanoparticles , which is in good agreement with previous work.3242,50 the liver and spleen have been described as the two dominant organs for biodistribution and metabolism of gold nanoparticles.3242 to quantify the toxicity of the peg - coated gold nanoparticles , the next important step is assessment of standard hematology and biochemistry , which is very useful for toxicity.5053 we selected standard hematology markers for analysis , ie , platelets , hematocrit , hemoglobin , red blood cells , white blood cells , mean corpuscular volume , mean corpuscular hemoglobin , and mean corpuscular hemoglobin concentration .
the white blood cells in mice treated with 5 nm and 30 nm particles decreased significantly , while white blood cells from mice treated with 10 nm particles increased at a dose of 4000 g / kg .
similarly , red blood cells from mice treated with 5 and 30 nm particles decreased significantly , while the red blood cells from mice treated with 10 nm and 60 nm particles increased .
in addition , platelets , hematocrit , and hemoglobin from mice treated with 5 and 10 nm particles also increased , but this does not indicate a size - dependent trend associated with treatment .
the mean corpuscular volume , platelets , mean corpuscular hemoglobin , and mean corpuscular hemoglobin concentration changed , but no statistically significant difference was found .
the rise in white blood cells seen in mice treated with 10 and 60 nm particles indicate an inflammatory response , and the decrease in white blood cells seen in mice treated with 5 nm and 30 nm particles may be associated with infection .
red blood cells are derived from hemopoietic stem cells in the bone marrow . following a series of maturation steps , and directed largely by the hormone erythropoietin ,
thus , any variation in red blood cell levels can be related to the hematopoietic system .
the increase in red blood cells found in mice treated with 10 and 60 nm particles indicates that particles of this size have an effect on the hematopoietic system .
the four sizes of gold nanoparticles used in this study could cause different reactions in the mice .
the 10 and 60 nm particles caused a more serious toxic response than the 5 nm and 30 nm particles .
finally , we investigated the biochemical effects of 5 , 10 , 30 , and 60 nm peg - coated particles , as shown in figure 7 , including for alanine transaminase , aspartate transaminase , blood urea nitrogen , globulin , creatinine , total protein , albumin , and total bilirubin .
it was found that alanine transaminase and aspartate transaminase in mice treated with the 10 and 60 nm particles increased significantly , and globulin is decreased , indicating that the liver was damaged after injection of the nanoparticles .
creatinine levels in mice treated with the 60 nm particles decreased sharply , indicating kidney damage in the mice .
total protein and albumin in mice treated with the 10 and 60 nm particles also decreased after peg - coated gold injection , while total bilirubin and blood urea nitrogen showed no significant change for any size of particles .
these results show clearly that the 10 nm particles are highly toxic to the liver and that the 60 nm particles are toxic to both the kidney and liver .
however , the 5 nm and 30 nm particles did not cause any significant liver and kidney damage .
alanine transaminase and aspartate transaminase are mainly distributed in liver cells , and their levels rise with necrosis of liver cells .
the levels of these enzymes correspond well with the extent of liver cell damage , and are commonly used indicators of liver function .
alanine transaminase mainly exists in the cytoplasm of liver cells , whereas aspartate transaminase mainly exists in the cytoplasm and mitochondria of liver cells .
therefore , the increase in alanine transaminase in our mice treated with 10 and 60 nm gold nanoparticles indicates damage to liver cells .
however , their biodistribution shows that the concentration reached by 60 nm gold particles in the liver was not as high as that reached by 10 nm particles , indicate that the liver damage caused by the 60 nm particles was due to metabolism of the gold nanoparticles .
in contrast , the 5 nm particles also reached high concentrations in the liver , but liver function was not significantly affected , showing that the 5 nm particles did not caused direct damage to the liver .
the 5 nm particles are promising for the treatment of liver cancer without liver damage , which is very important for further work .
creatine mainly generates creatinine slowly through nonenzymatic dehydration , which is then released into the blood , with excretion in the urine .
however , serum creatinine is not entirely consistent with the creatinine clearance rate , and creatinine clearance is more sensitive than serum creatinine . in early renal dysfunction ( decompensated ) , creatinine clearance rate and serum creatinine are normal . when the glomerular filtration rate rises to above 50% of normal , serum creatinine begins to rise rapidly .
therefore , when the serum creatinine is significantly higher than normal , kidney function is seriously damaged . the decrease in creatinine seen in mice treated with the 60 nm particles
is closely related to kidney function , although the kidney is not the main target organ for gold distribution .
the 5 nm particles did not induce any kidney damage , but the 10 nm particles caused some damage by decreasing total protein and globulin . in summary ,
the 60 nm particles induced serious toxicity and damage to the liver and kidney , but had a relatively low distribution in the liver , spleen , and kidney .
it is proposed that this toxicity may be due to the metabolism of peg - coated gold particles , which is similar to that previously reported for 100 nm peg - coated gold particles.36 the toxicity of the 10 nm particles was also high , due to liver and kidney damage , as well as an inflammatory response , and large amounts of gold can accumulate in the liver .
the present results are in good agreement with the results of cho et al , showing that 13.5 nm peg - coated gold particles can induce serious toxicity.36,38 our 5 nm and 30 nm particles showed low toxicity , although accumulation of 5 nm particles did occur in the liver and kidneys , and the 30 nm particles preferentially remained in the spleen .
therefore , we suggest that 10 nm peg - coated gold particles are not sufficiently safe to be administered at a concentration of 4000 g / kg . if we want to use these particles to encapsulate drugs for use in the clinical setting , metabolism must be considered .
the most important finding for the size - dependent toxicity of peg - coated gold nanoparticles are that the 5 nm and 30 nm particles are safe , but the 10 nm and 60 nm particles are toxic , which is not consistent with previous in vitro findings , ie , the smaller the particle , the greater the toxicity .
a size - dependent in vivo toxicity study of peg - coated gold nanoparticles in mice was carried out . in the study animals , survival , weight ,
hematology , biochemistry , and morphology were characterized 28 days after administration of the gold nanoparticles at a concentration of 4000 g / kg .
our results showed that the 5 nm and 10 nm particles mainly accumulate in the liver , and that the 30 nm particles preferentially accumulate in the spleen .
the 60 nm particles had a wider distribution , with limited accumulation in the organs .
blood chemistry revealed that white blood cells were increased in mice treated with the 10 nm and 60 nm particles , while those treated with the 5 nm and 30 nm particles showed decreased white blood cells .
furthermore , alanine transaminase and aspartate transaminase increased in mice treated with the 10 and 60 nm particles , while creatinine decreased with the 60 nm particles , indicating that the 10 and 60 nm particles caused liver and kidney damage .
the present work clearly shows that 10 and 60 nm peg - coated gold nanoparticles are not sufficiently safe , and that the 5 and 30 nm particles have relatively low toxicity .
these conclusions are very important for future cancer therapy , drug delivery , and diagnosis .
Output:
| backgroundgold nanoparticle toxicity research is currently leading towards the in vivo experiment .
most toxicology data show that the surface chemistry and physical dimensions of gold nanoparticles play an important role in toxicity . here
, we present the in vivo toxicity of 5 , 10 , 30 , and 60 nm peg - coated gold nanoparticles in mice.methodsanimal survival , weight , hematology , morphology , organ index , and biochemistry were characterized at a concentration of 4000 g / kg over 28 days.resultsthe peg - coated gold particles did not cause an obvious decrease in body weight or appreciable toxicity even after their breakdown in vivo .
biodistribution results show that 5 nm and 10 nm particles accumulated in the liver and that 30 nm particles accumulated in the spleen , while the 60 nm particles did not accumulate to an appreciable extent in either organ .
transmission electron microscopic observations showed that the 5 , 10 , 30 , and 60 nm particles located in the blood and bone marrow cells , and that the 5 and 60 nm particles aggregated preferentially in the blood cells .
the increase in spleen index and thymus index shows that the immune system can be affected by these small nanoparticles .
the 10 nm gold particles induced an increase in white blood cells , while the 5 nm and 30 nm particles induced a decrease in white blood cells and red blood cells .
the biochemistry results show that the 10 nm and 60 nm peg - coated gold nanoparticles caused a significant increase in alanine transaminase and aspartate transaminase levels , indicating slight damage to the liver.conclusionthe toxicity of peg - coated gold particles is complex , and it can not be concluded that the smaller particles have greater toxicity .
the toxicity of the 10 nm and 60 nm particles was obviously higher than that of the 5 nm and 30 nm particles .
the metabolism of these particles and protection of the liver will be more important issues for medical applications of gold - based nanomaterials in future . |
PubmedSumm118587 | ***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: angiography should also be considered in low ejection fraction ( ef ) patients with evidence of reversible myocardial ischemia on non - invasive testing.1 ) however , coronary angiography is applied for the elucidation of the etiology of low ef . as the prognosis of patients with ischemic etiology already remains worse,2 )
prediction of atherosclerosis burden may obviate the need for an unnecessary angiography with potential risks and harms to these vulnerable patients .
it is known that inflammation has a substantial role in the initiation and production of the complex atherosclerotic process3 ) that lies beneath cardiovascular disease ( cvd ) .
the role of inflammation in cvd has been studied and the relationship between various inflammatory markers has been established in the past.4)5 ) platelets and leukocytes are the important components of these processes associated with the development of atherosclerosis6 ) platelet - to - lymphocyte ratio ( plr ) is a new prognostic index that integrates the risk prediction of these 2 parameters .
increased plr values emerged as a valuable predictor adverse cardiovascular events in certain types of acute coronary syndromes in the long term7 ) and in predicting critical limb ischemia in peripheral artery disease.8 ) moreover , higher plr values emerged as a significant index that may independently predict the severity of coronary arterosclerotic disease.9 ) to date , no study has evaluated the role of plr in asymptomatic low ef patients .
we hypothesized that plr levels could predict the severity of coronary atherosclerosis in the setting of asymptomatic systolic hf .
the study herein is a single - center and retrospectively designed study , consisting of 156 consecutive patients eligible for selective ( cag ) between may 2013 and july 2014 in our clinic .
the study was approved by the local ethics committee , and was implemented in complete concordance with the declaration of helsinki on human research .
we selected only subjects with systolic hf that persisted with an unknown etiology after an initial non - invasive clinical assessment .
inclusion criteria were : left ventricular ejection fraction ( lvef ) < 40% with global left ventricular hypokinesia and age of 18 years .
information including gender , age , smoking status , hyperlipidemia , hypertension ( ht ) , and diabetes mellitus ( dm ) were gathered .
the definition of ht appeared as a systolic blood pressure ( bp ) value of 140 mmhg and/or a diastolic bp value of 90 mmhg at least on > 2 office bp measurements or being on an antihypertensive therapy .
the definition of dm comprised a blood sugar value of 126 mg / dl ( 7.0 mmol / l ) in the fasting state or being on an antidiabetic therapy whereas the status of hyperlipidemia was based on the presence of a blood cholesterol level of 200 mg / dl or a triglyceride level of 150 mg / dl in the fasting state .
smoking was defined as currently smoking or ex - smokers who forwent smoking within the past 6months .
patients with moderate or advanced cardiac valvulopathy , malignancy , clinically decompensated congestive hf , haematological disorder , severe kidney or liver dysfunction , active infection or systemic inflammatory conditions , or autoimmune disorders and patients using steroids were excluded from the study .
dry tubes were used for biochemical analysis , and edta tubes were used for hematological tests .
white blood cells and erythrocyte counts , hemoglobin along with hematocrit levels were analysed by an automated hematology device coulter counter lh series ( beckman coulter inc , hialeah , fl , usa ) .
the biochemical measurements were determined by an automated analyzer of biochemistry ( abbott laboratories , abbott park , il , usa ) .
all patients enrolled in the study underwent selective cag by judkins technique through the femoral artery .
the gensini scoring system was harnessed to identify the severity of coronary artery disease.10 ) according to this score , 1% to 25% of stenosis in the lumen of coronary arteries is assigned a score of 1 whereas the stenoses of 26% to 50% , 51% to 75% , 76% to 90% , 91% to 99% and 100%
( totally occluded ) represent the scores of 2 , 4 , 8 , 16 and 32 .
the score based on the stenosis degree is thereafter multiplied by a constant number in accordance with the location of lesions along the coronary arteries .
a multiplication constant of 5 points is generally assigned for left main coronary artery ( lmca ) lesions whereas 2.5 points are assigned for left circumflex ( lcx ) or proximal left anterior descending ( lad ) artery lesions .
regarding lcx and lad , lesions involving mid segments and distal segments are given the points of 1.5 and 1 , respectively .
the lesions involving the first obtuse marginal ( om ) and diagonal branches , intermediate and posterior descending arteries ( pda ) are generally multiplied with a constant of 1 point while the lesions in second om and diagonal branches are assigned the multiplication constant of 0.5 .
assessment of gensini score was made by 2 interventional cardiologists totally blinded to the laboratory and clinical data and the coronary evaluation of the other cardiologist . in the case of disagreement ,
the rest was categorized into two based on their gensini score : mildly atherosclerotic group ( n=64 ; score of < 25 points ) and severely atherosclerotic group ( n=32 ; score of 25 points ) .
all echocardiographic examinations were performed by a certified cardiologist experienced in this field using a vvd-7 ( ge healthcare , horten , norway ) device in compliance with american society of echocardiography ( ase ) guidelines.11 ) lvef was calculated from apical 4-chamber views , according to a modified simpson 's rule .
continuous variables were defined as means and standard deviation ; categorical variables were presented as percentages .
the normality of distribution for continuous variables was confirmed with the kolmogorov - smirnov test . according to the distribution pattern of continuous variables , mann - whitney u test or independent - sample t - test
was used for continuous variables , and the chi - square test was used for categorical variables .
one - way analysis of variance ( anova ) or kruskal - wallis test was used to compare 3 groups . when there was a significant difference between the three study groups , the comparison of two groups in terms of the relevant parameter
was performed with post hoc tests in a one - way anova and with mann - whitney u test after bonferroni correction in kruskal - wallis test .
correlations were assessed using either pearson 's correlation test or spearman 's rank test according to the distribution pattern of the variable .
independent associations between gensini score and independent variables were evaluated through a backward stepwise multiple linear regression analysis by comprehending all parameters showing p value of less than 0.1 on a univariate analysis .
coefficients of standardized regression along with their significance from the multiple linear regression analysis were also reported .
a receiver operating characteristic ( roc ) curve analysis was used to determine the optimum cut - off level of preprocedural plr values to predict severe coronary atherosclerosis .
chicago , il , usa ) . a two - tailed p value of < 0.05 was regarded as statistically significant .
the study herein is a single - center and retrospectively designed study , consisting of 156 consecutive patients eligible for selective ( cag ) between may 2013 and july 2014 in our clinic .
the study was approved by the local ethics committee , and was implemented in complete concordance with the declaration of helsinki on human research .
we selected only subjects with systolic hf that persisted with an unknown etiology after an initial non - invasive clinical assessment .
inclusion criteria were : left ventricular ejection fraction ( lvef ) < 40% with global left ventricular hypokinesia and age of 18 years .
information including gender , age , smoking status , hyperlipidemia , hypertension ( ht ) , and diabetes mellitus ( dm ) were gathered .
the definition of ht appeared as a systolic blood pressure ( bp ) value of 140 mmhg and/or a diastolic bp value of 90 mmhg at least on > 2 office bp measurements or being on an antihypertensive therapy .
the definition of dm comprised a blood sugar value of 126 mg / dl ( 7.0 mmol / l ) in the fasting state or being on an antidiabetic therapy whereas the status of hyperlipidemia was based on the presence of a blood cholesterol level of 200 mg / dl or a triglyceride level of 150 mg / dl in the fasting state .
smoking was defined as currently smoking or ex - smokers who forwent smoking within the past 6months .
patients with moderate or advanced cardiac valvulopathy , malignancy , clinically decompensated congestive hf , haematological disorder , severe kidney or liver dysfunction , active infection or systemic inflammatory conditions , or autoimmune disorders and patients using steroids were excluded from the study .
dry tubes were used for biochemical analysis , and edta tubes were used for hematological tests .
white blood cells and erythrocyte counts , hemoglobin along with hematocrit levels were analysed by an automated hematology device coulter counter lh series ( beckman coulter inc , hialeah , fl , usa ) .
the biochemical measurements were determined by an automated analyzer of biochemistry ( abbott laboratories , abbott park , il , usa ) .
all patients enrolled in the study underwent selective cag by judkins technique through the femoral artery .
the gensini scoring system was harnessed to identify the severity of coronary artery disease.10 ) according to this score , 1% to 25% of stenosis in the lumen of coronary arteries is assigned a score of 1 whereas the stenoses of 26% to 50% , 51% to 75% , 76% to 90% , 91% to 99% and 100%
( totally occluded ) represent the scores of 2 , 4 , 8 , 16 and 32 .
the score based on the stenosis degree is thereafter multiplied by a constant number in accordance with the location of lesions along the coronary arteries .
a multiplication constant of 5 points is generally assigned for left main coronary artery ( lmca ) lesions whereas 2.5 points are assigned for left circumflex ( lcx ) or proximal left anterior descending ( lad ) artery lesions .
regarding lcx and lad , lesions involving mid segments and distal segments are given the points of 1.5 and 1 , respectively .
the lesions involving the first obtuse marginal ( om ) and diagonal branches , intermediate and posterior descending arteries ( pda ) are generally multiplied with a constant of 1 point while the lesions in second om and diagonal branches are assigned the multiplication constant of 0.5 .
assessment of gensini score was made by 2 interventional cardiologists totally blinded to the laboratory and clinical data and the coronary evaluation of the other cardiologist . in the case of disagreement , a third blinded interventionalist assessed the coronary angiograms . according to their coronary angiograms ,
the rest was categorized into two based on their gensini score : mildly atherosclerotic group ( n=64 ; score of < 25 points ) and severely atherosclerotic group ( n=32 ; score of 25 points ) .
all echocardiographic examinations were performed by a certified cardiologist experienced in this field using a vvd-7 ( ge healthcare , horten , norway ) device in compliance with american society of echocardiography ( ase ) guidelines.11 ) lvef was calculated from apical 4-chamber views , according to a modified simpson 's rule .
continuous variables were defined as means and standard deviation ; categorical variables were presented as percentages .
the normality of distribution for continuous variables was confirmed with the kolmogorov - smirnov test . according to the distribution pattern of continuous variables , mann - whitney u test or independent - sample t - test
was used for continuous variables , and the chi - square test was used for categorical variables .
one - way analysis of variance ( anova ) or kruskal - wallis test was used to compare 3 groups . when there was a significant difference between the three study groups , the comparison of two groups in terms of the relevant parameter
was performed with post hoc tests in a one - way anova and with mann - whitney u test after bonferroni correction in kruskal - wallis test .
correlations were assessed using either pearson 's correlation test or spearman 's rank test according to the distribution pattern of the variable .
independent associations between gensini score and independent variables were evaluated through a backward stepwise multiple linear regression analysis by comprehending all parameters showing p value of less than 0.1 on a univariate analysis .
coefficients of standardized regression along with their significance from the multiple linear regression analysis were also reported .
a receiver operating characteristic ( roc ) curve analysis was used to determine the optimum cut - off level of preprocedural plr values to predict severe coronary atherosclerosis .
chicago , il , usa ) . a two - tailed p value of < 0.05 was regarded as statistically significant .
a total of 96 patients with coronary artery disease ( men 69% , mean age : 6111 years ) and 60 control subjects ( 71.2% male , mean age : 5413 years ) with normal coronary arteries were enrolled in the study .
baseline demographic , biochemical , and hematological characteristics of the groups are outlined in table 1 .
patients in the severe atherosclerosis group and mild atherosclerosis group were older compared to the control group .
fasting serum glucose , serum creatinine , triglyceride and hdl level of three groups were similar .
serum ldl was significantly higher in the severe atherosclerosis group than controls ( p<0.001 ) ; also , it was significantly higher in the mild atherosclerosis group than control group ( p=0.03 ) . in severe and mild atherosclerosis groups
ldl levels were similar ( 168.56.8 vs. 176.410.1 , p=0.51 , respectively ) among hematological parameters , hemoglobin levels and white blood cell count were similar between all three groups .
the severe atherosclerosis group had significantly higher platelet counts compared to the mild atherosclerosis group ( p<0.001 ) and controls ( p=0.001 ) , though platelet counts of the last two groups were similar ( p=0.094 ) .
lymphocyte count was higher in control groups than the others ( 1.910.63 vs. 1.840.76 and 1.780.70 ) but this is not statistically important ( p=0.704 ) .
plr was significantly higher in the severe atherosclerosis group compared to the mild atherosclerosis ( p<0.001 ) and control groups ( p<0.001 ) ( 183.561.6 vs. 145.296.5 vs. 118.440.4 respectively , p<0.001 for anova ) ( fig .
plr was also significantly higher in patients with coronary artery disease ( cad ) ( n=96 ) compared to controls ( n=60 ) ( 15888 vs. 11840 , p<0.001 ) . using a cut - off level of 132 , plr predicted severe atherosclerosis with a sensitivity of 76% and specificity of 60% .
the area under roc curve was 0.695 ( 95% ci : 0.612 - 0.779 , p<0.001 ) ( fig .
independent associations between gensini score and independent variables were assessed by multivariate linear regression analysis by including all parameters showing a correlation with a p value of less than 0.1 on a univariate analysis ( patient age , plr and ldl ) .
pre - procedural plr was independently associated with gensini score ( =0.347 , p=0.001 ) , together with ldl ( =0.259 , p=0.001 ) , age ( =-0.180 , p=0.014 ) ( table 3 ) .
the present study demonstrated that a high plr level was independently related to the severity and extent of atherosclerotic heart disease in asymptomatic low ef patients .
patients with high pre - procedural plr had significantly higher gensini scores , and there was a strong link between plr values and gensini scores of patients with cad .
additionally , this study showed that pre - procedural plr > 132 predicted severe atherosclerosis with a sensitivity of 76% and specificity of 60% .
plr had an independent association with gensini score on top of high ldl levels and age as demonstrated by a multivariate analysis .
this might reportedly be the first study demonstrating the link between plr and severity of cad in the setting of asymptomatic systolic hf . according to the recommendations of current guidelines for chronic heart failure , cardiac catheterization
should be considered in the etiological investigation of patients with left ventricular dysfunction in the presence of risk factors for coronary artery disease , angina , or refractory symptoms of heart failure.1 ) however demonstrate the ischemic or non ischemic etiology is important for prognosis in low ef patients .
bart et al.2 ) showed that ischemic etiology might still be considered as an important factor independently predicting a 5-year mortality . in a previous study for elucidation etiology in patients with left ventricle dysfunction ,
coronary angiography was performed and ischemic etiology was determined as 9.3%.12 ) gensini score was used in our study and the detection of the severe coronary artery disease was 20% of the study group . in a study , coronary computed tomography angiography ( ccta ) was compared with invasive cag in newly diagnosed heart failure patients in terms of detection of the severity of atherosclerotic heart disease has been determined with ccta similar to invasive coronary angiography.13 ) plr is a new prognostic marker that gives an idea about both the aggregation and inflammation pathways .
the role of leucocytes and platelets in atherosclerosis is well known.6)14 ) increased platelet and low lymphocyte counts has been shown with poor cardiovascular outcomes in earlier studies.14)15)16)17 ) it has been shown that plr is associated with long - term and shortterm mortality in acute coronary syndrome patients.7)18 ) yildiz et al.19 ) showed that higher plr was associated with poor prognosis in patients with cad .
acar et al.20 ) demonstrated that high plr is related with coronary collateral development in patients with chronic total occlusions .
sar et al.21 ) revealed that pre - procedural plr is associated with coronary atherosclerosis severity .
oxidized ldl ( atherogenic ) may emerge as a trigger of endothelial dysfunction strongly associated with the atherosclerotic process .
the association between the serum ldl and atherogenesis has been well established.22)23 ) in our study , pre procedural ldl levels also served as major factors independently predicting the severity of coronary atherosclerosis as expected .
our study has important clinical implications ; plr which is a simple , cheap , and readily available marker can be used as a prognostic indicator to determine asymptomatic low ef patients who are at higher coronary atherosclerosis risk . in patients with elevated plr ,
even if they are asymptomatic , investigation ischemia and performing coronary angiography may impact on prognosis . in patients with low plr
sample size was small , enrolment was retrospective and it was a single center design .
we know it does not provide sufficient data about the coronary plaque burden , and shows only the lumen of coronary arteries .
an intravascular ultrasound and/or coronary ct may provide necessary data about the amount of coronary atherosclerosis .
we had no data on inflammation markers including c - reactive protein , tumour necrosis factor - alpha , etc . however ,
we did not analyze other platelet indices including mean platelet volume , platelet distribution width , and inflammatory indices including neutrophil lymphocyte ratio ( nlr ) or correlation of these parameters with the plr .
notwithstanding these limitations , this is reportedly the first study focusing on plr with regard to its predictive value in asymptomatic low ef subjects , and more comprehensive studies are still warranted to corroborate our findings .
this is reportedly the first trial primarily focusing on the potential association between plr and the severity of atherosclerotic heart disease in asymptomatic low ef patients .
our results indicate that harnessing the index of plr as well as a variety of clinical variables including advanced age , dm and high ldl levels may work as valuable predictors of atherosclerotic burden , hence severity of atherosclerosis
. however , the current information on this issue is still at its infancy suggesting the need for future clinical studies to validate absolute implications of this index in the setting of atherosclerotic heart disease .
sample size was small , enrolment was retrospective and it was a single center design .
we know it does not provide sufficient data about the coronary plaque burden , and shows only the lumen of coronary arteries .
an intravascular ultrasound and/or coronary ct may provide necessary data about the amount of coronary atherosclerosis .
we had no data on inflammation markers including c - reactive protein , tumour necrosis factor - alpha , etc . however ,
we did not analyze other platelet indices including mean platelet volume , platelet distribution width , and inflammatory indices including neutrophil lymphocyte ratio ( nlr ) or correlation of these parameters with the plr . notwithstanding these limitations , this is reportedly the first study focusing on plr with regard to its predictive value in asymptomatic low ef subjects , and more comprehensive studies are still warranted to corroborate our findings .
this is reportedly the first trial primarily focusing on the potential association between plr and the severity of atherosclerotic heart disease in asymptomatic low ef patients .
our results indicate that harnessing the index of plr as well as a variety of clinical variables including advanced age , dm and high ldl levels may work as valuable predictors of atherosclerotic burden , hence severity of atherosclerosis
. however , the current information on this issue is still at its infancy suggesting the need for future clinical studies to validate absolute implications of this index in the setting of atherosclerotic heart disease .
Output:
| background and objectivescoronary angiography ( cag ) is generally needed in the setting of systolic heart failure ( hf ) with an unidentified etiology as a part of diagnostic strategy . on the other hand ,
the clinical value of this invasive strategy is largely unknown .
platelet - lymphocyte ratio ( plr ) has recently emerged as a novel inflammatory index that may serve as an important predictor of inflammatory state and overall mortality .
the present study aimed to search the predictive value of plr in determining the extent of coronary atherosclerosis in asymptomatic low ejection fraction ( ef ) patients.subjects and methods156 asymptomatic heart failure ( hf ) subjects ( without angina or hf symptoms , mean age : 58 years ; to male : 71.2% ) were enrolled , and thereafter a cag was performed .
gensini score was used to determine the severity of coronary artery disease ( cad ) on cag . according to this scoring system
, the overall study group was categorized into three distinct subgroups : control group with the score 0 , mild atherosclerosis group with the score 0 to 20 and severe atherosclerosis group with the score of > 20 .
thereafter , a comparison was made among groups with regard to mean values of plr.resultsthe severe atherosclerosis group had a substantially higher level of mean plr in comparison to other groups ( p<0.001 ) .
pre - cag plr levels as well as a variety of clinical variables including age , low density lipoprotein ( ldl)-cholesterol demonstrated an independent correlation with gensini score through a multivariate analysis.conclusionthese findings suggest the potential association of high plr levels with severe atherosclerosis in the setting of asymptomatic systolic hf . a simple measurement of plr helps to identify the severity of coronary atherosclerosis prior to conducting coronary angiography . |
PubmedSumm118588 | ***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: anterior sacral meningocele ( asm ) is an anomaly where the meninges protrude into retroperitoneal and presacral space through an anterior sacral defect .
we report a 19-month - old child with asm presenting with constipation and urinary problems which improved after surgery through abdominal approach .
bilateral rib and vertebral defects seen in our patient have not been described in literature earlier .
a 19-month - old female child presented to the hospital with complaints of constipation since 6 months of age and difficulty in passing urine for last 6 months .
the child was born out of non - consanguineous marriage between young parents at full term by an uncomplicated vaginal delivery .
the parents gave history of increasing constipation for which laxatives and enemas had been advised but did not provide relief .
the child weighed 7.2 kg and other anthropometric parameters including head circumference were appropriate for age .
chest examination revealed multiple rib defects on both sides but air entry was normal without any added sounds .
abdominal examination revealed a cystic mass in the suprapubic region arising out of pelvis and reaching up to umbilicus .
digital rectal examination showed normal tone of the normally placed anus but a large cystic mass was felt posteriorly which precluded higher examination .
hematological investigations showed hemoglobin of 11.2 g / dl , tlc of 12,000 per cc and platelets of 11710 per mm .
x - ray chest [ figure 1 ] showed multiple segmentation anomalies of cervicodorsal vertebrae along with fusion anomalies of ribs on both sides .
ultrasound of abdomen demonstrated a cystic lesion posterior to urinary bladder measuring 94 cm with well - defined dome shaped upper margin and tapering inferiorly .
barium enema demonstrated scimitar sign along with increased presacral space , displacement of the rectum anteriorly and sigmoid colon to the right [ figure 2a and b ] . computed tomography
[ figure 3a and b ] showed an anterior sacral dysraphic defect with large cystic mass in presacral region displacing the urinary bladder anteriorly and to the right side .
both the kidneys were displaced and rotated through their axis but there was no evidence of hydronephrosis .
plain x - ray chest showing multiple segmentation anomalies of cervicodorsal vertebrae along with fusion anomalies of ribs on both sides barium enema showing a ) scimitar sign ; and b ) increased presacral space and displacement of rectum computed tomography showing anterior sacral meningocele with a ) communication with the sacral defect ; and b ) displacement of urinary bladder to the left an exploratory laparotomy was performed by a suprapubic transverse incision with intent to excise the meningocele from anterior route .
a cystic lesion measuring about 84 was seen emerging within the leaves of sigmoid mesocolon from the anterior part of sacrum in the pelvis .
the sigmoid colon was pushed to the right while urinary bladder was pushed to the left side [ figure 4 ] .
the sac was opened at the apex , clear cerebrospinal fluid ( csf ) was aspirated and the sac was excised with watertight closure of the tapering base saving the nerve roots and controlling epidural veins .
closed dural defect was checked for leakage of csf and hemostasis and then covered with local tissue .
csf was sent for culture and sac was sent for histopathological examination ( hpe ) .
the csf culture was reported as sterile while hpe report showed fibrocollagenous and fibrofatty tissue with few entrapped blood vessels and occasional nerve fibers .
operative photograph showing the anterior sacral meningocele with displacement of urinary bladder and sigmoid colon there was no neurological deficit in the immediate postoperative period .
there was no evidence of constipation , urinary complaints or hydrocephalus at 6 months of follow - up .
although the rib defects have not caused any clinical problem till now , the child remains in follow - up to manage if need arises .
asm is an exceedingly rare form of spinal dysraphism characterized by protrusion of dural sac anterior through a defect in the anterior aspect of sacrum .
asms mostly result from failure of fusion of the sacrum with subsequent herniation of the sacrum meninges into the sacral hollow .
north et al . , have classified the possible mechanisms leading to asm as :
a)congenital :
sacral bone defectproliferation of arachnoidconnective tissue disorders
b)degenerative : ischemic lesionc)traumatic : nerve root avulsion or hemorrhaged)iatrogenic : during surgery
sacral bone defectproliferation of arachnoidconnective tissue disorders
proliferation of arachnoid connective tissue disorders degenerative : ischemic lesion traumatic : nerve root avulsion or hemorrhage iatrogenic : during surgery asm may be associated with syndrome like currarino syndrome which includes anorectal malformations , sacral bony defect and presacral mass ; and marfan 's syndrome wherein the etiology may be disorder of collagen biosynthesis and structure at the dural level .
bilateral multiple rib defects seen in the present case have not been described in the available english literature till now .
autosomal dominant transmission of the disease has been said to cause familial occurrence of asm.[57 ] owing to occult nature , these lesions usually present later in life .
more than three - fourth cases are seen in women of reproductive age who are more likely to have diagnosis of asymptomatic asm during pelvic examination . in this group of patients ,
young children mostly present with chronic constipation or retention of urine . a child with constipation may be treated with laxatives for long periods or misdiagnosed as hirschsprung 's disease .
rarely , these can be occupied by epidermoid cyst or could rupture into the rectum .
radiological investigations include plain and contrast radiographs , ultrasound , computed tomography and magnetic resonance imaging ( mri ) .
scimitar sign , a smooth curved unilateral sacral defect simulating shape of arabic sabre on plain x - ray , is considered to be pathognomonic of asm .
contrast enema , which may show displacement of rectum , sigmoid colon and urinary bladder , is now obsolete for diagnosis .
abdominal and spinal sonography should be the first diagnostic investigation and can diagnose asm and differentiate it from other cystic lesions in the pelvis . imaging for screening for asm and presacral teratoma should be directed at identifying the presacral mass rather than sacral bony defect . thus computed tomography or mri is recommended as the screening modality .
computed tomography , diagnostic in the present case , has been replaced by mri as the radiological investigation of choice .
good clinical examination and radiological investigations should be able to differentiate asm from other causes of cystic presacral masses in children which include a ) sacrococcygeal teratoma ( altman type 4 ) ; b ) tumors like dermoid , lipomas , neuroblastoma ; c ) neuroectodermal cyst ; d ) rectal duplication cyst ; e ) ovarian cyst and f ) pelvic kidney among others .
surgery should aim to obliterate the communication between meningocele and the spinal subarachnoid space ; to decompress the pelvic structures by meningocele excision ; and to untether the spinal cord , if necessary .
this route permits ligation of the base , to disrupt its connection with the thecal sac and also manage tethered cord if present .
one has to be careful to preserve nerve roots in the vicinity to prevent post operative neurological complications .
an open anterior transperitoneal abdominal approach was used in our case as the large asm was reaching up to the umbilicus and had a large neck .
anticipated difficulty in managing the large asm , excellent exposure available , and previous experience of this approach guided in preferring this approach .
limitation of this procedure is the management of caudal spinal cord anomalies as deep pelvic dissection is difficult .
. a posterior sagittal approach may be useful in management of asm associated with anorectal malformations in currarino syndrome .
Output:
| anterior sacral meningocele ( asm ) is a rare form of spinal dysraphism in children .
usually asymptomatic , it can present as constipation , urinary problems or rarely neurological symptoms .
high index of suspicion with careful clinical examination is necessary to make early diagnosis .
magnetic resonance imaging is the investigation of choice .
we describe a successfully managed young child with asm associated with rib and vertebral defects . |
PubmedSumm118589 | ***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: primary liver neoplasms in childhood are rare and constitute 1 - 2% of all pediatric tumors .
hepatocellular carcinoma ( hcc ) is the second most common primary hepatic malignancy in children following hepatoblastoma and accounts for approximately one - third of all primary hepatic malignancies in children and approximately 0.5% of all pediatric malignancies .
the age - standardized rates of hcc range from approximately 7.5 per 100,000 men in north america to as high as 20 per 100,000 men in eastern and southeastern asia [ 3 , 4 ] .
hcc in children is much rarer , with an age - adjusted incidence rate of 0.7 per 1,000,000 in the usa .
the incidence of hcc is significantly greater in eastern and southeastern asia and in africa , where hepatitis b infection is endemic .
hcc has also been observed in young children with inherited metabolic disorders and in older children with maternal transmission of hepatitis b infection [ 58 ] . while surgery remains the mainstream of treatment for patients with hcc , survival rates are poor . in a series of 218 pediatric hcc cases , allan et al . reported an overall 5-year survival of 24% and a 20-year survival of only 8% .
current knowledge regarding pediatric hcc is limited , and very few studies have examined treatment approaches and outcomes in children with hcc .
this study sought to examine a large cohort of adult and pediatric hcc from the surveillance , epidemiology , and end results ( seer ) database , in an effort to identify demographic , clinical , and treatment strategies which impact clinical outcomes and potentially guide therapeutic decision - making and assist in clinical trial development and appropriate accrual .
data for the current study was extracted from the surveillance , epidemiology , and end result ( seer ) database provided by the national cancer institute between 1973 and 2011 .
seer stat software version 8.0.4 was utilized to extract data from 18 seer registries ( alaska native tumor registry , arizona indians , cherokee nation , connecticut , detroit , georgia center for cancer statistics , greater bay area cancer registry , greater california , hawaii , iowa , kentucky , los angeles , louisiana , new jersey , new mexico , seattle - puget sound , and utah ) .
63,771 patients with histologically confirmed hepatocellular carcinoma were identified and exported to ibm spss v20.2 .
patients with a primary diagnosis of hcc were identified to form the final study cohort , using the seer international classification of disease for oncology ( icd - o-3 ) codes 8170/3 , 8171/3 , 8172/3 , 8173/3 , 8174/3 , and 8175/3 .
demographic and clinical data extracted included age , gender , race , tumor morphology , stage , grade , size , and type of treatment received ( surgery , radiation , both or no treatment ) .
the 63,771 patients included in this study were grouped into pediatric patients ( defined as age 19 years ) and adult patients ( defined as age 20 years ) .
patients with in situ cancers , those with nonspecific site of tumor origin , and those in whom histologic confirmation of their cancer was not available were excluded from the final study cohort .
endpoints examined included 1- , 2- , and 5-year overall survival , mortality , and cancer - specific mortality .
categorical variables were compared using the chi - square test , and continuous variables were compared using student 's t - test and analysis of variance ( anova ) .
method was performed to calculate odds ratios ( or ) and determine independent factors affecting survival .
63,771 cases of hcc were reported in the seer database between 1973 and 2011 . the mean age at diagnosis was 64 13 years .
99.6% of cases ( n = 63 , 514 ) occurred in adults with a mean age at diagnosis of 64 12 years , while only 0.4% of cases ( n = 257 ) occurred in pediatric patients with a mean age at diagnosis of 13 5 years ( table 1 ) .
the majority of hcc diagnoses occurred in caucasians ( n = 32 , 130 ; 50.5% ) , followed by asian , pacific islander or native americans ( n = 13 , 347 ; 21.0% ) , hispanics ( n = 10 , 285 ; 16.2% ) , and african americans ( n = 7 , 829 ; 12.3% ) , p < 0.05 .
hcc was more common among caucasians in both the pediatric and adult population groups ( 50.4% and 50.5% , p = 0.03 ) ; however , pediatric hcc was significantly more common among hispanics ( 19.3% versus 16.2% , p = 0.03 ) and less common among african americans ( 11.4% versus 12.3% , p = 0.02 ) and asian / pacific islander / native americans ( 18.9% versus 21.0% , p = 0.03 ) , compared to adult hcc . among all 63,771 hcc patients , 75.1% were male ( n = 47 , 862 ) , and 24.9% were female ( n = 15 , 909 ) , resulting in a male to female ratio of 3.01 : 1 , p < 0.001 .
hcc was more common among males in both the pediatric and adult populations ( 59.5% and 75.1% ) . among the 257 pediatric hcc patients , 59.5% were males (
n = 104 ) , resulting in a male to female ratio of 1.47 : 1 , p < 0.001 . among the 63,514 adult hcc patients , 75.1% were males ( n = 47 , 709 ) and 24.9% were females ( n = 15 , 805 ) , resulting in a male to female ratio of 3.02 : 1 , p < 0.001 . among pediatric patients , 24.1% ( n = 62 ) had fibrolamellar hcc ( fhcc ) , 1.2% ( n = 3 ) had clear cell hcc , and the remaining 74.7% ( n = 192 ) had hcc nos ( table 2 ) .
0.5% ( n = 336 ) had clear cell hcc , 0.3% ( n = 212 ) had fhcc , 0.1% ( n = 66 ) had scirrhous hcc , 0.1% ( n = 36 ) had spindle cell hcc , < 0.1% (
n = 17 ) had pleomorphic hcc , and 98.9% ( n = 62 , 847 ) had hcc nos .
the fhcc variant was far more common among pediatric patients , compared to adult patients ( 24.1% versus 0.3% , p = 0.71 ) .
47.9% ( n = 25 , 755 ) of hcc cases presented with localized disease , 31.2% ( n = 16 , 777 ) had regional involvement , and 20.8% ( n = 11 , 193 ) had metastatic spread at the time of diagnosis , p < 0.001 .
pediatric patients had a higher rate of regional disease ( 38.8% versus 31.2% , p < 0.001 ) and distant disease ( 33.1% versus 20.8% , p < 0.001 ) and a lower rate of localized disease ( 28.1% versus 48.0% , p
62.0% ( n = 24 , 255 ) of hcc were > 4 cm , 30.0% ( n = 11 , 720 ) were 24 cm , 7.9% ( n = 3 , 071 ) were < 2 cm , and 0.1% ( n = 45 ) were microscopic lesions , p < 0.05
. a greater percentage of pediatric patients had a tumor size greater than 4 cm ( 79.6% versus 62.0% , p = 0.02 ) compared to adult patients .
overall , 38.0% ( n = 8 , 467 ) of hcc were moderately differentiated , 35.1% ( n = 7 , 813 ) were well differentiated , and 23.9% ( n = 5 , 317 ) were poorly differentiated , p
< 0.05 . 3.0% ( n = 672 ) were undifferentiated , p = 0.06 .
pediatric patients more often presented with well differentiated tumors ( 35.8% versus 35.1% , p = 0.02 ) and less often with moderately ( 34.7% versus 38.0% , p = 0.01 ) or poorly differentiated tumors
20.9% ( n = 12 , 769 ) of all hcc patients were treated with surgery alone while 4.0% ( n = 2 , 459 ) of patients received radiation alone , and 0.5% ( n = 330 ) of patients were treated with both surgery and radiation .
74.5% ( n = 45 , 558 ) of patients received no treatment , p < 0.005 ( table 3 ) .
pediatric patients were more likely to receive treatment ( 52.6% versus 25.3% , p < 0.005 ) compared to adult patients . among those receiving treatment , surgical resection alone was the most common treatment modality in both pediatric and adult patients ( 92.4% and 82.0% ) .
more pediatric patients received surgery as primary treatment ( 48.6% versus 20.8% , p < 0.001 ) .
patients who received surgery as the primary modality of treatment experienced significant survival benefit ( mean survival 8.560 0.297 years ) , compared to those who received a combination of surgery and radiation ( 3.649 0.499 years ) , primary radiation only ( 1.190 0.064 years ) , or no treatment ( 1.253 0.046 years ) , p < 0.005 . pediatric patients who received surgery ( 13.107 1.306 years versus 8.324 0.302 years ,
p < 0.001 ) or a combination of both surgery and radiation ( 13.667 13.500 years versus 3.287 0.387 years , p < 0.005 ) had significantly longer survivals than adult patients .
pediatric hcc patients who received combination surgery and radiation had similar survival compared to surgery alone ( 13.667 13.500 years versus 13.107 1.306 years ) .
in contrast , adult hcc patients who received combination surgery and radiation had worse survival than those receiving surgery alone ( 3.287 0.387 years versus 8.324 0.302 years ) .
survival was slightly better among pediatric patients receiving radiation only ( 1.807 0.447 years versus 1.189 0.064 years , p < 0.001 ) or no treatment ( 2.072 0.598 years versus 1.243 0.046 years , p < 0.005 ) , compared to their adult counterparts .
overall , the fhcc variant was associated with the greatest survival ( 6.905 0.617 years ) .
pediatric fhcc experienced significant longer survival than adult fhcc ( 9.110 1.204 years versus 6.016 0.653 years , p = 0.002 ) .
the mean actuarial survival for pediatric patients was significantly higher than adult patients ( 7.988 0.845 years versus 2.781 0.075 years , p < 0.001 ) .
for all hcc patients , the overall and cancer specific mortality were found to be 81.9% and 62.7% , respectively , p < 0.001 ( table 3 ) .
overall and cancer - specific mortality among the pediatric patients ( 65.8% and 60.7% ) were significantly lower compared with adult patients ( 82.0% and 62.7% ) , p < 0.001 .
cumulative 1- , 2- and 5-year survival rates were significantly higher amongst the pediatric patients ( 61% , 47% , and 30% ) as compared to adult patients ( 34% , 23% , and 12% ) , p < 0.001 .
kaplan - meier curve illustrates significantly better 40-year actuarial survival for pediatric hcc patients compared to adults ( figure 1 ) .
274 cases of fhcc were reported , with a mean age of 64 12 years , representing 0.4% of all hcc cases .
( n = 62 ) were pediatric patients , while 77.4% ( n = 212 ) were adults .
fhcc was more common among males in both pediatric and adult populations with a male to female ratio of 1.21 : 1 among pediatric patients and 1.59 : 1 among adults ( table 4 ) .
non - fhcc had a much higher prevalence among males , with male - to - female ratios of 1.57 : 1 among pediatric patients and 3.03 : 1 among adults , p < 0.001 .
37.2% ( n = 96 ) of fhcc cases presented as localized disease , 33.3% ( n = 86 ) had regional disease , and 29.5% ( n = 76 ) had distant disease ( table 5 ) .
fhcc had a higher rate of regional disease ( 33.3% versus 31.2% , p < 0.001 ) and distant disease ( 29.5% versus 20.8% , p
< 0.001 ) and a lower rate of localized disease ( 37.2% versus 48.0% , p
most fhcc were moderately differentiated tumors ( 50.0% ; n = 41 ) , while 26.8% ( n = 22 ) were well differentiated , and 23.2% ( n = 19 ) were poorly differentiated .
fhcc had higher rates of moderately differentiated tumors ( 50.0% versus 38.0% , p > 0.05 ) and similar rates of poorly differentiated tumors ( 23.2% versus 23.9% , p > 0.05 ) , but lower rates of well differentiated tumors ( 26.8% versus 35.1% , p = ns ) . a greater proportion of fhcc had tumors > 4 cm ( 86.8% versus 61.9% , p > 0.05 ) .
90.9% of pediatric fhcc presented with tumors > 4 cm , while 85.3% of adult fhcc presented with tumors > 4 cm
. a greater proportion of fhcc patients received treatment ( 54.9% versus 25.3% , p < 0.001 ) , compared to non - fhcc ( table 6 ) .
surgery was the most common treatment modality utilized in both fhcc and non - fhcc ; however , significantly more fhcc patients received surgery alone ( 49.6% versus 20.8% ) or combination of surgery and radiation ( 2.6% versus 0.5% , p
. a greater proportion of fhcc received surgical resection alone in both pediatric ( 66.1% versus 42.8% , p < 0.001 ) and adult populations ( 44.7% versus 20.7% , p < 0.001 ) , compared to non - fhcc .
patients with fhcc treated with surgery ( mean survival 11.325 0.966 years ) and combination of surgery and radiation ( 7.393 2.937 years ) experienced significant survival benefit , compared to those who received radiation only ( 1.111 0.348 years ) or no treatment ( 1.916 0.464 years ) , p < 0.001 ( table 7 ) .
patients with fhcc treated with surgery ( 11.325 0.966 years versus 8.345 0.296 years ) and combination surgery and radiation ( 7.393 2.937 years versus 3.475 0.489 years ) had longer survivals than patients with non - fhcc , p < 0.001 . overall
( 66.1% versus 82.0% , p < 0.001 ) and cancer - specific mortality ( 56.2% versus 62.8% , p <
fhcc had a higher mean overall survival in both pediatric patients ( 9.110 1.1204 years versus 6.424 0.866 years ) and adult patients ( 6.016 0.653 years versus 2.657 0.072 years ) , compared to non - fhcc .
patients with fhcc also had longer 1-year , 2-year , and 5-year cumulative survival ( 67% , 50% , 31% ) compared to non - fhcc ( 34% , 23% , 12% ) .
kaplan - meier curve illustrates significantly better 20-year actuarial survival for fhcc compared to non - fhcc ( figure 2 ) .
multivariate analysis identified regional disease ( or 1.9 , ci = 1.13.1 ) , distant disease ( or 4.5 , ci = 2.38.8 ) , and tumor size > 4 cm ( or 4.5 , ci = 1.79.8 ) as being independently associated with increased mortality in the pediatric population , p < 0.005 .
similarly , adults with distant disease ( or 6.5 , ci = 4.39.1 ) , poorly or undifferentiated disease ( or 7.5 , ci = 5.39.6 ) , and tumor size > 4 cm ( or 8.1 , ci = 5.311.6 ) were found to have the highest odds of mortality on multivariate analysis , p < 0.005 .
fhcc was not found to be favorable in either pediatric , adult , or overall populations , p > 0.05 .
for the pediatric population with fhcc disease , distant disease ( or 3.2 , ci = 2.25.7 ) and tumor size > 4 cm ( or 1.6 , ci = 1.02.2 ) were independently associated with increased mortality , p < 0.001 .
the development of hcc is associated with multiple etiologies , high incidence rates , and high mortality .
the overall incidence of hcc varies from approximately 10 per 100,000 in north america to as high as 20 per 100,000 in countries where hepatitis b is endemic , such as southeastern asia [ 3 , 4 ] .
based on previous studies , the incidence of pediatric hcc in the united states has remained relatively stable , with some authors documenting reduction in hcc rates of > 10% following immunization against hepatitis b in endemic countries [ 1013 ] . while adult hcc is often associated with chronic hepatitis b infection and liver cirrhosis , most pediatric hcc are de novo tumors and
where pediatric hcc is associated with cirrhosis , it is most often in the context of biliary atresia , fanconi 's syndrome , and hepatitis b [ 6 , 7 , 14 ] .
pediatric hcc is also associated with metabolic diseases such as hereditary tyrosinemia and glycogen storage disease type ia [ 6 , 7 , 14 ] . despite being the second most common primary pediatric liver malignancy following hepatoblastoma , hcc is rare in children and adolescents under the age of 20 and accounts for less than 1% of all hcc cases .
similar to previously published data , this study identified a higher male hcc incidence rate for both pediatric and adult populations ( 59.5% and 75.1% ) as well as finding that hcc was more prevalent among caucasians in both populations [ 2 , 5 , 10 , 15 ] .
interestingly , a higher percentage of pediatric hcc occurred among hispanic patients , while much lower percentage of african americans were affected .
these results are consistent with previous retrospective studies conducted by mcateer et al . and allan et al . , in which over 60% of pediatric hcc occurred in caucasians [ 2 , 10 ] .
these results suggest that caucasian males in the pediatric population are at highest risk for hcc , and pediatricians should maintain a higher degree of suspicion for hcc when these patients present with suspicious or nonspecific signs and symptoms .
this study identified that pediatric patients present with more advanced disease and larger tumor sizes compared to adult hcc patients .
pediatric patients also exhibited higher rates of regional and distant disease , and lower rates of localized disease compared to adults .
a greater percentage of pediatric patients had tumors larger than 4 cm compared to adults .
these results are similar to the findings of allan et al . , which reported that 35% of pediatric patients had regional disease , 34% had distant disease , and only 27% had local disease .
conversely , mcateer et al . reported that most children affected with hcc presented with localized and regional disease ( 45.6% and 35.4% resp . )
most patients are asymptomatic until the tumor grows sufficiently large enough to cause abdominal symptoms or a palpable abdominal mass [ 1 , 14 , 16 , 17 ] .
the vague symptoms associated with hcc usually do not result in limitations in daily activities or signs of hepatic insufficiency , contributing to a delay in diagnosis and likely accounting for its more advanced stages and larger size .
this study identified that fhcc was more likely to present with larger tumors as well as regional and distant disease .
fhcc is the most common histology among pediatric patients , which could also account for the larger and less favorable stage distribution among pediatric hcc .
eggert et al . have previously reported on 47,040 hcc patients , including 183 fhcc patients , and also reported on greater proportions of fhcc presented with tumors > 5 cm ( 63% versus 34% ) and distant disease ( 33% versus 13% ) , compared to non - fhcc ,
surgical resection is the gold standard therapy for hcc [ 2 , 14 ] . in this study , pediatric patients were far more likely to be treated with surgical resection than adults , even though surgical resection was associated with a significantly improved survival in all patients . while complete excision of the hcc tumor remains the only chance for cure and prolonged survival , rates of complete excision remain low .
improved survival and high resectability rates in pediatric patients are at least in part due to a higher prevalence of the indolent fhcc variant among younger patients .
the significantly larger percentage of pediatric patients with fhcc observed in this study is consistent with a prior seer study in which fhcc variant was the most common variant found in the pediatric population and accounted for 41.3% of surgically treated pediatric hcc and 25.4% of nonsurgically treated pediatric hcc . in a retrospective seer study by allan et al . involving 218 patients ( 55 fhcc and 160 non - fhcc ) , fhcc was more likely to be treated with surgery ( 69% versus 46% , p = 0.003 ) and
surgically resected fhcc was associated with significantly higher 10-year survival rates compared to non - fhcc ( 59% versus 37% , p = 0.002 ) .
nonsurgical and adjuvant treatments for hcc , including chemoembolization , ethanol injection , and radiofrequency ablation , are often utilized when surgery is not possible or as a bridge to surgery with the goal of tumor shrinkage or for palliation in unresectable cancer .
radiation treatment alone is rarely used for the treatment of hcc , and only 4% of patients in this study received radiation alone .
chemotherapy for hcc is limited , and hcc remains one of the most chemoresistant tumors .
studied 42 patients and reported that while 49% of patients obtained a partial response to chemotherapy , survival improved by less than 5% among responders .
these authors also reported a 5-year survival of 28% and event - free - survival ( efs ) of 17% .
zhang et al . studied 45 pediatric hcc patients and reported a median survival of 6 months .
patients who had surgical resection had a significantly longer survival ( median survival of 28.6 months ) compared to those who received chemotherapy ( 4 months ) or no treatment ( 5 months ) , p < 0.001 . although surgery is the primary therapy for all hcc , approximately 80% of hcc patients
present with unresectable tumors , either due to large tumor burden , underlying hepatic dysfunction or metastatic disease .
surgery is most beneficial in patients with good hepatic function and the absence of cirrhosis but is typically contraindicated in patients with extensive cirrhosis for when transplant may play a more critical role [ 20 , 21 ] .
multiple studies have demonstrated that liver transplant confers both a significant survival advantage and a lower risk of recurrence versus surgical resection alone [ 2224 ] .
very limited data is available on liver transplant for pediatric hcc ; however , it also appears to improve overall survival in comparison to surgical resection [ 2529 ] .
studied 196 patients ( 41 patients with hcc and 135 patients with hepatoblastoma ) from the united network for organ sharing ( unos ) database and reported that the overall actuarial 1- , 5- , and 10-year survival for pediatric hcc liver recipients < 18 years of age were 86% , 63% , and 58% , which were similar to survival rates for pediatric liver transplants for hepatoblastoma ( 79% , 69% , 66% ) , p = 0.73 .
despite the successes shown with liver transplantation , its use is substantially limited by organ availability . although hcc remain an aggressive malignancy typically associated with poor overall and cancer - specific survival , affected pediatric patients fare far better than their adult counterparts , with significantly improved mean overall survival as well as 1- , 2- , and 5-year cumulative survival .
this is particularly interesting since pediatric patients typically present with more advanced disease and larger tumors .
prolonged survival among pediatric patients is likely at least partly a reflection of a much higher prevalence of the fhcc variant as well as lower rates of cirrhosis in affected children . as with nearly all cancers , advanced stage at presentation
makes it difficult to achieve total surgical resection and is therefore associated with poor prognosis [ 10 , 14 ] . in the current study ,
distant disease and tumor sizes > 4 cm were associated with increased mortality in both children and adults , which is consistent with prior reports [ 2 , 10 ] . despite presenting with larger tumors and more advanced disease ,
fhcc was associated with significantly prolonged survival compared to non - fhcc in both the pediatric and adult population .
the slow progressive , indolent disease course of fhcc accounts for the difficulty in diagnosing fhcc until later stages , as well as the prolonged survival .
furthermore , fhcc patients are more likely to receive initial treatment with radiofrequency ablation , surgical resection , or transplantation .
studied 47,040 hcc patients , including 183 fhcc patients , and reported that fhcc was associated with higher 5-year survival compared to non - fhcc ( 33.6% versus 16.1% ) .
allan et al . studied 218 pediatric hcc patients and reported significantly greater overall survival for fhcc compared to non - fhcc as demonstrated by 5-year kaplan meier curves ( p = 0.002 ) .
conversely , the childhood liver tumor strategy group ( siopel ) reported on 62 hcc patients ( 24 with fhcc and 38 with non - fhcc ) and reported no significant difference in efs at 3-year follow - up ( 22% versus 28% , p = 0.30 ) or 3-year overall survival ( 42% versus 33% , p = 0.24 ) between fhcc and non - fhcc .
they also reported that 42% of patients with non - fhcc died within 1 year , whereas only 2% of fhcc patients died .
first , the seer database did not accurately code for important clinical factors such as socioeconomic status , geography , tumor depth , method of diagnostic confirmation , hepatitis b vaccination status , liver transplantation information , and comorbidities such as hepatitis b infection and liver cirrhosis , which may have had an influence on survival .
data on surgical and radiation therapy utilized was available in the seer database ; however information on surgical resection margins and chemotherapy received was not , and this limits the study 's ability to comment on the impact of adjuvant or neoadjuvant therapy .
there may also be an element of selection bias in this data set , since seer registries are more likely to sample from urban rather than rural areas . despite these limitations ,
the seer database contains data from 26% of the united states population , and these findings can be generalized to the overall population .
despite being the second most common primary hepatic malignancy in children , hcc remains a rare disease among pediatric patients , accounting for approximately 0.5% of all new pediatric malignancies , with a world - wide age - adjusted incidence of approximately 2 per 100,000 persons .
similar to adults , hcc occurs most commonly among caucasian male children ; however , more hispanics and less african american children are affected .
given the rarity of pediatric hcc and the vague nonspecific presentation , diagnosing pediatric hcc is often delayed , resulting in more advanced disease and larger tumors . despite this fact , a significantly greater proportion of pediatric patients
are affected with the indolent fhcc histologic variant , which is more amenable to surgery .
although radiation is associated with poorer outcomes in the adult population , adjuvant radiation may prolong survival in the pediatric population . given the limited number of patients who received radiotherapy in the current study , as well as the grim prognosis of pediatric hcc and the high overall and cancer - specific mortality associated with this disease , additional studies investigating the role of radiation in pediatric hcc treatment are required to more precisely identify its role in the treatment of these patients .
Output:
| introduction .
hepatocellular carcinoma ( hcc ) is a rare pediatric cancer accounting for 0.5% of all pediatric malignancies .
this study examines a large cohort of hcc patients in an effort to define the factors impacting clinical outcomes in pediatric hcc patients compared to adults . methods .
demographic and clinical data on 63,771 hcc patients ( 257 pediatric patients 19 and 63,514 adult patients age 20 ) were abstracted from the seer database ( 19732011 ) . results .
hcc was more common among males ( 59.5% pediatric and 75.1% adults ) and caucasians ( 50.4% and 50.5% ) , p < 0.05 . children more often presented with fibrolamellar variant hcc ( 24.1% versus 0.3% , p = 0.71 ) and advanced hcc , including distant disease ( 33.1% versus 20.8% , p
< 0.001 ) , and tumors > 4 cm in size ( 79.6% versus 62.0% , p = 0.02 ) .
pediatric hcc patients undergoing surgery ( 13.107 versus 8.324 years , p < 0.001 ) had longer survival than adult hcc patients .
overall mortality was lower ( 65.8% versus 82.0% , p < 0.001 ) in the pediatric hcc group .
conclusion .
hcc is a rare pediatric malignancy that presents most often as an advanced tumor , > 4 cm in caucasian males .
children with hcc achieve significantly longer mean overall survival compared to adults with hcc , primarily attributable to the more favorable fibrolamellar histologic variant , and more aggressive surgical intervention , which significantly improves survival . |
PubmedSumm118590 | ***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: orbital and infratemporal fossa ( itf ) metastasis as initial presentation of adenocarcinoma of lung is extremely rare .
we report a 46-year - old asian woman , who presented with right eye proptosis and diffuse swelling over right cheek [ figure 1 ] .
a contrast enhanced computed tomographic ( cect ) scan of face and neck revealed a solid mass in the right orbit with extension to the itf [ figure 2 ] .
histopathologic examination of the biopsy from the mass showed poorly differentiated metastatic adenocarcinoma [ figure 3 ] , which was thyroid transcription factor 1-positive [ figure 4 ] .
a total - body cect scan revealed a large heterogeneously enhancing mass lesion in the upper and middle lobe of the right lung [ figure 5 ] .
ct guided biopsy from the lung mass revealed poorly differentiated adenocarcinoma [ figure 6 ] .
therefore , she was diagnosed as a case of metastatic lung adenocarcinoma ( t3n0m1 , stage iv ) , and planned for palliative chemotherapy with pemetrexed ( 500 mg / m ) plus carboplatin ( auc = 5 ) , iv on day 1 , every 3 weekly .
one month after completion of radiation , there was complete reduction of proptosis [ figure 7 ] .
but , cect thorax , done after 3 cycles of chemotherapy , revealed clear progression of the primary lung mass . the patient died 5 weeks later as a result of respiratory failure .
initial presentation with right eye proptosis and right cheek swelling cect scan of face and neck showing a solid mass in the right orbit with extension to the itf histopathologic study of the orbital mass showing proliferation of adenocarcinoma cells ( h and e , 400 ) the tumor cells were positive for thyroid transcription factor 1 ( 400 ) cect scan of thorax showing large heterogeneously enhancing mass lesion in the upper and middle lobe of the right lung histopathologic study of the ct guided biopsy from the lung mass , showing poorly differentiated adenocarcinoma ( h and e , 100 ) one month post radiation , complete reduction of right eye proptosis
Output:
| orbital metastasis as initial presentation of adenocarcinoma of lung is an extremely rare phenomenon . here ,
we report a 46-year - old non - smoker asian woman , who presented with right eye proptosis due to right orbital and infratemporal fossa metastasis , as the first presentation of adenocarcinoma of right lung . |
PubmedSumm118591 | ***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: stroke is a cerebrovascular event in which a blood vessel of the brain either becomes
blocked or ruptured1 .
the neurological
loss is determined by the occurrence area , which may stimulate psychological disorders of
anger and depression , and physical function disorders affecting factors such as sensory ,
exercise , balance , and walking ability1 , 2 .
stroke may cause posture instability due to
weakening of muscular strength and anesthesia , making it difficult to maintain balance2 , 3 .
the loss of balance limits daily activities and the gait of stroke patients1 , 3 .
depression may occur in cases without a history mental illness and is a common psychological
problem among stroke patients2 .
physical function recovery becomes delayed in patients who have
depression , which decreases their quality of life2 ,
4 .
therefore , stroke patients must be
comprehensively treated for both physical function disorders and depression .
horseback riding is receiving attention as a method that preserves function in patients
with physical disability or patients with damaged motor ability5 .
the rhythmical and repetitive movement of the horse
stimulates all of the senses in order to rotate the center of the body upwards and downwards
and to the left , and right6 .
it has been
reported that this is similar to the movement pattern of the pelvis when a person is
walking5 , 6 .
horse - riding movements increase physical function , improving
muscular strength , agility , balance , weight support , coordination , and blood
circulation5,6,7,8 .
they also have a positive influence on psychological problems ,
including self - esteem , pride , motivation , and space perception5,6,7,8 .
moreover , it has been
reported to help the physical recovery of patients who have cerebral palsy , multiple
sclerosis , stroke , and spinal cord damage7,8,9,10 .
many studies of horseback riding have been conducted , but there is still insufficient
information about how horseback riding influences physical and psychological functions .
thus , the purpose of this study was to find out how horseback riding influences physical and
psychological function , as well as to suggest an effective treatment .
this study selected 30 stroke patients as subjects and divided the patients into two
groups : 15 ( 8 males and 7 females ) in the experimental group , and 15 ( 8 males and 7 females )
in the control group .
subjects with no visual disability , no orthopedic diseases in the
upper or lower limbs , who scored more than 24 points in mini - mental state examination
( mmse ) , and who were able to walk more than 10 meters using auxiliary equipment were
selected .
all the participants were informed about the research purpose and provided their
informed consent before the experiment .
the study protocol was approved by the institutional
review board of seonam university and was conducted in accordance with the ethical
principles of the declaration of helsinki .
the general characteristics of the subjects are
shown in table 1table 1.general characteristics of subjectseg ( n=15)cg ( n=15)gender ( male / female)8/78/7age ( years)68.42.167.03.2weight ( kg)71.23.270.65.6height ( cm)168.67.1169.23.1paretic side ( right / left)7/86/9onset ( months)11.52.112.13.1meansd . eg : experimental group , cg : control group . the experimental group had an average age of 68.4.12.1 years , an average
height of 168.67.1 cm , an average weight of 71.23.2 kg , and an average time since stroke
onset of 11.52.1 months .
the control group had an average age of 67.03.2 years , an average
height of 169.23.1 cm , an average weight of 70.65.6 kg and an average time since stroke
onset of 12.13.1 months .
eg : experimental group , cg : control group both groups received neurodevelopment treatment for 30 minutes every day , 5 times a week ,
for a total of 6 weeks . additionally , the experimental group performed mechanical horseback
riding training for 30 minutes every day , 5 times a week , for a total of 6 weeks .
horseback
riding equipment delivers 5 types of movements ( twisting , up - down sliding , front to back
slide , front to back roll , and left to right roll ) to simulate three - dimensional movement .
this study conducted parts of courses and whole body courses using the software installed on
the horseback riding equipment .
based on the level , adaptability , and motor ability of the
subjects , they were asked to start at level 1 and continue to level 4 .
the subjects were
able to control their posture while using the horseback riding equipment by holding onto the
handles with their hands and by maintaining proper posture .
physical function was evaluated using the berg balance scale ( bbs ) and the timed up and go
test ( tugt ) .
it comprises 14 items , divided into three sections of sitting ,
standing , and change of posture .
each item is scored from 0 to 4 points , and the maximum
possible score is 56 .
the
tugt assesses functional mobility by measuring the time taken to stand up from a chair , walk
forward 3 m , turn around , walk come back , and sit back down on the chair .
it comprises 21 items , including emotional , cognitive , motivational ,
and physiological symptoms .
each item is scored from 0 to 3 points , and the maximum possible
score is 63 : 0 to 9 points indicates not depressed ; 10 to 15 points indicates slight
depression status ; 16 to 23 indicates mild depression ; and 24 to 63 indications severe
depression .
spss version 12.0 ( spss , chicago , il , usa ) was used for the statistical analysis .
the
general characteristics of the subjects are expressed as the mean and standard deviation
using technical statistics .
the paired t - test was used to compare the pre- and post - test
results of each group .
the independent t - test was conducted to compare the changes of the
two groups .
the changes in bbs , tugt , and bdi are shown in table 2table 2.comparison of the results of the bbs , tugt , and bdi between the experimental
and control groupsgroupprepostd - valuebbseg42.21.345.11.3 * 2.91.1(score)cg41.01.441.71.30.71.0tugteg18.71.216.11.6*2.61.8(sec)cg18.60.818.21.00.40.8bdieg20.61.018.21.9*2.41.6(score)cg20.81.420.21.30.60.8meansd . *
eg : experimental group , cg : control group , bbs : berg balance scale , tugt : timed up
and go test , bdi : beck depression inventory . for the experimental group , the bbs , tugt , and bdi showed
significant improvements after the intervention .
the experimental group s bbs , tugt , and bdi
showed significantly better improvements than those of the control group . meansd .
eg : experimental group , cg : control group , bbs : berg balance scale , tugt : timed up
and go test , bdi : beck depression inventory
the purpose of this research was to determine how horseback riding training influences the
physical function of stroke patients . to assess physical function ,
the experimental group s bbs and tugt showed
significant improvements ( p<0.05 ) , and the changes in the experimental group s bbs and
tugt were significant compared to their values in the control group ( p<0.05 ) .
lee et
al.7 , kim and lee11 , and han et al.,12 conducted horseback riding training for stroke patients and
reported significant improvements in the experimental group s bbs , similar to the results of
this study .
when a continuous movement pattern is administered the body
muscles are activated in trying to maintain an upright stance while resisting gravity7 , 13 .
learning about the instability of the body , improves the vestibular sense and
proprioception , improving balance ability5 , 13 .
gait speed significantly increased in the
experimental group of stroke patients that received horseback riding training in the study
of lee et al7 .
kim and lee11 reported an increase in gait ability as a
result of horseback riding training for stroke patients , which is also consistent with the
results of this study .
these
results demonstrate that horseback riding training helps to increase the physical function
of stroke patients .
it is a serious complication that has a negative
influence and also affects disability level15 .
the present study showed that horseback riding training influences
the psychological state of stroke patients .
there was a significance improvement in the bdi of the experimental group
( p<0.05 ) .
the experimental group s bdi also significantly improved compared to the
control group ( p<0.05 ) .
horseback riding training is reported to be effective at widening
a subject s one s outlook , breaking free from everyday life , and overcoming depression16 .
asselin et al.9 conducted horseback riding exercise for patients with a
damaged spinal cord and found that patients self - esteem increased a similar result to that
of the present study .
one limitation of this study was that the generalization of the results is limited by the
small number of subjects .
moreover , the durability of the effect was not confirmed through a
follow - up .
there was also difficulty in accurate assessment because the assessment tools
used in this study were clinical measurements .
future studies should address these
limitations by increasing the number of subjects and making long - term assessments to clarify
the effect of horseback riding training .
Output:
| [ purpose ] the purpose of this study was to determine the influence of horseback riding
training on the physical function and psychological problems of stroke patients .
[ subjects
and methods ] thirty stroke patients were divided evenly into an experimental group and a
control group .
both groups carried out neurodevelopmental treatment .
the experimental
group additionally performed mechanical horseback riding training for 30 minutes a day , 5
days a week , for 6 weeks .
physical function was evaluated using the berg balance scale
( bbs ) and the timed up and go test ( tugt ) .
psychological problems were assessed using the
beck depression inventory ( bdi ) . in order to compare differences within groups between
before and after the experiment ,
the paired t test was conducted . in order to compare
differences between groups before and after the experiment , the independent t test was
conducted .
[ results ] in the experimental group , the bbs , tugt , and bdi showed significant
improvements after the intervention .
the experimental group s bbs , tugt , and bdi
post - intervention changes were significantly better than those observed in the control
group .
[ conclusion ] according to our results , horseback riding training has a positive
effect on the physical function and psychological problems of stroke patients . |
PubmedSumm118592 | ***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 coagulation factor vii ( fvii ) is a glycoprotein with a molecular mass of 50 kda .
it is synthesized in the liver and circulates in the blood at a plasma concentration of 0.5g / ml ( 1 ) . in 1972 dike ,
bidwell and rizza reported the preparation and clinical use of a concentrate of factor vii as a by - product of the preparation of a therapeutic concentrate of factors ii , ix and x by adsorption on deae - cellulose ( 2 ) . in 1973 , it was concluded that deae - sephadex was more suitable than deae - cellulose for routine large - scale production of the prothrombin complex ( 3 ) . in 1980 , batch adsorption on deae - sepharose cl-6b followed by elution on a chromatographic column , concentrated factor vii about 25-fold without a need for further dialysis or concentration steps ( 4 ) . in 2003 ,
an activated factor vii ( fviia ) concentrate , prepared from human plasma on a large scale became available for clinical use for haemophiliacs with antibodies against fviii and fix ( 5 ) .
the management of bleeding episodes in patients with inhibitors may require different therapeutic approaches , among which factor viia ( 6 - 10 ) and prothrombin complex concentrates ( 11,12 ) have been successfully used .
feiba ( factor eight inhibitor bypassing activity , immuno , vienna , austria ) is an activated prothrombin complex concentrate which has been widely used in the treatment of hemophilia patients with inhibitors ( 13 ) .
factor vii concentrates are used in patients with congenital or acquired factor vii deficiency or treatment of hemophilia patients with inhibitors ( 4 - 6 ) .
it was shown that high levels of fviia in prothrombin complex concentrates containing factor vii , may contribute to the thrombogenic potential of these preparations ( 14 ) , therefore purifying fvii from ppsb should improve its thrombogenecity .
this study was planned to improve tolerance and safety in the treatment of patients with preparing highly purified factor vii from ppsb using immunoaffinity chromatography technique ( 15 - 18 ) .
first , it was washed by sodium citrate 0.01 m , ph 7.0 , and sodium chloride 0.2 m ; followed by eluting with sodium citrate 0.01 m , ph 7.0 , and sodium chloride 2.0 m. the eluted prothrombin complex was used as starting material for purification of coagulation factor vii . for the purpose of virus inactivation , the solvent / detergent method was applied .
prothrombin complex ( 50 ml ) was treated with a mixture of 0.3% tri-(n - butyl ) phosphate ( tnbp ) as solvent and 1% tween 80 ( detergent ) at 24c for 6 h with continuous stirring .
antiserum against human fvii ( assera factor vii , stago ) was further purified by ammonium sulphate 50% , after centrifugation dialyzed in coupling buffer ( 0.1 m nahco3 , ph 8.3 containing 0.5 m nacl ) for overnight at 4c .
preparation of the cn br - activated sepharose 4b gel ( 2 g powder ) , coupling the ligand ( assera factor vii ) with coupling buffer rotating overnight at 4c , blocking excess remaining groups with tris buffer ( ph:8 , 0.1 m ) for 2 h and packing of the gel were performed .
the ligand to be coupled , was dissolved in coupling buffer , 0.1 m nahco3 ph8.3 containing 0.5 m nacl .
five ml of coupling solution was used per gram of cn br - activated sepharose 4b .
the excess ligand was washed away with 5 volumes of coupling buffer ( 0.1 m nahco3 ph8.3 ) . for blocking any remaining active groups ,
the medium was transferred into the 0.1 m tris - hcl buffer , ph 8.0 for 2 hours .
the mixture of prepared prothrombin complex ( 50 ml ) in the pbs buffer ( ph : 7.4 ) was filtered ( 0.22 ) and then chromatographed ( pharmacia lkb fraction collector 2210 ) on a column ( k 9/15 pharmacia ) containing cnbr - activated sepharose 4b coupled with specific antibody .
, elution was performed by glycine buffer ( 0.1 m , ph:2.5 ) and fvii collected in collection phosphate buffer ( 1.0 m , ph:8 ) fractions .
factors ii , ix , vii , x and viia were assayed on the fractions by one stage clotting assay method using stago kits
. fractions of 48 - 50 were pooled and lyophilized as a factor vii concentrate .
agarose gel electrophoresis was performed using barbital buffer ( ph:8.6 ) at 220 v for 35 min with ciba corning equipment .
elution pattern of fvii from ppsb is shown in figure 1 . in this pattern the major peak of fvii ( fractions 48 - 50 ) and
the minor peak of fix ( fractions 46 - 51 ) has been shown ; activity of other coagulation factors was lower .
elution pattern of factor vii from prothrombin complex concentrate ( ppsb ) using immunoaffinity chromatography .
table 1
indicates the results of preparation of human coagulation fvii concentrate from ppsb by immunoaffinity chromatography step .
specific activity and purification - fold of fvii concentrate were 55.6 and 3971 , respectively .
table 1 shows higher purity of factor vii concentrate with lower coagulation activities of fii , fix and fx during its preparation by immunoaffinity chromatography .
the amount of activated factor vii ( fviia ) in fvii concentrate was higher than ppsb ( 4.4-fold ) and the yield was 62% .
* purification - fold was determined with regard to the specific activity of fvii in plasma ( 0.013 ) .
table 2 shows the characteristics of coagulation factor vii and ppsb concentrates and confirms higher purity of factor vii concentrate .
the result of gel electrophoresis ( figure 2 ) indicated that factor vii concentrate contained approximately 89% alpha-2 proteins , providing evidence of its improved purity as compared with ppsb which contains three major bands of alpha-1 , alpha-2 and beta proteins .
these findings revealed that factor ix migrated as alpha-1 and factor vii as alpha-2 proteins .
line 1 , ppsb ; line 2 , normal plasma ; line 3 highly purified fvii concentrate ( fractions 48 - 50 ) .
apart from human plasma fractionation ( 20 - 26 ) , the affinity chromatography is usually used as one of the final steps in the purification process of proteins .
it combines advantages of time - saving and high capacity of selection and concentration of the target protein from a complex mixture of contaminating substances in a large sample volume ( 27 ) . in this study we demonstrated that factor vii concentrate , essentially free of factors
ii , ix and x , can be further purified from prothrombin complex using immunoaffinity chromatography ; and a virus inactivation step of solvent - detergent treatment could also be included .
the specific activity of fvii in our procedure was increased from 0.16 to 55.6 with purification - fold of 3975 and the yield was 62% .
activity of activated factor vii ( fviia ) in our purified concentrate and ppsb were 250% and 555% respectively .
it indicates that factor vii concentrate similar to recombinant activated factor vii , may be used for treatment or prevention from bleeding in patients with factor ix inhibitors .
viral inactivation and chromatographic methods are being used increasingly in the preparation of high purity plasma or blood component products and can also contribute to improve viral safety of the product ( 28 - 36 ) .
the potential ability of chromatography for eliminating viruses has been reviewed and up to more than 3 - 8 log10 removal of various viruses used as models during some chromatographic steps ( 37 - 39 ) .
on the other hand , in this method lower ph : 2.5 conditions within the elution buffer may lead to further viral inactivation ( 40 ) .
it seems that application of both solvent - detergent method and immunoaffinity chromatography can increase viral safety efficiently in comparison with other purification methods .
it may be concluded thatcnbr - activated sepharose 4b immuonoaffinity chromatography can be a suitable choice for large - scale production of factor vii concentrate with higher purity , safety tolerability , activated factor vii and may be used for treatment or prevention of bleeding in patients with factor ix inhibitors .
Output:
| background : factor vii concentrates are used in patients with congenital or acquired factor vii
deficiency or treatment of hemophilia patients with inhibitors . in this research , immunoaffinity
chromatography
was used to purify factor vii from prothrombin complex ( prothrombin-
proconvertin - stuart factor - antihemophilic factor b or ppsb ) which contains coagulation factors ii ,
vii , ix and x. the aim of this study was to improve purity , safety and tolerability as a highly purified
factor vii concentrate .
methods : ppsb was prepared using deae - sephadex and was used as the starting material for purification
of coagulation factor vii .
prothrombin complex was treated by solvent / detergent at 24c
for 6 h with constant stirring .
the mixture of ppsb in the pbs buffer was filtered and then chromatographed
using cnbr - activated sepharose 4b coupled with specific antibody .
factors ii , ix , vii ,
x and viia were assayed on the fractions .
fractions of 48 - 50 were pooled and lyophilized as a factor
vii concentrate .
agarose gel electrophoresis was performed and tween 80 was measured in the factor
vii concentrate .
results : specific activity of factor vii concentrate increased from 0.16 to 55.6 with a purificationfold
of 347.5 and the amount of activated factor vii ( fviia ) was found higher than ppsb ( 4.4-fold ) .
results of electrophoresis on agarose gel indicated higher purity of factor vii compared to ppsb ;
these finding revealed that factor vii migrated as alpha-2 proteins . in order to improve viral safety
,
solvent - detergent treatment was applied prior to further purification and nearly complete elimination
of tween 80 ( 2 g / ml ) .
conclusion : it was concluded that immuonoaffinity chromatography using cnbr - activated sepharose
4b can be a suitable choice for large - scale production of factor vii concentrate with higher
purity , safety and activated factor vii . |
PubmedSumm118593 | ***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 coronary syndrome ( acs ) is a leading cause of morbidity and mortality worldwide , and was responsible for 7.2 million deaths in 2003 .
coronary artery disease has been reported to be the leading cause of mortality in saudi arabia , not much data is available on the rates of presentation and mortality due to acs among south asian workers in saudi arabia .
recent figures indicate that saudi arabia has 3.5 million south asians expatriates ( 13% of total population ) .
this is a cross - sectional study , conducted at the emergency department of a general hospital in saudi arabia .
patients who were diagnosed with acute myocardial infarction ( ami ) for a 6 month period ( january to june 2009 ) were included in the study .
patients were saudi citizens , south asians ( indian subcontinent origin : indians , pakistani , and bangladeshi ) , and arabs other than saudi .
ami was diagnosed by emergency department ( ed ) physicians as per world health organization ( who ) criteria . a patient is diagnosed with coronary syndrome if two ( probable ) or three ( definite ) of the following criteria are satisfied :
clinical history of ischemic type chest pain lasting for more than 20 minutes.changes in serial ecg tracings.rise and fall of serum cardiac biomarkers such as creatine kinase - mb fraction and troponin .
rise and fall of serum cardiac biomarkers such as creatine kinase - mb fraction and troponin .
when patients were diagnosed by ed physicians according to the above criteria , they were included in the study .
physicians managed these patients according to hospital guidelines . the data collection form consisted of patients characteristics , presenting symptoms , physical sings ( blood pressure , body mass index ) , ecg changes , cholesterol level , co - morbidity ( hypertension and diabetes ) , and complications ( arrhythmia and pulmonary edema ) .
univariate analysis ( frequencies and percentages ) and bivariate analysis ( associations ) were performed .
a total of 190 patients were diagnosed with ami at the ed were included , of them 121 ( 63.70% ) were saudi , 50 ( 26.3% ) were south asians , and 19 ( 10.0% ) were from arab nationalities ( non - saudi ) .
the mean age was 53.9 ( sd = 14.6 ) , the minimum age was 21 years , and the maximum was 91 years .
south asians were the youngest who developed acs ( 90% were below 50 years ) while saudi and the other arabs were older , that is , 73.3 and 42.1% , respectively were above 50 years .
majority of the patients were married ( 98.4% ) and most of them were males ( 85.6% ) .
there was no statistical difference between the 3 groups ( p = 0.725 and 0.075 , respectively ) .
south asians ( 86.0% ) did not live with their families ( at the time of the study ) , while the majority of saudi patients ( 98.3% ) and two - thirds of the other arabs ( 63.2% ) were living with their families ( p = 0.000 ) .
saudi patients ( 81.8% ) had high - skilled jobs , while south asians and the other arabs had mainly low - skilled jobs ( 80.0% and 63.2% , respectively ; p = 0.000 ) . 23.1% and 26.3% of saudi and the other arabs , respectively , and 82.0% of south asians had normal body mass index ( bmi ) ( p = 0.000 ) .
on the other hand , table 2 shows that the mean bmi for south asians was 24.6 while it was higher in saudi ( 27.4 ) and the other arabs ( 28.3 ) .
saudi patients were the lowest of the three groups who smoked cigarette and/or shisha ( 26.6% ) , while south asians were the highest ( 60.0% ; p = 0.000 ) .
around half of the saudi patients ( 52.9% ) were diabetics , and to a lesser extent ( 41.3% ) they were hypertensive , while south asians had much lower values almost one - half of these readings ( p = 0.004 for diabetes and 0.039 for hypertension ) .
socio - demographic characteristics and comorbidity mean and standard deviation for important risk factors - continuous data table 2 shows that the mean systolic blood pressure ( sbp ) was the highest among saudi patients 142.7 mm hg ( p = 0.004 ) , while the mean diastolic blood pressure ( dbp ) readings were almost similar among the three groups ( p = 0.378 ) .
total cholesterol readings were almost similar among the three groups ( 5.0 mmol ; p = 0.163 ) .
the order of chest pain types ( from highest to lowest ) among saudi patients were squeezing ( 23.1% ) , tightness ( 14.9% ) , crushing ( 14.0% ) , and heaviness ( 12.4% ) . in the other hand ,
south asians had different order , where crushing was the most experienced pain ( 26.0% ) , followed by tightness ( 20.0% ) , squeezing ( 12.0% ) , and lastly , burning sensation ( 10.0% ) .
those who did not experience chest pain were from saudi ( 24.0% ) , and among south asians ( 6.0% ) .
radiation of pain to left arm and/or shoulder was the most experienced type ( 55.0% ) and it was the most frequent among all nationalities , followed by neck and jaw ( 18.9% ) , then the upper back ( 15.3% ) .
60.1% presented with high blood pressure , 56.8% presented with sweating , 12.1% with palpitation , and 7.4% with acute pulmonary edema .
inferior coronary syndrome ( ics ) was the most prevalent ( 46.9% ) , followed by anterior and anteroseptal ( 22.5% for each ) , the lowest was the anterolateral ( 8.1% ) .
although south asians constitute 13% of saudi arabian population , the incidence of ami is doubled ( 200% ) among them ( 26.3% ) . the south asian worker who is living in saudi arabia
has two times the risk of developing ami compared to the saudi citizen , several studies have documented the higher rate of ami among south asians living in various countries other than saudi arabia .
most of them ( 90% ) were younger than 50 years as compared to saudi citizens who developed the disease at an older age ( 73.3% older than 50 years ) .
this goes with the findings of enas and senthilkumar , who found that acs bangladeshi patients were the youngest . the number of south asian patients presented with chest pain was higher ( 94% ) as compared to 76% in saudi patients .
although , the difference is not statistically significant , it reflects the higher rates of diabetes among saudi patients which masks chest pain .
while the order was crushing , tightness , squeezing , and burning sensation in south asians ; it was squeezing , tightness , crushing , and heaviness among saudi patients .
electrocardiogram ( ecg ) changes shows that the blood vessels affected were similar in all groups with this order ; inferior , anteroseptal , anterolateral and anterior coronary syndrome .
the order was not similar to the findings of hussein 1997 where the order was anterior , inferior and lateral .
63.9% of saudi patients and 55.3% of south asians had high blood pressure at time of presentation but the difference is not statistically significant .
the three groups had no significant differences as regards to symptoms , signs and location of coronary syndrome .
compared to other groups , majority of south asians ( 80% ) were low - skilled workers which reflect their low socio - economic status and low income , which was consistent with the findings of a study by bhopal , et al . and thomas et al .
although , there was no difference between the three groups with regards to the percentage of marriage ( almost all patients were married ) , the majority of south asians ( 86% ) were living without their families ( p = 0.000 ) , which may be stress triggers in two ways ; first the worker will keep thinking of his family , and second is the burden of living alone .
south asians acs patients consisted of more smokers ( 60% ) than the other groups ( p = 0.000 ) .
on the other hand , saudi acs patients were older ( 73.3% were above 50 years ) , with more comorbidity .
76.9% were overweight and obese ( p = 0.000 ) , 52.9% were diabetic ( p = 0.004 ) , and 41.3% were hypertensive ( p = 0.039 ) .
these findings reflect the high prevalence of obesity , diabetes , and hypertension among saudi population .
alhabib , et al . , ali , et al . , and others found that saudi patient with acs had higher rates of hypertension and diabetes .
in contrast , thomas , et al . and other authors who found that south asians with acs who were living in europe and overseas had higher prevalence of hypertension and diabetes .
total cholesterol level was almost similar among the groups ( p = 0.163 ) , high cholesterol is considered an independent risk factor for acs with controversy of racial variation .
saudi patients had more diabetes mellitus ( dm ) , hypertension , and obesity compared to south asians who were poor and smoked more .
two questions may be raised ; first , why south asians had double incidence of acs despite the lower number of risk factors ; the second , why south asian got the disease at young age .
smoking may be claimed to be the cause of acs among the young south asians , however , other factors like genetics , social and occupational stresses may be claimed as well .
a number of studies have shown an association between the apolipoprotein e ( apoe ) genotype with the incidence of coronary syndrome in young south asians .
this genotype also adversely affects ldl and hdl cholesterol levels , both of which contribute to premature atherosclerosis .
the leiden factor v and prothrombin 20210 gga polymorphisms have no value in disease association studies in south asian population . in smokers ,
the thrombomodulin ala455val variant allele emerges as a significant risk factor for coronary heart disease .
the sudden onset of arrhythmia and acute pulmonary edema occurred in less than 10% of the patients .
one limitation to our study is that the study was conducted at one community hospital in a relatively small city which may affect the extrapolation of the results
. detailed history of lifestyle , death of a relative with coronary syndrome , type of foods were not reported which if done , may have added to the result and conclusion .
another limitation is that there are significant differences in our study population ; saudi patients differ from other patients as they have significantly higher comorbidities such as diabetes and hypertension . whereas , south asian patients have higher smoking rates .
also , details of smoking history were not available ( e.g. , number of cigarettes smoked per day ) .
one limitation to our study is that the study was conducted at one community hospital in a relatively small city which may affect the extrapolation of the results .
detailed history of lifestyle , death of a relative with coronary syndrome , type of foods were not reported which if done , may have added to the result and conclusion .
another limitation is that there are significant differences in our study population ; saudi patients differ from other patients as they have significantly higher comorbidities such as diabetes and hypertension . whereas , south asian patients have higher smoking rates .
also , details of smoking history were not available ( e.g. , number of cigarettes smoked per day ) .
south asians had two - fold rate of acs incidence ; they were younger , lower socio - economic status , with more social and occupational stresses , more cigarette smokers , and less diabetics and hypertensive than other patients .
Output:
| introduction : acute coronary syndrome ( acs ) is the leading cause of death in saudi arabia as elsewhere . although , many studies found that south asians had increased rates of acs , others did not .
the aim of the study is to explore the extent of difference between south asians and saudi presentation and risk factors of acs patients.materials and methods : all patients who were diagnosed as having acute myocardial infarction ( ami ) based on world health organization ( who ) criteria in 6 month period were included in the study.results:a total of 190 patients confirmed acs were included ; 121 ( 63.70% ) were saudi , 50 ( 26.3% ) were south asians , and 19 ( 10.0% ) were other arab nationalities .
the mean age was 53.9 ( sd 14.6 ) .
out of the total south asians 82% had normal body mass index ( bmi ) ( p = 0.000 ) .
saudi patients were the lowest of the three groups who smoked cigarette and/or shisha ( 26.6% ; p = 0.000 ) .
52.9% of saudi patients were diabetics and 41.3% were hypertensive ( p = 0.004 ) .
more south asians were presented with chest pain ( 94% vs 76%).discussion : south asians had a double rate of acs incidence ; they were younger , lower socio - economic status , more cigarette smokers , and less diabetics and hypertensive than other patients .
an association between the apolipoprotein e ( apoe ) genotype with the incidence of acs in young south asian is proposed.conclusion:south asians had double rate of acs incidence ; they were younger , lower socio - economic status , more cigarette smokers , and less diabetics and hypertensive than other patients . |
PubmedSumm118594 | ***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: apelin is an adipocytokine and a endogenous ligand for the angiotensin - like 1 receptor ( apj ) .
increased apelin expression has been found in coronary vessels , cardiomyocytes , large conduit vessels,1 ) vascular smooth muscle cells , and endothelial cells.2 ) apelin plays an opposite role to the renin - angiotensin - aldosterone system .
apelin has been found to be reduced in patients with heart failure.3 ) some functions of apelin such as positive inotropism,4 ) endothelium - dependent vasodilation,5 ) cardiac contractility,6 ) and reduction of vascular wall inflammation7 ) have been described .
coronary artery ectasia ( cae ) has been defined as abnormal dilatation of a segment of the coronary artery that is 1.5 times larger than the diameter of an adjacent normal segment of artery.8 ) the incidence of cae has been reported to be 0.3% to 4.9% in patients who have undergone coronary angiography.9 ) it has been demonstrated that cae could predispose to adverse coronary events such as vasospasm , thrombosis , dissection , and even myocardial infarction.10 ) although the exact mechanism leading to cae is not clear to date , atherothrombosis , endothelial dysfunction , and vasculitis have been suggested as possible responsible factors.11 ) the relation between cae and chronic vascular inflammation is known .
according to the data , we suggested a possible relationship between apelin and isolated cae . in this study , we aimed to examine the relation between serum apelin level and isolated cae .
study population included a total of 54 patients who were admitted to the cardiology department .
twenty - six patients with isolated cae ( 53.68.1 years ) were categorized into the cae group , and 28 patients with normal coronary arteries proven by angiography ( 51.68.8 years ) and with similar risk factors and demographic characteristics as the cae group served as the control group .
patients with malignancy , heart failure , acute coronary syndrome , renal disease , collagen tissue diseases , vasculitis , and coronary artery disease were excluded from the study .
biochemical tests were performed by an abbott architect c16000 auto - analyzer ( architect c16000 auto - analyzer abbott laboratory , abbott park , il , usa ) with original kits and hematological counts were measured by an automated hematology analyzer ( abbott cell - dyn 3700 ; abbott laboratory , abbott park , il , usa ) in peripheral venous blood samples .
standard methods were used to measure total and high density lipoprotein cholesterol ( hdl - c ) , triglycerides , and fasting glucose .
apelin levels were measured using an enzyme - linked immunoassay kit ( phoenix pharmaceuticals , inc .
, ca , usa ) according to the manufacturer 's instructions , and expressed as ng / ml . minimal detectable limit of apelin was 0.07 ng / ml . coronary angiography was routinely performed using the allura xper fd10 ( philips , amsterdam , netherlands ) through the femoral artery by the judkin 's technique without the use of nitroglycerin .
the contrast agent used was iopamiro 370 ( bracco , milan , italy ) in all patients .
each angiogram was evaluated concurrently by two interventional cardiologists who were blinded to the study and to each other .
angiographically , cae was diagnosed when the diameter of a dilated segment of the coronary artery was 1.5 times larger than that of an adjacent normal segment.8 ) the study was approved by the local ethics committee and informed consent was obtained from each patient .
data were analyzed with statistical package for the social sciences ( spss ) software version 18.0 for windows ( spss inc . ,
the kolmogorov - smirnov test was used to verify that continuous variables were normally distributed .
continuous variables are expressed as meanstandard deviation , and categorical variables are expressed as percentages . the independent sample t - test or mann - whitney u test
was used for continuous variables and the chi - square test was used for categorical variables .
data were analyzed with statistical package for the social sciences ( spss ) software version 18.0 for windows ( spss inc . ,
chicago , il , usa ) . the kolmogorov - smirnov test was used to verify that continuous variables were normally distributed .
continuous variables are expressed as meanstandard deviation , and categorical variables are expressed as percentages . the independent sample t - test or mann - whitney u test
was used for continuous variables and the chi - square test was used for categorical variables .
the cae group included 26 patients with isolated coronary artery ectasia ( mean age 53.68.1 years ) , with 73.1% ( n=19 ) of these patients being males .
the control group included 28 patients with normal coronary arteries ( mean age 51.68.8 years ) , with 64.3% ( n=18 ) of these patients being males .
there was no difference between the two groups in terms of basal demographic data ( p>0.05 ) .
we found that the apelin level in the cae group was significantly lower ( apelin=0.1810.159 ng / ml ) than that in the control group ( apelin=0.6460.578 ng / ml ) ( p=0.033 ) ( fig .
1 ) . glucose , creatinine , total cholesterol , triglyceride , low density lipoprotein cholesterol ( ldl - c ) , and hdl - c levels were not significantly different between the two groups ( p>0.05 ) .
the main finding of the present study is that patients with isolated cae had significantly lower plasma apelin levels compared with patients with angiographically normal coronary arteries . to the best of our knowledge ,
this is the first study in the literature that has investigated the relation between apelin and isolated cae .
cae has been defined as an abnormal dilatation of a coronary artery that is 1.5 times larger than the diameter of adjacent normal segments.8 ) the etiology of cae is not completely understood . in approximately half of the cases , cae occurs due to atherosclerosis . in a minority of cases
the intima is intact , but extensive media degeneration and hyalinization , possibly as a result of chronic vascular inflammation , are commonly seen in all cases of cae.11 ) another mechanism of cae is proteolysis of the extracellular matrix proteins by metalloproteinases.12 ) overexpression of matrix metalloproteinases ( mmps ) , especially mmp-3 leads to enhanced vessel wall degradation of various matrix proteins , such as proteoglycans , laminin , fibronectin , and collagen types iii , iv , v , and ix ; thus mmps may lead to excessive vessel wall dilatation.13 ) in addition , another mechanism of cae is the inflammatory vascular hypothesis . according to this hypothesis , the presence of cae is related to elevated plasma levels of high sensitivity c - reactive protein ( hscrp),14 ) interleukin-6 ( il-6),15 ) intercellular adhesion molecule , vascular cell adhesion molecule , and e - selectin .
this hypothesis suggests the presence of extensive chronic inflammation in patients with cae.16 ) the cardiovascular system is the main target of apelin and its receptor apj .
positive inotropism , vasodilation , decreased blood pressure,17 ) and reduction of vascular wall inflammation,7 ) are some of the effects of apelin on the cardiovascular system .
ellinor et al.18 ) reported a mean apelin level of 304 pg / ml in the normal population .
li et al.19 ) reported an apelin level of 1.98 ng / ml in the healthy group .
kadoglou et al.20 ) reported that the apelin level in the healthy control group was 2.991.52 ng / ml .
we found that the mean apelin level in the control group was 0.6460.578 ng / ml . the relationship between cae and apelin is not clear .
japp et al.17 ) demonstrated that apelin is a direct coronary vasodilator that increases myocardial contractility in humans via nitric oxide - dependent mechanisms and causes a reduction in left ventricular end - diastolic pressures . in another
study,3 ) it has been suggested that the apelin / apj pathway is a regulator of cardiovascular function .
apelin has been shown to have a positive effect on contractility , and experiments using myocardial injury rat models have suggested that apelin also has a positive inotropic effect on failing myocardium.21 ) simpkin et al.22 ) reported that apelin has a cardioprotective effect against reperfusion injury . in an in vivo and in vitro rodent model of myocardial ischemia / reperfusion
loss of musculoelastic components of the vessel media plays an important role in the pathogenesis of cae .
attenuation of the vessel wall has been shown in nonatherosclerotic forms of cae by rath et al.11 ) the cause of attenuation was degeneration of media of the vessel wall and hyalinized collagen that replaced the smooth muscle.11 ) li et al.23 ) reported that apelin may have a regulatory effect on proliferation of vascular smooth muscle cells and nitric oxide production .
apelin expression in adipose tissue of mice has been shown to be up - regulated by tumor necrosis factor- ( tnf-).24 ) in another study,25 ) apelin was negatively correlated with inflammatory markers ( hscrp and il-6 ) in patients with cae .
it has been suggested that the apelin pathway may provide a mechanism for systemic inflammatory monitoring and adaptive regulation of cardiovascular function.25 ) leeper et al.7 ) reported that apelin infusion was associated with significantly reduced aortic il-6 and tnf- messenger - rna levels .
they suggested that apelin prevents aortic aneurysm formation by inhibiting macrophage proinflammatory cytokines.7 ) c - reactive protein ( crp ) levels have been reported to be associated with coronary events.26 ) also , the relationship between inflammation and cae has been reported in some studies .
turhan et al.16 ) reported that crp levels were significantly higher in patients with isolated cae compared to patients with coronary artery disease and subjects with angiographically normal coronary arteries .
ayhan et al.27 ) reported that the neutrophil to lymphocyte ratio was higher in patients with cae compared to subjects with normal coronary arteries .
additionally , sincer et al.28 ) reported that serum levels of hscrp in the cae group were higher than those in controls .
apelin and other adipocytokines are associated with inflammation and its clinical consequences.29 ) apelin is a member of the adipocytokine family like adiponectin .
dagli et al.30 ) reported that there was a negative correlation between ectatic coronary artery diameter and plasma adiponectin level . in this study
, we reported that the plasma apelin level in patients with isolated cae was significantly lower than that in controls .
based on the recent data , we suggest that apelin has cardioprotective effects and it may protect the vessels from ectasia by decreasing vessel wall inflammation .
one of the limitations of the study is that intravascular ultrasound ( ivus ) was not performed in patients for establishing the diagnosis .
ivus may be useful for identifying the atherosclerotic plaques that can not be seen by coronary angiography .
larger studies are required to verify the relationship between apelin and cae . in this study
, we showed that patients with isolated coronary artery ectasia have decreased plasma apelin levels compared with subjects with normal coronary arteries . according to the findings
, we suggested that apelin has a protective role in the development of isolated cae .
one of the limitations of the study is that intravascular ultrasound ( ivus ) was not performed in patients for establishing the diagnosis .
ivus may be useful for identifying the atherosclerotic plaques that can not be seen by coronary angiography .
in this study , we showed that patients with isolated coronary artery ectasia have decreased plasma apelin levels compared with subjects with normal coronary arteries . according to the findings
, we suggested that apelin has a protective role in the development of isolated cae .
Output:
| background and objectivesthe etiopathogenesis of coronary artery ectasia ( cae ) is not known completely . in most of the cases ,
cae is associated with atherosclerosis ; however , isolated cae has a nonatherosclerotic mechanism .
the association between atherosclerotic coronary artery disease and apelin has been examined in previous studies . however , the role of plasma apelin in isolated coronary artery ectasia has not been studied . in this study
, we investigated the relationship between plasma apelin levels and isolated coronary artery ectasia.subjects and methodsthe study population included a total of 54 patients .
twenty - six patients had isolated cae ( 53.68.1 years ) ; 28 patients with normal coronary arteries ( 51.68.8 years ) and with similar risk factors and demographic characteristics served as the control group .
apelin levels were measured using an enzyme - linked immunoassay kit.resultsapelin level in the cae group was significantly lower ( apelin=0.1810.159 ng / ml ) than that in the control group ( apelin=0.6460.578 ng / ml ) ( p=0.033 ) .
glucose , creatinine , total cholesterol , triglyceride , low density lipoprotein cholesterol , and high density lipoprotein cholesterol levels were not significantly different between the two groups.conclusionin this study , we showed that patients with isolated cae have decreased plasma apelin levels compared with the control group .
based on the data , a relationship between plasma apelin and isolated cae was determined . |
PubmedSumm118595 | ***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: viral infection and antiviral defence are universal phenomena and viral infections are reported across the metazoa [ e.g. 24 ]
. however , research tends to focus more on the coevolution of vertebrates ( and plants ) and their viruses than on invertebrates and their viruses , and relevant genetic data on viruses and antiviral resistance are lacking for almost all invertebrate phyla .
if major lineages differ systematically in their molecular or ecological interaction with viruses , as might be expected given the differences in immune mechanisms , then the research bias could skew our overall perspective of host virus ( co)evolutionary process [ e.g. 5 ] . in this review we present data from arthropods that broadly suggest viruses do indeed drive invertebrate evolution
selective sweeps , resistance polymorphisms , and elevated rates of protein evolution have all been attributed to virus - mediated selection . however , whether this is part of a strict coevolutionary process is less clear : viruses certainly evolve in response to invertebrate hosts , but as yet there is relatively little evidence demonstrating that this occurs as part of a reciprocal selective process .
selection by viruses could drive frequent and rapid fixations in invertebrate populations , reducing genetic diversity at the selected loci and elevating divergence between species .
selection on amino - acid sequences , which may be common for antagonistic host virus interaction , could additionally elevate the rate of non - synonymous substitution ( dn ) .
comparison of such footprints of selection between immune genes and genes with other functions argues in favour of pathogen - mediated selection in arthropods generally [ e.g. 811 ] , and identifies the antiviral rnai pathway as a potential coevolutionary hotspot in drosophila .
genes mediating antiviral rnai [ ago2 and dcr2 , reviewed in 14 ] are among the fastest evolving 3% of protein sequences across d. melanogaster and d. simulans , with adaptive amino - acid fixations in this pathway estimated to happen every 1040 thousand years .
moreover , there is evidence for positive selection and recent selective sweeps in antiviral rnai genes from multiple drosophila lineages , while homologous
arms race with viruses is appealing , first because virus - encoded suppressors of rnai ( vsrs ) are widespread among rna viruses [ reviewed in 17 ] , second because some vsrs are known to interact directly with ago2 and dcr2 [ e.g. 1820 ] , and third because vsrs from drosophila nora viruses can be highly specific to the host species ago2 .
however , other invertebrate antiviral genes are not reported to display extensive positive selection , and it remains possible that selection on drosophila rnai genes has been mediated by other selective agents . to test whether such potential hot spots of immune system evolution are a general phenomenon will require data from a wider range of invertebrate taxa , and based on sequence analysis alone
virus - mediated selection may also be inferred using high - frequency large - effect host resistance polymorphisms , as these can result from negative frequency dependent selection ( i.e. when rare alleles have higher fitness ) or incomplete / ongoing selective sweeps [ reviewed in 7 ] .
a large - effect polymorphism in the d. melanogaster autophagy - pathway gene ref(2)p conveys resistance to the vertically - transmitted drosophila melanogaster sigma virus ( dmelsv ) , with the resistant allele reducing viral transmission by 90% in females and 60% in males [ reviewed in 23 ] .
the resistant allele occurs at 2535% in european populations , and population - genetic analyses suggest it arose roughly 110kya and has increased in frequency recently .
a second large - effect dmelsv resistance polymorphism comprises a natural doc transposable element insertion into chkov1 followed by a partial duplication and inversion involving chkov1 and chkov2 .
the doc insertion exists at high frequency ( 80% in a north american population ) and reduces infection rates by 50% .
the subsequent rearrangement gave rise to a virus - inducible chkov2 transcript associated with an 80140 fold decrease in viral titre .
again , population genetic analyses of this locus suggest resistance is derived and has recently increased in frequency .
resistance to drosophila c virus ( dcv ) is associated with segregating variants in pastrel ( 50% increase in survival time ) and anaphase promoting complex 7 ( > 100% increase , but this currently lacks experimental verification ) , although both resistant alleles are currently rare [ 15% and 3% of surveyed alleles in the wild , see 28 ] .
finally , experimental evolution under recurrent challenge with dcv also identified functional polymorphism in pastrel , and further identified virus - resistant alleles segregating in ubc - e2h and cg8492 .
the dcv - resistant alleles of pastrel and ubc - e2h respectively displayed a 24% and 14% selective advantage under experimental conditions , and knock - downs of gene expression reduced survival after challenge .
high - frequency large - effect viral resistance polymorphisms have also been reported from other invertebrates .
for example , segregating resistance to the orsay virus in the nematode caenorhabditis elegans maps to a non - functional truncation of drh-1 , one of three dicer - related helicases involved in rnai . here the susceptible allele is derived , but is nevertheless found at a global frequency of 23% and appears to have spread recently , perhaps suggesting the action of selection at a linked locus .
polymorphism in the antiviral rnai pathway ( dicer-2 ) has also been proposed to underlie some of the genetic variance for resistance to dengue virus in the mosquito aedes aegypti . in other cases
for example , some populations of the pest moth cydia pomonella have recently evolved resistance to its granulosis virus , via a single dominant sex - linked allele that blocks viral replication . similarly ,
resistance to white spot syndrome virus in the shrimp penaeus monodon has been mapped to single marker associated with a 2000-fold reduction in viral titre , which occurs at a frequency of 4060% .
such polymorphisms are consistent with negative frequency dependent selection or with incomplete / ongoing selective sweeps [ e.g. 28 ] , but because the resistant allele is often recently derived and increasing in frequency , it seems likely that many may be in the process of fixing .
however , robustly attributing evolution to virus - mediated selection is challenging , and selection by other agents [ e.g. doc insertion in chkov1 ; 27 ] , and at linked loci [ e.g. drh-1 deletion ; 30 ] have been proposed in some cases .
nevertheless , experimental evolution shows that virus - mediated selection can lead to a rapid evolutionary response in drosophila and can select for segregating variants such as pastrel and ref(2)p .
it seems certain that viral evolution occurs in response to invertebrates , if only because hosts always dominate the viral environment .
for example , viral adaptation may underlie host - specificity seen in some insect viruses [ e.g. 21,37,38 ] , and adaptation to the invertebrate host has been attributed to specific amino - acid changes in several invertebrate - vectored viruses , including chikungunya virus , venezuelan equine encephalitis virus , and west nile virus [ 3941 ] . such adaptation to the host
may also be reflected by the tendency for sigma viruses to replicate more effectively in closer relatives of their natural hosts . given this , it is interesting to ask whether virus evolution occurs in response to specific host immune mechanisms .
genotype by genotype interactions with host polymorphism for resistance and viral polymorphism for overcoming that resistance may be indicative of negative frequency - dependent selection or incomplete on - going selective sweeps in the virus , driven by selection mediated by host resistance . for example , genotype by genotype interactions
have been reported between dengue virus 1 and aedes aegypti mosquitoes [ e.g. 43,44 ] .
the best - studied invertebrate case may be the interaction between ref(2)p and dmelsv [ reviewed in 23,45 ] , where a viral lineage capable of overcoming ref(2)p resistance arose a few hundred years ago and subsequently spread to become the most common form .
the rapid spread of this resistance - insensitive virus was documented as it occurred in two european populations , and experiments suggest that the ref(2)p - insensitive virus can replace the sensitive virus in a resistant ref(2)p host background indicating that host resistance may indeed drive viral evolution .
the rapid spread of a viral lineage may often be indicative of a selective sweep , and such expansions have also been seen in the sigma virus of d. obscura .
however , without additional evidence of pre - sweep genotypes or genomic regions such potential sweeps can not be differentiated from expansions [ e.g. an epidemic , 51 ] , and can not be attributed to host - mediated selection .
it is often argued that if host resistance drives the recurrent appearance of novel viral protein variants , then this may elevate the ratio of non - synonymous to synonymous variants ( dn / ds ) in the virus [ e.g. 52 , but see 53 ] .
this is widely accepted for some viral genes interacting with the vertebrate immune system [ e.g. 52,54 ] , but although several multi - isolate invertebrate datasets are available [ 46,47,50,5564 ] , few present whole genomes or analyse patterns of protein evolution [ c.f .
. however , some vertebrate and plant viruses interact with their invertebrate vectors , allowing the additional impact of invertebrate - mediated selection over and above that mediated by vertebrates or plants to be detected .
previous analyses of viral surface proteins which often interact directly with host proteins suggests that dn / ds is lower in vector - borne viruses [ dn / ds = 0.07 vs 0.17 for vertebrates , 0.10 vs 0.19 for plants ; see 65,66 ] , either because of increased constraint imposed by alternating selective environments , or because of reduced positive selection .
it was suggested that vector - borne vertebrate viruses may display reduced dn / ds partly because the impact of positive selection ( detected as sites with dn > ds ) is reduced ; first , because fewer viruses tested positive for adaptive evolution [ 1 of 17 vs 12 of 27 ; 65 ] , and second , because the difference in dn / ds between vectored and non - vectored viruses was reduced when putatively positively selected sites were excluded [ dn / ds = 0.13 vs 0.06 ; 65 ] .
interestingly , the only viruses in which positive selection was often detectable were non - vectored vertebrate viruses [ detected in 12 of 27 , vs 1 of 17 for vectored vertebrate viruses , and 2 of 24 and 1 of 10 for vector - borne and non vector - borne plant viruses ; 65,66 ] . taken together , these data may suggest that constraint is higher in vector - borne viruses , but that neither plants nor invertebrates are as likely as vertebrates to drive viral dn detectably above ds .
we were unable to identify any systematic difference between the viruses of plants , insects and vertebrates in either the median dn
however , while invertebrate viruses are not strikingly different from the others , the extremely small sample size ( n = 4 ) precludes any firm conclusions regarding patterns of viral protein evolution in invertebrate hosts .
despite the evidence for strong positive selection acting on some antiviral immunity genes , there are generally few sites in the viruses of vertebrates , arthropods , or plants which exhibit detectable positive selection using the dn > ds test , and the number does not differ significantly between these groups ( figure 1 ) . there is generally little evidence for pervasive diversifying selection in either surface proteins or vsrs .
however , even assuming that dn > ds is a good metric of positive selection , there are at least two reasons why it may be hard to detect an arms race using such data from rna viruses .
first , if hosts drive global selective sweeps to fixation in the virus , then standing dn / ds within a population will not strongly reflect the impact of positive selection .
second , even if different viral lineages respond in parallel to selection so that comparisons between the lineages might be expected to display elevated dn / ds the disparity in evolutionary rates means that host fixations will be so infrequent , compared to viral mutations , as to have virtually no impact on viral dn / ds [ e.g. 67 ] .
therefore it is perhaps unsurprising that the well - known examples of pervasive diversifying selection in viruses are not driven by coevolution with the host population , but by virus evolution in response to the rapidly changing adaptive immune response of vertebrates [ e.g. 54 ] . given the difficulty associated with inferring invertebrate - virus coevolution from historic patterns of protein evolution , the best evidence instead comes from patterns of functional polymorphism .
although the most compelling case is arguably the ref(2)p - dmelsv system , in which resistance and the ability to overcome it have both arisen recently and increased in frequency , and each is known to be selectable by the other [ reviewed in 23 ] , such large - effect polymorphisms increasingly appear common in invertebrate - virus interaction .
virus interaction and some other invertebrate pathogen systems [ e.g. 69 ] , where large - effect host polymorphisms for resistance and/or virus polymorphisms for evasion or suppression seem almost universal [ i.e. gene - for - gene and matching alleles models ; see 70 ] , and suggest that ongoing and/or incomplete sweeps may be widespread . indeed ,
if viral insensitivity to resistance often arises rapidly , before the resistant allele has fixed , then reciprocal invertebrate
virus coevolution may be much more widespread than is evident from reciprocal sweeps to fixation .
papers of particular interest , published within the period of review , have been highlighted as: of special interest of outstanding interest of special interest of outstanding interest
Output:
| highlightsno genetic data are available on viruses or antiviral defence for most animal phyla.the research bias may bias understanding of host
virus coevolution.antiviral rnai genes of drosophila display rapid adaptive evolution.there is no difference between plant , vertebrate , and insect viruses in median dn / ds ratio.high-frequency large - effect segregating polymorphisms provide evidence for coevolution . |
PubmedSumm118596 | ***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: pharmacopuncture is a treatment that combines herbal medicine and acupuncture , and is characterized by injections at acupoints .
on the basis of the drug toxicity testing standards of the korea food and drug administration ( kfda ) , toxicity test should be carried out in case of injections .
single - dose toxicity tests [ 2 - 9 ] and repeated dose toxicity tests [ 10 - 15 ] have been performed on many pharmacopuncture . in 2012 ,
samjeong solution ( ss ) , which has an anti- inflammation effect , and consists of taraxaci herba , lonicerae flos , rehmanniae radix , forsythiae fructus , coptidis rhizoma , scutellariae radix , phellodendri cortex and gardeniae fructus , underwent many safety and efficacy tests for use as eye drops and it was found to be a non toxic , non irritating medicine . in order to use samjeong pharmacopuncture ( sp ) administered by intramuscular injection ,
in this study , we tested the toxicity of a single - dose of sp administered by intramuscular injection , and we evaluated its approximate lethal dose .
the ss used in this study was manufactured by using a low temperature extracting process and was made at the good manufacturing practice ( gmp ) facilities of the korea pharmacopuncture institute ( kpi ) .
the ss was used for the experimental groups , and normal saline ( ns ) was used for control group . because sprague - dawley ( sd ) rats ( orientbio inc .
, korea ) are widely used for safety tests , they were used in this study .
visual inspections were done when the 5 week old sd rats ( males : 24 , females : 24 ) were received , and their weights were 119.0 142.9 g ( males ) and 104.0 119.9 g ( females ) . during the 6 days stabilization period , the general symptoms were observed daily .
the body weights , general symptoms and weight changes were measured on the last day of stabilization .
six week old sd rats ( males : 20 , females : 20 ) were used in the experiment , and their weights were 180.3 197.5 g ( males ) and 139.1 156.1 g ( females ) .
five rats of each sex were assigned to each of four groups : one control group and three experimental groups . during the observation period ,
sd rats were bred in cages ( 260 ( w ) 350 ( d ) 210 ( h ) ) .
the breeding environment was maintained at a temperature of 21.1 22.9 , a relative humidity of 43.2% 59.6% , and a ventilation rate 10 15 times / hour with artificial lighting from 07:00 to 19:00 ( 150 300 lux ) .
animals were allowed free access to pellet feed ( teklad certified irradiated global 18% protein rodent diet 2918c ) and irradiation sterilized water .
the results of a pilot test ( biotoxtech study no . : b13479p ) showed no deaths for a single - dose intramuscular injection of 1.0 ml / animal in both male and female sd rats .
based on that result , in this study , we divided 40 sd rats into four groups of 5 male and 5 female rats per groups : 1 control group and 3 experimental groups ( table 1 ) .
the injected doses in the experimental groups were 1.0 ( high dose ) , 0.5 ( mid dose ) and 0.25 ( low dose ) ml / animal ; the injected were done by using disposable syringes ( 1 ml , 26 g ) . in the high dose group ( 1.0 ml / animal of sp ) and the control groups ( 1.0 ml / animal of ns ,
0.5 ml was injected intramuscularly into both thighs . in the mid and the low dose groups ,
general symptoms , toxic signs , onset and recovery times , etc . , were noted at 30 minutes , 1 , 2 , 4 and 6 hours after the first injection .
body weights were measured on the day of the injection ( before injection ) , and on the third , seventh and fourteenth days after injection .
after all animals had fasted for about 18 hours before necropsy , the animals were anesthetized by using isoflurane anesthesia , and blood was collected from the abdominal aorta on the fifteenth day ( necropsy day ) .
the collected blood was encased in a bottle containing ethylenediaminetetraacetic acid ( edta ) ; hematologic examinations were performed by using a blood counting analyzer ( advia 2120i , siemens , germany ) .
items measured were the erythrocyte count ( rbc ) , hemoglobin ( hgb ) , hematocrits ( hct ) , mean corpuscular volume ( mcv ) , mean corpuscular hemoglobin ( mch ) , mean corpuscular hemoglobin concentration ( mchc ) , platelets ( plt ) , leucocyte count ( wbc ) , wbc differential count ( neutrophils , lymphocytes , monocytes , eosinophils , basophils ) and reticulocytes ( reti ) . about 2 ml of the taken blood was placed into a tube containing 3.2% sodium citrate and after centrifugation ( 3,000 rpm ) for 10 minutes , coagulation tests were performed by taking the blood plasma . the prothrombin time ( pt ) and the activated partial thromboplastin time ( aptt ) were measured by using an automated coagulation analyzer ( coapresta 2000 , sekisui , japan ) .
blood biochemical examinations were performed after the blood samples taken from the abdominal aorta had been centrifuged at 3,000 rpm for 10 minutes .
items , including alanine aminotransferase ( alt ) , aspartate aminotransferase ( ast ) , alkaline phosphatase ( alp ) , gamma glutamyl transpeptidase ( ggt ) , blood urea nitrogen ( bun ) , creatinine ( crea ) , total bilirubin ( t - bili ) , total protein ( tp ) , albumin ( alb ) , albumin / globulin ( a / g ) ratio , total cholesterol ( t - chol ) , triglycerides ( tg ) , phosphorus ( p ) , glucose ( glu ) , calcium ( ca ) , chloride ( cl ) , sodium ( na ) and potassium ( k ) were measured by using a blood biochemical analyzer ( 7180 , hitachi , japan ) and an electrolyte analyzer ( avl9181 , roche , germany ) .
after the observation period , necropsies were conducted , and detailed visual inspections of the organs and the tissues of all animals were done . the harvested organs and tissues were fixed with 10% neutral buffered formalin .
the sections of the fixed organs and tissues were made by using a routine tissue processing procedure .
in addition , histopathological examinations of the injection sites were done , and all organs and tissues were visually inspected .
weights and hematology and blood biochemistry data were analyzed by using statistical analysis system ( sas , version 9.3 , sas institute inc .
if the test showed equal variance , the data were analyzed by using the oneway analysis of variance ( anova ) ( p < 0.05 ) .
the multiple range test was dunnett s t - test for a post - hoc analysis ( p < 0.05 , p < 0.01 ) .
if the test did not show equal variance , the data were analyzed by using the kruskal - wallis test ( p < 0.05 ) .
during the observation period , no mortalities or abnormalities of clinical signs were found neither male or female rats in the control or experimental groups .
no statistically significant changes in the weights of either male or female rats were observed between the control and the experimental groups ( figs .
hematology and blood biochemistry data on both male and female rats in the control and the experimental groups showed no significant changes ( tables 2 , 3 , 4 , 5 ) .
after necropsy , detailed visual inspections of the organs and tissues of both male and female sd rats showed no abnormal changes ( table 6 ) .
histopathological findings for both male and female sd rats in the control and the experimental groups showed no abnormal changes ( table 7 ) . in local tolerance tests at the injection sites ,
mild inflammation was observed in two male sd rats in experimental group 3 , but the inflammation was found not to be a treatment related effect .
pharmacopuncture , taking the form of an injection , requires at least two factors for safe use .
one is safety in the manufacturing process and the other is the safety of the manufactured products .
gmp facilities are required to manufacture injections . at gmp facilities , the biological clean rooms in which the injections are manufactured
general equipment of kpi maintains a class 100 zone , and subdivision and filtration equipment maintain a class 10 zone .
injections manufactured in kgmp facilities follow the toxicity testing standards of the kfda for a safe use .
pharmacopuncture preparations at kpi are done in kgmp facilities , and toxicity testing for safe use has been continuously performed .
ss for use as eye drops was found to be a non toxic , non irritanting medicine .
ss , which consists of taraxaci herba , lonicerae flos , rehmanniae radix , forsythiae fructus , coptidis rhizoma , scutellariae radix , phellodendri cortex and gardeniae fructus , is used for heat clearing and detoxicating , heat clearing and cooling blood and heat clearing and dispelling dampness . in clinics ,
ss with an anti - inflammation effect can be used to treat a number of diseases involving inflammation .
if sp by the intramuscular injection is to be used , the toxicity of a single - dose intramuscular injection of sp must be investigated . according to the results of a pilot test ( biotoxtech study no . :
b13479p ) , the clinical dose of sp was an intramuscular injection of 1.0 ml / time . based on that result , in this study , we divided 40 sd rats into 4 groups of 5 male and 5 female rats per group : 1 control group ( ns , 1.0 ml / animal ) and 3 experimental groups ( sp , 0.25 , 0.5 , and 1.0 ml / animal ) ( table 1 ) . during the experimental period ,
observed items were mortality , clinical signs , weight changes , hematological and blood biochemistry finding , necropsy findings , histopathological findings . after sp had been injected , no abnormal changes in the clinical signs , weights , hematological and blood biochemistry results , and necropsy findings were observed . in the histopathological findings for the organs and tissues , except for slight changes , no particular abnormalities were observed .
therefore , those changes were found to be accidental changes with no toxicological significance . as a result ,
now , a repeated dose toxicity test of sp is required to confirm its safety for clinical use .
under the conditions of this test , the results from the injection of sp suggest that the approximate lethal dose is above 1.0 ml / animal for both male and female sd rats .
ns , normal saline ; sp , samjeong pharmacopuncture ; rbc , red blood cell ; hgb , hemoglobin ; hct , hematocrit ; mcv , mean corpuscular volume ; mch , mean corpuscular hemoglobin ; mchc , mean corpuscular hemoglobin concentration ; plt , platelet ; reti , reticulocytes ; wbc , white blood cell ; neu , neutrophils ; lym , lymphocytes ; mono , monocytes ; eos , eosinophils ; baso , basophils ; pt , prothrombin time ; aptt , activated partial thromboplastin time .
ns , normal saline ; sp , samjeong pharmacopuncture ; rbc , red blood cell ; hgb , hemoglobin ; hct , hematocrit ; mcv , mean corpuscular volume ; mch , mean corpuscular hemoglobin ; mchc , mean corpuscular hemoglobin concentration ; plt , platelet ; reti , reticulocytes ; wbc , white blood cell ; neu , neutrophils ; lym , lymphocytes ; mono , monocytes ; eos , eosinophils ; baso , basophils ; pt , prothrombin time ; aptt , activated partial thromboplastin time .
ns , normal saline ; sp , samjeong pharmacopuncture ; alt , alanine aminotransferase ; ast , aspartate aminotransferase ; alp , alkaline phosphatase ; ggt , gamma glutamyl transpeptidase ; glu , glucose ; bun , blood urea nitrogen ; crea , creatinine ; t - bil , total bilirubin ; t - chol , total cholesterol ; tg , triglycerides ; tp , total protein ; alb , albumin ; a / g ratio , albumin / globulin ratio ; p , phosphorus ; ca , calcium ; na , sodium ; k , potassium ; cl , chloride .
ns , normal saline ; sp , samjeong pharmacopuncture ; alt , alanine aminotransferase ; ast , aspartate aminotransferase ; alp , alkaline phosphatase ; ggt , gamma glutamyl transpeptidase ; glu , glucose ; bun , blood urea nitrogen ; crea , creatinine ; t - bil , total bilirubin ; t - chol , total cholesterol ; tg , triglycerides ; tp , total protein ; alb , albumin ; a / g ratio , albumin / globulin ratio ; p , phosphorus ; ca , calcium ; na , sodium ; k , potassium ; cl , chloride .
Output:
| objectives : this study was carried out in order to find both the single - dose intramuscular injection toxicity and the approximate lethal dose of samjeong pharmacopuncture ( sp ) in sprague - dawley ( sd ) rats.methods:the sd rats in this study were divided into four groups , one control group ( 1.0 ml / animal , normal saline ) and three experimental groups ( 0.25 , 0.5 , and 1.0 ml / animal , sp ) .
all groups consisted of five male and five female rats .
sp was injected as a single - dose intramuscularly at the thigh .
after the injection , general symptoms and weight were observed for 14 days .
after the observations had ended , hematologic and serum biochemical examinations , necropsy and a local tolerance test at the injection site were performed .
the experiments were carried out at the good laboratory practice firm , biotoxtech co. ( cheongwon , chungbuk ) .
animal experiments were approved by the ethics committee ( approval number : 130379).results : no deaths occurred in any of the three experimental groups .
the injection of sp had no effects on the general symptoms , body weights , results of the hematologic , and serum biochemical examinations , and necropsy findings .
in local tolerance tests at the injection sites , mild inflammation was observed in the experimental group , but it did not appear to be a treatment related effect.conclusion:under the conditions of this test , the results from the injection of sp suggest that the approximate lethal dose of sp is above 1.0 ml / animal for both male and female sd rats .
therefore , the clinical use of sp is thought to be safe . |
PubmedSumm118597 | ***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: all patients who underwent surgical treatment for a proximal humeral fracture with a locking plate during the study period were collected from the hospital trauma registration and reviewed for the study .
the criteria for inclusion in the present study were a proximal humeral fracture that had been treated surgically up to three weeks after the initial injury .
the cut off value of age at the time of surgery was 65 years or older .
we excluded patients with isolated fractures of the greater tuberosity or lesser tuberosity , a pathological fracture , patients with polytrauma , and patients who were not able to comprehend the given informed consent reliably .
in addition , those patients with four part fracture dislocation who required prosthetic replacement were also excluded .
individuals who were managed non - operatively ( as a consequence of being deemed unfit for surgery ) were excluded from the analysis .
surgery was performed with the patient in the beach - chair position on a radiolucent table .
the fracture was exposed and special attention was paid to minimize surgical trauma to the adjacent soft tissue .
we did not expose the medial soft tissue hinge in order to reduce the fracture .
the lcp was positioned 2 cm posterior to the bicipital groove , with care being taken to ensure that a sufficient gap was maintained between the plate and the long head of the biceps .
medial hinge was considered an important radiographic indicator when assessing initial reduction accuracy . when fracture reduction and subsequent screw positioning was considered adequate
, the plate was fixed definitively with the insertion of locking screws into the humeral head .
postoperatively , the arm was immobilized in a sling and controlled passive mobilization exercise with abduction and flexion beyond 90 was started within three weeks postoperatively , depending on the stability of the osteosynthesis and the bone quality .
true anteroposterior and axillary lateral radiographs were made postoperatively and at each follow - up visit .
the assessment of radiographs was done at three points in the postoperative period , immediate postoperative , at 3 months postoperative , and a final follow - up ( average , 11 months ; range , 8 to 17 months ) .
all radiographs were taken by the same two technicians in the same setting as standard protocol in order to minimize potential errors .
the neck - shaft angle was measured as described by agudelo et al.9 ) ( fig .
radiographs were assessed to find the presence of bridging osseous trabeculae , which is suggestive of healing , as well as failure of the fixation .
a fracture pattern was determined and confirmed by the senior surgeons based on the neer classification.10 ) severity of osteoporosis in the proximal humerus was assessed using cortical thickness suggested by tingart et al.11 ) on the anteroposterior view , we measured the lateral and medial cortical thickness at two different levels and calculated the mean of the four measurements .
level 1 was the most proximal level of the humeral diaphysis and level 2 was 20 mm distal to level 1 .
the presence or absence of medial support , as described by gardner et al.12 ) was assessed .
we divided the patients into two groups ; those with medial support and those without medial support . on the anteroposterior view
, we determined that the fracture has medial support when 1 ) the medial cortex was intact without comminution , and reduced anatomically , and/or 2 ) the shaft was impacted into the head fragment , and/or 3 ) a locking screw was placed in the inferomedial quadrant of the humeral head within 5 mm of the subchondral bone .
changes in neck - shaft angle ( difference between the immediate postoperative angle and the last follow - up angle ) were compared with fracture pattern and presence or absence of medial support using t - test .
we also used t - test to see whether the fall in the angle during the first 3 months was higher than the fall in the angle between 3 months and the final follow - up period .
we fitted univariate regression for age and combined cortical thickness ( cct ) to see if there is any association between the neck - shaft angle changes and continuous variables of age and cct .
in addition , we fitted a linear mixed model to see whether changing pattern over time is statistically significant .
the linear mixed model includes additional random - effect terms , so it is often appropriate for clustered data or data gathered over time regarding the same individuals.13 ) all reported p - values were 2-sided , and p - values < 0.05 were considered statistically significant .
a package developed by pinheiro and bates13 ) and r software were used for all statistical analyses .
surgery was performed with the patient in the beach - chair position on a radiolucent table .
the fracture was exposed and special attention was paid to minimize surgical trauma to the adjacent soft tissue .
we did not expose the medial soft tissue hinge in order to reduce the fracture .
the lcp was positioned 2 cm posterior to the bicipital groove , with care being taken to ensure that a sufficient gap was maintained between the plate and the long head of the biceps .
medial hinge was considered an important radiographic indicator when assessing initial reduction accuracy . when fracture reduction and subsequent screw positioning was considered adequate ,
the plate was fixed definitively with the insertion of locking screws into the humeral head .
postoperatively , the arm was immobilized in a sling and controlled passive mobilization exercise with abduction and flexion beyond 90 was started within three weeks postoperatively , depending on the stability of the osteosynthesis and the bone quality .
true anteroposterior and axillary lateral radiographs were made postoperatively and at each follow - up visit .
the assessment of radiographs was done at three points in the postoperative period , immediate postoperative , at 3 months postoperative , and a final follow - up ( average , 11 months ; range , 8 to 17 months ) .
all radiographs were taken by the same two technicians in the same setting as standard protocol in order to minimize potential errors .
the neck - shaft angle was measured as described by agudelo et al.9 ) ( fig .
radiographs were assessed to find the presence of bridging osseous trabeculae , which is suggestive of healing , as well as failure of the fixation .
a fracture pattern was determined and confirmed by the senior surgeons based on the neer classification.10 ) severity of osteoporosis in the proximal humerus was assessed using cortical thickness suggested by tingart et al.11 ) on the anteroposterior view , we measured the lateral and medial cortical thickness at two different levels and calculated the mean of the four measurements .
level 1 was the most proximal level of the humeral diaphysis and level 2 was 20 mm distal to level 1 .
the presence or absence of medial support , as described by gardner et al.12 ) was assessed .
we divided the patients into two groups ; those with medial support and those without medial support . on the anteroposterior view
, we determined that the fracture has medial support when 1 ) the medial cortex was intact without comminution , and reduced anatomically , and/or 2 ) the shaft was impacted into the head fragment , and/or 3 ) a locking screw was placed in the inferomedial quadrant of the humeral head within 5 mm of the subchondral bone .
changes in neck - shaft angle ( difference between the immediate postoperative angle and the last follow - up angle ) were compared with fracture pattern and presence or absence of medial support using t - test .
we also used t - test to see whether the fall in the angle during the first 3 months was higher than the fall in the angle between 3 months and the final follow - up period .
we fitted univariate regression for age and combined cortical thickness ( cct ) to see if there is any association between the neck - shaft angle changes and continuous variables of age and cct .
in addition , we fitted a linear mixed model to see whether changing pattern over time is statistically significant .
the linear mixed model includes additional random - effect terms , so it is often appropriate for clustered data or data gathered over time regarding the same individuals.13 ) all reported p - values were 2-sided , and p - values < 0.05 were considered statistically significant .
a package developed by pinheiro and bates13 ) and r software were used for all statistical analyses .
the average age of the patients was 70 years ( range , 65 to 82 years ) .
twenty - one ( 84% ) patients were women and four ( 16% ) were men .
twenty - two ( 88% ) patients sustained the fracture due to a trivial fall such as falling from a standing position , two were involved in a motor - vehicle accident and one was physically assaulted .
there were ten ( 40% ) neer type 2 fractures and fifteen ( 60% ) neer type 3 fractures .
there were no deep infections , nerve or vascular injuries , complications related to hardware such as loosening or screw cutout , nonunion or osteonecrosis of the humeral head .
the mean neck shaft angles at different points in time are represented in table 1 and fig .
2 . the mean loss of neck shaft angle between the immediate postoperative and the final follow - up period was 5.6 ( range , 0 to 14 ) ( fig .
2 ) . the mean loss in the neck - shaft angle in the first 3 months was 3.8 as compared to 1.3 in the period between 3 months and the final follow - up .
this was statistically significant ( p = 0.002 ) , indicating that most of the decrease in neck shaft angle occurs in the first three months after surgery .
only three patients showed a total loss of reduction of greater than 10. we considered an immediate postoperative neck shaft angle of less than 120 to be varus malalignment.9 ) there were three cases with varus malalignment in our series .
the mean fall in the neck shaft angle in these was 5.3. there was a trend that with increasing patient age , the fall in neck shaft angle decreased , but this was not statistically significant ( p = 0.29 ) ( fig .
the mean decrease in 2-part fractures was 5.9 and in 3-part fractures it was 4.7. there was no statistically significant relationship between the change in neck shaft angle and fracture pattern ( p = 0.41 ) ( fig .
mean value of the combined cortical thickness was 4.8 mm ( range , 3.4 to 6.8 mm ) . with regards to univariate regression ,
this , however , was not statistically significant ( p = 0.21 ) ( fig . 5 ) . based on gardner 's definition ,
those with medial support presented a loss in neck shaft angle of 5 at the final follow - up compared to 5.8 in the group without medial support .
we analyzed the relation between initial reduction accuracy and the change in neck - shaft angle by dividing the patients into two groups , those with an initial reduction angle less than 135 and those equal to or more than 135. the mean loss was greater in the former group ( 5.5 ) compared to that in the latter ( 4.8 ) .
there was no statistically significant difference between the two groups ( p = 0.65 ) .
the mean neck shaft angles at different points in time are represented in table 1 and fig .
2 . the mean loss of neck shaft angle between the immediate postoperative and the final follow - up period was 5.6 ( range , 0 to 14 ) ( fig .
2 ) . the mean loss in the neck - shaft angle in the first 3 months was 3.8 as compared to 1.3 in the period between 3 months and the final follow - up .
this was statistically significant ( p = 0.002 ) , indicating that most of the decrease in neck shaft angle occurs in the first three months after surgery .
only three patients showed a total loss of reduction of greater than 10. we considered an immediate postoperative neck shaft angle of less than 120 to be varus malalignment.9 ) there were three cases with varus malalignment in our series .
there was a trend that with increasing patient age , the fall in neck shaft angle decreased , but this was not statistically significant ( p = 0.29 ) ( fig .
the mean decrease in 2-part fractures was 5.9 and in 3-part fractures it was 4.7. there was no statistically significant relationship between the change in neck shaft angle and fracture pattern ( p = 0.41 ) ( fig .
mean value of the combined cortical thickness was 4.8 mm ( range , 3.4 to 6.8 mm ) . with regards to univariate regression ,
this , however , was not statistically significant ( p = 0.21 ) ( fig . 5 ) . based on gardner 's definition , 20 patients were determined as intact medial support and 5 were without medial support .
those with medial support presented a loss in neck shaft angle of 5 at the final follow - up compared to 5.8 in the group without medial support .
we analyzed the relation between initial reduction accuracy and the change in neck - shaft angle by dividing the patients into two groups , those with an initial reduction angle less than 135 and those equal to or more than 135. the mean loss was greater in the former group ( 5.5 ) compared to that in the latter ( 4.8 ) .
there was no statistically significant difference between the two groups ( p = 0.65 ) .
there was a trend that with increasing patient age , the fall in neck shaft angle decreased , but this was not statistically significant ( p = 0.29 ) ( fig .
the mean decrease in 2-part fractures was 5.9 and in 3-part fractures it was 4.7. there was no statistically significant relationship between the change in neck shaft angle and fracture pattern ( p = 0.41 ) ( fig .
mean value of the combined cortical thickness was 4.8 mm ( range , 3.4 to 6.8 mm ) . with regards to univariate regression , as the combined cortical thickness increased the fall in neck shaft angle increased .
this , however , was not statistically significant ( p = 0.21 ) ( fig . 5 ) .
based on gardner 's definition , 20 patients were determined as intact medial support and 5 were without medial support .
those with medial support presented a loss in neck shaft angle of 5 at the final follow - up compared to 5.8 in the group without medial support .
we analyzed the relation between initial reduction accuracy and the change in neck - shaft angle by dividing the patients into two groups , those with an initial reduction angle less than 135 and those equal to or more than 135. the mean loss was greater in the former group ( 5.5 ) compared to that in the latter ( 4.8 ) .
there was no statistically significant difference between the two groups ( p = 0.65 ) .
the majority of patients with proximal humeral fractures are above sixty years old , and most of these fractures in this population are related to osteoporosis.14 ) nevertheless , stable reduction is essential for healing of the fracture and for achieving early functional recovery of the shoulder .
management of an older patient who has a proximal humeral fracture is challenging because of the hazards posed by the osteopenic bone and the potential for medical complications due to associated comorbidities .
kristiansen et al.14 ) reported satisfactory or excellent results in only nine of twenty patients who had fixation of a proximal humeral fracture with a t - buttress plate , and there was a high rate of fixation failure .
fixed angled devices such as the angled blade plate were considered useful as they resisted angular deformation and torsion.15 ) however , meier et al.16 ) did not recommend internal fixation with angled blade plate in unstable proximal humerus fractures due to the high rate of complications ( 33% ) including protrusion of the blade into the glenohumeral joint ( 22% ) .
disadvantages of the percutaneous pinning technique include the potential for pin migration , loss of reduction , and pin - site infection .
injury to important anatomic structures concerning the shoulder is also a potential concern with this technique.17 ) moreover , fixation using intramedullary nailing has also shown variable results.18,19 ) the lcp is a relatively new modality in the armamentarium of the surgeon in tackling this category of fractures.20 ) several advantages have been outlined in recent literature . according to bjorkenheim et al.,8 )
the main advantage of this plate was apparent in elderly patients , since there were no failures of the internal fixation in this group , and they were able to attain an activity level , which was sufficient to satisfy their needs regarding independent daily living .
the plate is precontoured for the proximal humerus , and the insertion of locking screws obviates the need for a plate - to - bone compression , preserving the blood supply to the bones.20 ) the insertion of multiple polyaxial locking screws through the specific targeting device into the fragments of the humeral head provides fixed - angle support in multiple planes , which in theory should maintain the reduction achieved , while allowing for early mobilization.21 ) the key to this technology is the fixed - angle relationship between the screws and plate .
the threaded screw heads are locked into the threaded plate holes in order to prevent screw toggle , slide , and pull - out , thus diminishing the possibility of a primary or secondary loss of reduction.6 ) the load is transmitted from the bone to the plate via the screw - plate threaded connection .
since the plate and screws form a single stable system , the stability of the fracture depends on the stiffness of the entire construct.6 ) the mean age of the patients in our study group was 70 years .
the demographic and fracture - related characteristics in our study group were thus comparable to those in previous studies.7,15,16 ) we observed two complications in 25 patients during the one - year follow - up .
there was one case with a superficial infection , which was effectively treated with antibiotics .
this is similar to the 5% superficial infection rate reported by koukakis et al.22 ) the other was postoperative delirium from which the patient recovered within 24 hours . while complications such as subacromial impingement , initial malreduction , nonunion , and osteonecrosis have been reported in literature , the overall complication rate in our study was encouraging.2,7 ) this may be due to our exclusion of neer type 4 fractures , which have reported a prevalence of 21% to 75% regarding osteonecrosis.23 ) we did have three cases with initial varus malalignment , but the mean fall in neck shaft angle in these cases ( 5.3 ) matched that of the entire sample ( 5.6 ) . in our series ,
the mean loss of neck shaft angle was 5.9 in two part fractures and 4.7 in three part fracture patients .
zhang et al.24 ) reported an early loss of fixation in the initial 12 weeks after surgery .
they reported a mean loss of 1.6 1.3 in patients with medial support and 1.3 1.2 in patients without medial support in two part fractures , and a mean loss of 3.5 2.4 in patients with medial support and 6.1 3.1 in patients without medial support in three part fractures .
we observed that the patient age did not significantly affect the loss in neck shaft angle .
moonot et al.25 ) demonstrated no significant difference in the functional outcome between patients under and over 65 years old at a mean follow - up of 11 months post philos plate fixation .
the lcp may thus provide an acceptable surgical option in proximal humerus fractures irrespective of patient age .
we used the combined cortical thickness as described by tingart et al.11 ) as an indicator of bone quality .
siwach et al.26 ) concluded in their study that proximal humerus fractures with grade iv osteoporosis by singh 's index did worse as compared to those with grade ii osteoporosis .
bjorkenheim et al.8 ) used an lcp in 72 patients and concluded that this method was safe and recommended its use in treating proximal humerus fractures in elderly patients with poor bone stock . in this study , we found that tingart 's cortical index presented minimal effect on the decrease of neck shaft angle .
this is in accordance to a recent biomechanical study on locking plates in the proximal humerus where the authors concluded that the mechanical strength of the plate was unaffected based on a threshold combined proximal humerus cortical thickness of 4 mm.27 ) evaluation of fractures on the basis of medial support as described by gardner et al.12 ) revealed that the loss of neck shaft angle was less when there was medial support , although this was not statistically significant .
we could not replicate the statistical results obtained by gardner et al.12 ) but two part fractures showed a slightly better result than three part fractures .
gardner et al.12 ) stressed the importance of recreating continuity of the medial column or placement of inferomedial screws in the humeral head .
analysis of the histomorphometry and microstructural architecture of the humeral head bone stock also demonstrates that trabecular thickness and density are the greatest in the medial region.28 ) liew et al.29 ) also found screw purchase to be significantly greater in screws placed into the medial subchondral bone .
yang et al.30 ) in a recent study concluded that medial support and fracture pattern were the only two factors significantly related to the functional outcome , with the two part and three part fractures performing better than the four part fractures .
analysis of the fracture pattern with changes in the neck shaft angle in our study did not reveal any significant correlation .
the mean loss of neck shaft angle was 5.9 for 2 part fractures and 4.7 for 3 part fractures . in two part and three part fractures ,
we also analyzed the effect of immediate postoperative neck shaft angle on the final outcome .
division of patients into two groups , those with a neck shaft angle less than 135 and those with a neck shaft angle equal to or more than 135 , revealed a slightly higher fall in the former group , though not statistically significant .
agudelo et al.9 ) found a statistically significant association between varus malreduction immediately following surgery and early loss of fixation .
leonard et al.20 ) reported a better outcome in patients with intraoperative restoration of the humeral neck shaft angle to greater than 90 compared to those who were fixed with an angle less than 90 , though it was not statistically significant .
they advocate optimal restoration of the neck shaft angle in order to avoid the potential complication of varus collapse .
also , we have not clinically assessed the patients nor applied functional scoring and hence could not correlate the functional outcome with the radiological findings .
however , the results from our radiological analysis demonstrate that the locking plate with its ease of use , respect for biology , polyaxial fixation and low complication rates , is a useful tool in treating neer type 2 and type 3 proximal humerus fractures in patients over the age of 65 years .
although age and the deterioration of bone quality with age may be areas of concern , the proximal humerus locking plate offers a reliable option to the surgeon in order to treat these types of fractures in the elderly .
our findings emphasize the fact that a meticulous surgical technique , concerning the initial reduction and correct placement of the locking plate and screws , can provide a better outcome and fewer complications .
Output:
| backgroundwe conducted this radiographic study in the elderly population with proximal humeral fracture aiming to evaluate 1 ) the serial changes of neck - shaft angle after locking plate fixation and 2 ) find relationship between change in neck shaft angle and various factors such as age , fracture pattern , severity of osteoporosis , medial support and initial reduction angle.methodstwenty-five patients who underwent surgical treatment for proximal humeral fracture with locking plate between september 2008 and august 2010 are included .
true anteroposterior and axillary lateral radiographs were made postoperatively and at each follow - up visit .
measurement of neck shaft angle was done at immediate postoperative , 3 months postoperative and a final follow - up ( average , 11 months ; range , 8 to 17 months ) .
severity of osteoporosis was assessed using cortical thickness suggested by tingart et al.resultsthe mean neck shaft angles were 133.6 ( range , 100 to 116 ) at immediate postoperative , 129.8 ( range , 99 to 150 ) at 3 months postoperative and 128.4 ( range , 97 to 145 ) at final follow - up .
the mean loss in the neck - shaft angle in the first 3 months was 3.8 as compared to 1.3 in the period between 3 months and final follow - up .
this was statistically significant ( p = 0.002 ) , indicating that most of the fall in neck shaft angle occurs in the first three months after surgery .
relationship between neck shaft angle change and age ( p = 0.29 ) , fracture pattern ( p = 0.41 ) , cortical thickness ( p = 0.21 ) , medial support ( p = 0.63 ) and initial reduction accuracy ( p = 0.65 ) are not statistically significant.conclusionsthe proximal humerus locking plate maintains reliable radiographic results even in the elderly population with proximal humerus fracture . |
PubmedSumm118598 | ***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: internal carotid artery ( ica ) atherosclerotic stenosis is responsible for a significant proportion of transient ischemic attacks ( tia ) and approximately 30% of ischemic strokes ( 1 ) .
population - based epidemiological studies using ultrasound have shown that the prevalence of asymptomatic carotid artery stenosis ( cas ) 50% varies between 4% and 8% in adults ( 2 ) .
the annual risk of ipsilateral neurologic deficits for asymptomatic cas was published in several studies ( 2 - 8 ) .
the screening of individuals with asymptomatic significant cas is important to find the patients who need serial surveillance , medication , intervention or surgery . in korea , however , the prevalence of cas in the asymptomatic people has not been reported .
the role of screening depends on the incidence of the disease in the population , and the subpopulation in which the screening has a cost - effective benefit must be identified . in this study
, we attempted to investigate the prevalence of asymptomatic cas in korea , and we wanted to identify the risk factors of cas .
we investigated the prevalence of cas according to the subpopulation with a combination of risk factors .
twenty thousand seven hundred twelve neurologically asymptomatic people underwent carotid artery duplex ultrasound for health screening between march 2005 and march 2010 .
the population was divided into four groups according to the degree of cas with using real - time b - mode high resolution ultrasonography as group a , below 29% of cas ; group b , 30% to 49% of cas ; group c , 50% to 74% of cas ; group d , above 75% of cas .
duplex ultrasound was performed by radiologists or registered vascular technologists . and the carotid artery diameter was measured on a longitudinal and transverse view of the proximal ica and carotid bifurcation on both sides . the intima - media thickness ( imt ) ,
the rate of diameter reduction and the peak systolic velocity in the internal carotid artery ( just distal to the carotid bifurcation ) were measured .
the degrees of cas were measured by the rate of diameter reduction according to the european carotid surgery trial ( ecst ) method .
ultrasonography scanner equipped with 9-to-4-mhz linear - array transducer and a 5-mhz pulsed doppler ( siemens , antares , germany ) or a 10-mhz linear - array transducer and a 4.4-mhz pulsed doppler ( ge , logiq 9 , waukesha , wi , usa ) were used for duplex ultrasound . to identify the risk factors of cas , univariate analysis with fisher 's exact test
, chi - square tests , kruskal - wallis tests and multivariate analysis with a binary logistic regression model was conducted using the individuals ' demographics ( age , gender ) and the clinical variables ( hypertension , diabetes mellitus , ischemic heart disease , total cholesterol , hdl - cholesterol , ldl - cholesterol , hba-1c ) .
a total of 8,622 ( 41.6% ) people did not provide information about their exact current status of smoking , so the history of smoking was excluded from the risk factor analysis . according to the subgroups with a combination of risk factors
this study was reviewed and approved by the institutional review board of the samsung medical center ( no .
this study was reviewed and approved by the institutional review board of the samsung medical center ( no .
the mean age of the population was 55.1 yr ( range : 18 to 91 yr ) and 83% were male .
the prevalence of cas according to the degree of stenosis is shown in table 2 .
the prevalence of cas was 5.5% in group b , 0.9% in group c and 0.1% in group d. the prevalence of cas over 50% was 1% among the entire study population .
on univariate analysis ( table 3 ) , cas was more common in people aged over 65 yr ( p < 0.001 ) , males ( p <
0.001 ) , people with hypertension ( p < 0,001 ) , people with diabetes mellitus ( p < 0.001 ) and people with ischemic heart disease ( p < 0.001 ) .
the total cholesterol ( p = 0.003 ) and ldl - cholesterol ( p = 0.042 ) levels were higher in the people with cas , and the hdl - cholesterol ( p = 0.001 ) level was lower in the people with cas .
on multivariate analysis ( table 4 ) , the risk factors for cas more than 50% were old age ( or , 1.11 ; 95% ci , 1.10 - 1.13 ) , male gender ( or , 3.46 ; 95% ci , 2.12 - 5.66 ) , hypertension ( or , 1.69 ; 95% ci , 1.25 - 2.28 ) , diabetes mellitus ( or , 1.41 ; 95% ci , 1.00 - 1.99 ) and ischemic heart disease ( or , 1.93 ; 95% ci , 1.29 - 2.87 ) .
table 5 demonstrates the prevalence of cas 50% according to the subpopulations with a combination of the risk factors .
the prevalence of cas 50% was 3.1% among the people aged over 65 yr , and it was 4.0% among males aged over 65 yr .
it was 4.8% among males aged over 65 yr with hypertension , and it was 6.7% among males aged over 65 yr with hypertension and diabetes mellitus .
it was 5.6% among males aged over 65 yr with hypertension , diabetes mellitus and ischemic heart disease .
the prevalence of cas 30% was 14.8% , 18.2% , 22.8% , 26.9% and 30.6% in each of the above subgroups , respectively .
eighty - eight percent of strokes are ischemic , and 20% or fewer of these are due to large - artery stenosis ( 9 - 15 ) .
a subgroup of these has cas , and cas can be approached with endarterectomy or stenting .
the screening of asymptomatic cas followed by the best medical therapy or an invasive procedure is expected to reduce the risk of tia and stroke in the general population .
the presence of cas predisposes people to tia and stroke , and the risk is correlated with the severity of cas . for the people with 0 to 29% stenosis , tia or stroke occurred in 2.1% each year . for the people with 30% to 74% stenosis , tia or stroke occurred in 5.7% , and for the people with 75% to 100% stenosis , tia or stroke occurred in 19.5% ( 16 ) .
o'holleran reported that the 60% of the people with more than 75% stenosis had a stroke or tia during 5 yr of follow - up ( 17 ) .
the reported risk of tia or stroke in the people with asymptomatic cas has varied , and the stroke risk depends on more than just the degree of carotid artery narrowing .
most studies consider stenosis of 50% or greater , or 60% or greater to be clinically important . in the randomized trials that have evaluated the role of carotid endarterectomy ( cea ) in asymptomatic patients ,
the 5-yr risk of stroke in the individuals with cas more than 60% was 11.0%-11.8% without performing cea ( 18 , 19 ) . several population - based cohort and cross - sectional studies
the estimates of the prevalence of cas from population - based studies have ranged from 0.5% to 8% ( 2 , 11 , 20 - 22 ) .
the prevalence of clinically important cas ( 60% to 99% ) is estimated to be about 1% in people aged over 65 yr ( 23 ) . in our study , the prevalence of cas more than 50% was 1% in the overall population . but with the combination of the risk factors , the prevalence was increased ( table 5 ) . especially in the male population aged over 65 yr , the prevalence of cas more than 50% was 4% .
the clinical importance of our study is that it is one of the first reports that have defined the prevalence of cas in korea based on a large population .
the cas more than 50% is regarded as the indication for intervention or surgery if it is accompanied by neurologic signs or symptoms or it shows an unfavorable morphology .
if the degree of stenosis is less than 50% , then serial surveillance and medication are needed . as seen in the table 5 ,
the population who need serial surveillance and medication is high according to the combination of risk factors .
the role of aspirin or other antiplatelet agents in patients with asymptomatic carotid lesions has been established in several trials . the cutoff value of cas that needs medical therapy has not been defined .
but the high prevalence of cas more than 30% was reported in our study , especially in the old male population .
for example , in males aged over 65 yr , the incidence of cas more than 30% was 18.2% .
medical therapy for these individuals with mild cas can be expected to reduce the risk of cardiovascular events .
one of the purposes of carotid screening with duplex ultrasound is to find the population who are the potential candidates for surgical intervention .
but the actual benefit of carotid screening followed by surgical intervention for the proper candidate has not been defined .
based on the results of our study , we calculated the benefit of carotid screening for the male population aged over 65 yr from the point of view of stroke prevention .
the prevalence of cas more than 50% was 4% in the males aged over 65 yr . in the 2004 asymptomatic carotid surgery trial ( acst ) , the 5-yr risk of stroke in the patients with cas more than 60% was 11.8% without cea .
the relative risk reduction of cea was 46% ( 19 ) . from the data of the acst , we regarded the 5-yr risk of stroke in the population with cas more than 50% as roughly 10% , and the relative risk reduction of cea as roughly 50% . with these suppositions , among the 1,000 males aged over 65 yr , carotid screening with duplex ultrasound can detect 40 patients with cas more than 50% . among them , 4 patients are potential victims of stroke within 5 yr . if cea is performed in the proper candidates , then stroke can be prevented in 2 patients . although this is not direct evidence of benefit of carotid screening with duplex ultrasound , it can be expected that carotid screening followed by cea for the proper candidates can prevent at least 1 stroke per 1000 male population aged over 65 yr .
there still is not direct evidence that screening adults with duplex ultrasound for asymptomatic cas reduces fatal or nonfatal stroke ( 23 ) .
the actual benefit of carotid screening with duplex ultrasound and the cost - effectiveness must be defined in further studies .
this study was performed on the subjects who visited a tertiary medical center for routine health screening .
so the subjects of this study may not be the real representatives of general korean population .
carotid duplex ultrasound is necessary for people with risk factors such as male gender , old age , hypertension , diabetes and ischemic heart disease .
prevalence of asymptomatic carotid stenosis in korea based on health screening population young - nam roh , shin - young woo , nari kim , seonwoo kim , young - wook kim and dong - ik kim carotid artery ( ca ) stenosis is responsible for a significant proportion of ischemic attacks in brain . in korea , however , the prevalence of ca stenosis in the asymptomatic people has not been reported .
we analyzed the health screening records of ca ultrasonography ( 20,712 cases ) and found that the prevalence of ca stenosis > 50 & was 1&. old age , male gender , hypertension , diabetes mellitus and ischemic heart disease were significantly higher in ca stenosis group .
Output:
| we attempted to investigate the prevalence and risk factors of carotid artery stenosis in korea .
twenty thousand seven hundred twelve individuals who underwent carotid artery ultrasonography for health screening between march 2005 and march 2010 were retrospectively evaluated .
the population was divided into four groups , according to the degree of stenosis , as group a , below 29% ; group b , 30% to 49% ; group c , 50% to 74% ; group d , above 75% .
the medical records of the individuals were investigated , and fisher 's exact test , chi - square tests , kruskal - wallis tests and a binary logistic regression model were used for statistical analysis .
the prevalence of carotid stenosis was group b , 5.5% ; group c , 0.9% ; group d , 0.1% .
old age , male gender , hypertension , diabetes mellitus and ischemic heart disease were significantly higher in groups c and d ( p = 0.001 , 0.001 , 0.001 , 0.048 , and 0.001 , respectively ) . among the males aged over 65 yr , the prevalence of carotid stenosis 50% and 30% were 4.0% and 18.2% , respectively .
asymptomatic carotid stenosis is not uncommon in korea .
carotid ultrasonography is necessary for people with above - listed risk factors . |
PubmedSumm118599 | ***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 advent and implementation of conjugate antipneumococcal vaccines , 7valent conjugate vaccine ( pcv7 ) followed by 13valent conjugate vaccine ( pcv13 ) , have led to a tremendous progress being achieved in both prevention and care of severe infections caused by the streptococcus pneumoniae in the pediatric populations . in spite of this progress , severe infections due to streptococcus pneumoniae still represent an important cause of both mortality and morbidity in children under the age of 5 years in industrialized countries 1 , 2 .
the generalization of the 7valent conjugate vaccine in 2000 had , by itself , rapidly , led to 87% reduction in the incidence of severe infections in children aged<1 year , 58% in those aged < 2 years , and 62% in children aged < 5 years in the united states of america 3 .
concurrently , the pcv7 vaccine had also led to a significant reduction ( by 38% ) of otitis media as consequence to the reduction in pneumococcal ear , nose , and throat ( ent ) infections . in 2010 , although the centre for disease control , atlanta , confirmed the benefits of the new pcv7 vaccine in reducing both the resistance and carriage of pathologies due to streptococcus pneumoniae serotypes contained in pcv7 , it also expressed , however , a concern over the rise in the incidence of infections caused by the emerging strains not contained in the vaccine ( serotypes 1 , 19a , 3 , 6a and 7f ) 4 .
similar findings were to be reported , later , by other studies 5 , 6 . in order to counter the changing epidemiology of streptococcus pneumoniae infections and therefore ,
broaden the conjugate vaccine spectrum to cover the emerging serotypes ( 1 , 3 , 6a , 7f et 19a ) , the 13valent conjugate vaccine ( pcv13 ) was developed and commercialized in france , as early as june 2010 . despite the fact that the benefits of this new vaccine are being universally recognized ,
some cases of vaccination failures have been reported , mostly in those immunecompromised and/or in children with underlying predisposing conditions 5 , 7 .
we report a case of a 13monthold immunecompetent male child , who was diagnosed with streptococcus pneumonaie meningitis serotype 19a contained in the vaccine , despite having been correctly vaccinated with three doses of pcv13.our aim is to remind clinicians that pcv13 vaccination failure is possible and therefore , a high level of suspicion is required in ill children , even in those correctly immunized .
a 13monthold male child was referred to our emergency department , by his family doctor , with a 4day history of fever ( 40c ) , loss of appetite , loose stools , and vomiting .
he was reported to have lost 8% of his usual body weight . upon admission ,
his weight was 10.395 kg , height 90.5 cm , and bp 105/65 mm hg , and his capillary refill time was prolonged ( 3 sec ) despite being apyrexial ( 36c ) .
the child 's glasgow coma scale score was 13/15 ; his neurologic and ent examinations were both unremarkable , and his skin examination revealed no purpuric lesions or any other abnormalities .
the personal past medical history was unremarkable : he was a termborn child following in vitro fertilization ( ivf ) , with birth weight of 3.820 kg , birth length of 52 cm , and head circumference of 36 cm ; his vaccinations were up to date , according to the french immunization schedule , including three pcv13 injections ( at 2 , 4 , and 12 months of age , respectively ) and one neisseria meningitidis group c ( neisvac ) vaccine .
lumbar puncture revealed abnormal cerebrospinal fluid ( csf ) findings with elevated protein level at 1.7 g / l , chloride 120 mmol / l , and glucose 0.80 mmol / l .
csf cytology was positive , revealing an increased leukocytes count ( 1780/mm with 75% polynuclear neutrophils , 24% monocytes , 1% lymphocytes , and rbcs 4/mm ) .
csf soluble antigens were positive , and cultures grew numerous colonies of streptococcus pneumoniae ( 19a serotype ) .
plasma white blood cell count , urea and electrolytes , and liver function tests were within normal limits .
he was started on antibiotics ( cefotaxime 300 mg / kg / day for 14 days associated with dexamethasone 0.15 mg / kg 6 h for 2 days ) and subsequently did well .
the child 's immune system screening was unremarkable ( igg 6.84 g / l ; iga 0.47
g / l ; complement ( c3 1.45 g / l [ 0.691.32 ] ; c4 0.18 g / l ) ) .
postvaccination antibody titers against streptococcus pneumonia showed normal level ( igg 12.4 mg / l [ normal > 3.3 mg / l ] ) . an abdominal ultrasound was performed and showed a normally located spleen .
this report highlights the fact that severe infections due to streptococcus pneumoniae are still a threat and may occur in wellvaccinated immunocompetent children with pcv13 .
streptococcus pneumoniae is a complex bacterium that contains over 90 known serotypes , all different from each other in prevalence and virulence 8 .
the earlier implementation of pcv7 vaccination had led to a tremendous reduction in severe pneumococcal infections worldwide 3 , 4 , 5 , 6 , 7 . in france
, the 2007 epibac study showed similar results after the introduction of pcv7 in national vaccination schedules 9 .
the incidence of severe pneumococcal infections was reduced by 32% for acute meningitis and by 38% for bacteremia 9 .
the same study additionally reported , however , a considerable rise in the incidence of both meningitis and severe bacteremia due to serotype 19a in toddlers , as reported by others 2 , 4 , 9 , 10 . in another study by bekri et al .
10 , authors concluded that the impact of pcv7 was modest with regard to pneumococcal purulent pleuritis after reporting the highest incidence of serotypes 19a and 1 reaching around 50% of pneumococcal infections after the advent of pcv7 11 .
essential of criticism formulated against pcv7 was , therefore , mainly related to the emergence of non vaccine serotypes , although cases of vaccination failures had also been reported in well or partially vaccinated children 12 , 13 .
the immunogenicity studies , performed after the introduction of pcv13 in immunization schedules , have shown that this conjugate vaccine was able to induce antibody production well above the recommended coverage level of 0.35 g / ml against the six additional serotypes , that caused concern with pcv7 ( 1,3,5,6a,7f and 19a ) , in 96.8100% children who had received three injections 14 , 15 . however , two cases of pcv13 failures ( due to serotypes 19a and 19f ) have been reported by godot et al . 7 : one in a child aged 15.4 months at the time of diagnosis , who had received three pcv13 doses and had no underlying predisposing condition related to his vaccination failure . the second child , aged 57.1 months ,
had received three doses of pcv7 and a booster dose with pcv13 ; he , however , had a cochlear implant as the likely underlying condition .
our patient with streptococcus pneumoniae serotype 19a meningitis at the age of 13 months , after having been correctly vaccinated with three doses of pcv13 , around 35 days following the 3rd injection .
it is a wellknown fact that severe infections due to encapsulated bacteria are common in children with known underlying predisposing conditions such as asplenia , deficiency in the complement system , immunoglobulin deficiencies .
although we have no explanation as to why our patients whose postvaccinal antibody titer was within normal protective range presented with serotype 19a meningitis , the fact that we did not perform the opsonophagocytic assay may constitute a bias and temper our statement .
we speculate that pcv13 will contribute to further reduction in severe pneumococcal infections , but the likelihood of nonvaccine serotypes emergence can not be excluded .
besides , failure cases remain relatively rare with regard to the extent of successful coverage in the large majority of children .
the occurrence of severe pneumococcal infection in a wellvaccinated child should lead to explore his immune system ( complement system , immunoglobulin titer , opsonophagocytic assay , postvaccination antibody titer , etc . ) and perform an abdominal ultrasound to exclude asplenia 16 .
this case illustrates the necessity for clinicians to remain alert and maintain high level of suspicion in children , especially those in
looks bad category in pediatric emergency rooms . in spite of this rare failure , pcv13 remains a real medical progress and should strongly be recommended in children under the age of 5 years .
Output:
| key clinical messagewe report a 13monthold immunecompetent male child who was diagnosed with pneumococcal serotype 19a meningitis despite having received three pcv13 injections .
clinicians are reminded that bacterial meningitis can still occur , even in correctly vaccinated children .
investigations should include immune system screening along with abdominal ultrasound to exclude asplenia . |
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