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PubmedSumm8800 | ***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: polycystic ovarian morphology is displayed on ultrasound imaging in approximately 11.92.4 of women ( 1 ) .
the most common features of pcos are hyperandrogenism , unovulation , infertility and weight gain .
these women are at the risk of diabetes , atherosclerosis , and cardiovascular diseases ( 1 , 3 ) .
since obesity is the most common cause of insulin resistance and hyper - androgenism , weight reduction might be the first recommendation for pcos women ( 4 , 5 ) .
many researchers introduced hypocaloric diet as an operant treatment for weight loss and improvement of fertility in the overweight / obese pcos women .
however , only 5 - 10% weight loss has a useful effect on insulin resistance and cardiovascular hemodynamic function ( 46 ) .
weight loss up to 5 - 7% during 6 month can restore ovulation and fertility in more than 75% of women ( 5 ) .
weight loss induced by hypocaloric diet was intensified by treatment with metformin ( 7 , 8) .
in addition , several studies have shown weight loss reduces the severity of insulin resistance ( 9 , 10 ) .
treatment with insulin sensitizer agents may also alter endocrine imbalance , improves ovulation and fertility ( 11 ) .
even some researchers recommended 3 months of pretreatment with metformin for obese women ( 12 , 13 ) .
pasquali et al . showed hirsutism and irregular menses in pcos patients who received metformin were significantly improved in comparison to placebo group and also hypocaloric diet reduced bmi and waist circumference ( wc ) in pcos patients as well as the controls . in both groups , treatment with metformin reduced weight and bmi significantly ( 14 ) .
treatment with metformin reduces lh and androgens level and restores regular menses and ovulation ( 1 , 2 ) . also , treatment with the antiandrogen drugs such as flutamide reduced hirsutism and abdominal fat ( 15 ) . in sahin
however , flutamide only reduces androgen levels without improvement of insulin resistance in non - obese patients ( 16 ) .
studied 40 obese pcos patients during 6 months and showed that hypocaloric diet with metformin or flutamide alone or in combination had a significant effect on body lipid distribution , androgen levels , hirsutism and menses ( 17 ) .
gambineri in another study evaluated 80 women within 12 months and showed the benefits of long term treatment with metformin and flutamide and their compounds in obese pcos patients under hypocaloric diet . in his study , flutamide reduced visceral fat , androgen levels and lipid profile after 12 months and improved glucose tolerance value in comparison to placebo and metformin though there was no synergistic effect in patients who simultaneously received the combination of the two drugs ( 18 ) .
however , the other study showed that hypocaloric diet with metformin or flutamide alone or in combination had a better therapeutic effect ( 14 ) .
more recently , literature revealed contradictory findings about adding medicine to the diet and especially there has been little agreement on the beneficial effects of polytherapy ; hence , in this study , an attempt was made to address the following question : do metformin and flutamide alone or combination of both improve anthropometric indices and laboratory tests in overweight and obese pcos patients under hypocaloric diet ?
first , 156 overweight and obese infertile pcos women entered this single blind clinical trial ( clinical trial registration number : irct13880 7271760n3 , may 21 , 2010 ) .
these patients were referred to our pcos clinic ( fatemezahra infertility and reproductive health research center ) in babol ( north of iran ) in 2009 . out of them , 117 women were recruited and randomized to the treatment after considering exclusion and inclusion criteria .
this study was approved by the ethical committee of babol university of medical science . at the beginning , all participants signed an informed consent and entered the study .
inclusion criteria included all pcos women of 18 - 40 years of age , body mass index ( bmi ) > 19 and < 35
the diagnosis of pcos was determined by presence of two or more following conditions of rotterdam criteria ; oligo - ovulation or anovulation ( manifested as oligomenorrhea or amenorrhea ) , hyperandrogenemia ( elevated levels of circulating androgens ) , hyperandrogenism ( clinical manifestations of androgens excess ) and polycystic ovaries detected by ultrasonography ( 20 ) .
exclusion criteria were any drug consumers ( hormonal and metformin ) or cases who tried weight loss in 3 recent months , cases with hyperprolactinemia , cushing syndrome , late onset congenital adrenal hyperplasia , thyroid dysfunction , diabetes , cardiovascular , renal and liver diseases , pregnancy and also athletes .
they were advised to use barrier methods of contraception throughout the study . before the initiation of the study
, the patients underwent the physical examination focused on anthropometric indices ( weight , bmi , waist and hip circumferences and hirsutism ) .
the clinical examination focused on the evaluation of anthropometric and parametric values ( height , weight and waist circumference ) and also hirsutism using the ferriman - gallwey score ( 21 ) .
waist circumference was obtained as the minimum value between the iliac crest and the lateral costal margin , whereas hip circumference was determined as the maximum value over the glottal region to cm .
waist and hip circumferences were measured to the nearest centimeter with a soft tape ( cm ) according to world health organization ( who ) criteria . before the study
hormonal and metabolic determinations included the evaluation of circulating concentrations of free and total testosterone , dehydroepiandroster - one sulfate ( dhea - s ) , sex hormone - bonding globulin ( shbg ) , triglyceride ( tg ) , total and high - density lipoprotein ( hdl ) and low - density ( ldl ) cholesterol and triglycerides ( tg ) in fasting blood samples .
also , fasting glucose test , 2-hour oral glucose tolerance test ( ogtt ) with 75 gr glucose ( parsazmoon co , iran ) and fasting insulin test were administered .
all blood tests were performed , regardless of the menstrual cycle , at baseline and after 6 months .
a qualified laboratory examined the blood samples ( at baseline and the following 6-month reevaluation ) through the same methods and materials .
it should be noted that no significant differences were seen in the anthropometric indices and laboratory tests . to eliminate the confounding effect of diet ,
all patients received a standardized hypocaloric diet containing 1200 - 1400 kcal / day from a research dietitian .
the diet consisted of 50% carbohydrates , 30% proteins and 20% fat prescribed by the same dietician attending our division , who calculated the dietary energy composition by subtracting at least 500 kcal from the usual energy intake of an individual .
it should be noted that all women were visited monthly for compliance with both dietary and pharmacological treatments .
diet was evaluated by the dietician at each monthly visit , according to previously defined criteria providing quantitative information on daily energy intake and composition of the diet consumed during the previous month .
there was a strong reason to initiate the hypocaloric diet before treatment with medicine ; all patients equally underwent the similar diet as the only impressive element without any medication intervention .
furthermore , patients were checked for their usual physical activity throughout the treatment by the standard physical activity questionnaire ( the persian version with high validity ) before , 3 months following and at the end of the study ( 21 , 22 ) . from total of 156 overweight or obese pcos women ,
following one month of diet , the participants were visited again . while continuing dietary treatment , the patients who had anthropometric indices and the recording of all preliminary laboratory tests , were randomly divided in 4 groups including , 1 : metformin hydrocloride ( tablet , 500 mg , tehran - shimi co. , tehran , iran ) , orally , 3/day , 2 : flutamide - biosyn ( tablet , 250 mg , sobhan co. , tehran , iran ) , 2/day , 3 : metformin 500 mg , 3/day+ flutamide 250 mg , 2/day and 4 : placebo group .
patients were randomly assigned to groups to receive the drugs ( active or placebo ) using a computer generated sequence concealed from the study participants and then allocation sequence was done by a third party .
fatemezahra investigation pharmacy transferred metformin , flutamide and placebo capsules with appropriate dose and the same color , then packed and labeled them according to subject number .
all subjects were given a 1-month supply of capsules and they returned for monthly visits . also , to evaluate compliance with medications and to assess the side effects , patients were visited monthly .
to evaluate the liver and renal toxicity at the beginning which were probably the results of medicines , renal and liver functional tests were requested and repeated every 2 months . moreover ,
the remaining capsules were counted and a new supply of capsules was given to the patients .
patients recruited during 6-month treatment with hypocaloric diet and placebo , metformin , flutamide , or metformin+flutamide finally , at the end of the sixth month of treatment , physical examination focusing on anthropometric indices and all preliminary laboratory tests were done again and hirsutism was reevaluated .
all patients underwent anthropometric , hormonal and metabolic evaluation at baseline and 6 months following .
the sample size was calculated by g*power software and set error prob to 0.05 , power to 0.80 .
the values in anova had normal distribution and the variances of assumed variables were equal .
paired t - test was performed to estimate the within - group modification ( before and after treatment at each time point ) .
a one - way anova ( post hoc ) was applied to compare values amongst the four groups at each time point ( baseline , 6 months following ) , whereas tukey test was applied to find differences amongst the groups .
before the initiation of the study , the patients underwent the physical examination focused on anthropometric indices ( weight , bmi , waist and hip circumferences and hirsutism ) .
the clinical examination focused on the evaluation of anthropometric and parametric values ( height , weight and waist circumference ) and also hirsutism using the ferriman - gallwey score ( 21 ) .
waist circumference was obtained as the minimum value between the iliac crest and the lateral costal margin , whereas hip circumference was determined as the maximum value over the glottal region to cm .
waist and hip circumferences were measured to the nearest centimeter with a soft tape ( cm ) according to world health organization ( who ) criteria . before the study , the baseline values of anthropometric parameters were measured .
hormonal and metabolic determinations included the evaluation of circulating concentrations of free and total testosterone , dehydroepiandroster - one sulfate ( dhea - s ) , sex hormone - bonding globulin ( shbg ) , triglyceride ( tg ) , total and high - density lipoprotein ( hdl ) and low - density ( ldl ) cholesterol and triglycerides ( tg ) in fasting blood samples .
also , fasting glucose test , 2-hour oral glucose tolerance test ( ogtt ) with 75 gr glucose ( parsazmoon co , iran ) and fasting insulin test were administered .
all blood tests were performed , regardless of the menstrual cycle , at baseline and after 6 months .
a qualified laboratory examined the blood samples ( at baseline and the following 6-month reevaluation ) through the same methods and materials .
it should be noted that no significant differences were seen in the anthropometric indices and laboratory tests . to eliminate the confounding effect of diet ,
all patients received a standardized hypocaloric diet containing 1200 - 1400 kcal / day from a research dietitian .
the diet consisted of 50% carbohydrates , 30% proteins and 20% fat prescribed by the same dietician attending our division , who calculated the dietary energy composition by subtracting at least 500 kcal from the usual energy intake of an individual .
it should be noted that all women were visited monthly for compliance with both dietary and pharmacological treatments .
diet was evaluated by the dietician at each monthly visit , according to previously defined criteria providing quantitative information on daily energy intake and composition of the diet consumed during the previous month .
there was a strong reason to initiate the hypocaloric diet before treatment with medicine ; all patients equally underwent the similar diet as the only impressive element without any medication intervention .
furthermore , patients were checked for their usual physical activity throughout the treatment by the standard physical activity questionnaire ( the persian version with high validity ) before , 3 months following and at the end of the study ( 21 , 22 ) .
from total of 156 overweight or obese pcos women , 117 women were recruited and randomized to the treatment ( figure 1 ) . following one month of diet , the participants were visited again . while continuing dietary treatment , the patients who had anthropometric indices and the recording of all preliminary laboratory tests , were randomly divided in 4 groups including , 1 : metformin hydrocloride ( tablet , 500 mg , tehran - shimi co. , tehran , iran ) , orally , 3/day , 2 : flutamide - biosyn ( tablet , 250 mg , sobhan co. , tehran , iran ) , 2/day , 3 : metformin 500 mg , 3/day+ flutamide 250 mg , 2/day and 4 : placebo group .
patients were randomly assigned to groups to receive the drugs ( active or placebo ) using a computer generated sequence concealed from the study participants and then allocation sequence was done by a third party .
fatemezahra investigation pharmacy transferred metformin , flutamide and placebo capsules with appropriate dose and the same color , then packed and labeled them according to subject number .
all subjects were given a 1-month supply of capsules and they returned for monthly visits . also , to evaluate compliance with medications and to assess the side effects , patients were visited monthly .
to evaluate the liver and renal toxicity at the beginning which were probably the results of medicines , renal and liver functional tests were requested and repeated every 2 months . moreover ,
the remaining capsules were counted and a new supply of capsules was given to the patients .
patients recruited during 6-month treatment with hypocaloric diet and placebo , metformin , flutamide , or metformin+flutamide finally , at the end of the sixth month of treatment , physical examination focusing on anthropometric indices and all preliminary laboratory tests were done again and hirsutism was reevaluated .
all patients underwent anthropometric , hormonal and metabolic evaluation at baseline and 6 months following .
the sample size was calculated by g*power software and set error prob to 0.05 , power to 0.80 .
the values in anova had normal distribution and the variances of assumed variables were equal .
paired t - test was performed to estimate the within - group modification ( before and after treatment at each time point ) . a one - way anova ( post hoc )
was applied to compare values amongst the four groups at each time point ( baseline , 6 months following ) , whereas tukey test was applied to find differences amongst the groups .
out of 156 pcos patients who were eligible , 39 women were excluded ; 32 women had no inclusion criteria , 6 women declined to participate and one woman met the exclusion criteria .
117 women were randomized in 4 groups ; 28 women were allocated to receive metformin , 28 received flu - tamide ( 1 woman had no contribution ) and 31 women received metformin+flutamide ( 1 woman had no contribution ) and 27 women received placebo . out of the metformin group ,
3 women ( 1 woman for high transaminase level and 2 women for refusing to follow up ) , from the flutamide group , one woman for wrong use of medicine , were lost to follow up .
also , from the metformin+flutamide group , 4 women ( 2 women for the high transaminase level , 1 for refusing the follow up and one woman for the wrong use of medicine ) and from placebo group , one woman were lost to follow up ( for changing the place of living ) .
finally , 25 women in the metformin group , 27 in the flutamide group , 27 in the metformin+flutamide group and 26 in the placebo group were analyzed .
no significant difference was seen in the anthropometric indices and laboratory tests in baseline values .
table 1 summarizes the anthropometric indices and laboratory test changes ( before and after treatment ) within the four groups . to determine the within - group changes ,
changes in anthropometric indices and laboratory tests within the 4 groups under study ( before and after treatment ) changes ( post treatment value- pre treatment value ) was significant at p<0.05 changes ( post treatment value- pre treatment value ) was significant at p<0.01 changes ( post treatment value- pre treatment value ) was significant at p<0.001 comparing changes between groups was significant at p<0.05 comparing changes between groups was significant at p<0.01 ferriman - gallway score as well as placebo , the groups treated with metformin , flutamide , and metformin+flutamide showed significant reduction in all antropometric indices following 6 months in comparison to their baseline ( p<0.01 ) except hc in flutamide group which was not significant . in the glucose profile ,
the fbs initially demonstrated significant reduction within metformin+flutamide group and then within placebo group before and after treatment , respectively ( p<0.001 ) ( p<0.05 ) .
however , the fasting insulin showed no further modification after treatment compared to baseline except within metformin+flutamide group ( p<0.001 ) .
in the lipid profile , ldl had significant reduction in all groups except metformin+ flutamide following the treatment compared to baseline ( metformin ; p<0.001 ) , ( flutamide ; p<0.01 ) ( placebo ; p<0.05 ) . in sex hormones
, all groups demonstrated no significant reduction except dhea ( s ) in which significant reduction was seen in metformin+flutamide group and also placebo after treatment compared to the baseline .
the anthropometric indices and laboratory tests of four groups after treatment are summarized in table 2 .
parametric indices and metabolic parameters of women among the four groups under study results are expressed as meansd .
the values were evaluated with the post hoc test ; no significant differences among groups in baseline values ; difference by group p-0.05 ; ns = non significant > 0.05 ; met = metformin ; flu = flutamide ; p = placebo the difference between groups ( in a row ) is significant ferriman - gallway score there were no significant differences in the baseline values in our study .
in anthropometric indices , significantly greater reductions were observed in bmi , wc and hc in the metformin group after treatment in comparison to other groups ( p < 0.001 ) . in sugar profile ,
the post treatment fasting blood sugar and fasting insulin were diminished significantly in metformin+flutamide group compared to other groups after treatment ( p<0.001 ) , while in the lipid profile , metformin+flutamide revealed reduction in tg and placebo reduced ldl significantly after treatment compared to other groups ( p<0.001 ) . in sex hormone profiles ,
the flutamide group was superior to others in reduction of total testosterone ( p<0.01 ) and in the placebo , the reduction of dhea(s ) was observed after treatment ( p<0.05 ) ( table 2 ) .
it should be mentioned that , throughout the study , markers of liver dysfunction such as transaminases and lactate dehydrogenase were checked monthly and they remained unaltered except among 3 women .
table 1 summarizes the anthropometric indices and laboratory test changes ( before and after treatment ) within the four groups . to determine the within - group changes ,
changes in anthropometric indices and laboratory tests within the 4 groups under study ( before and after treatment ) changes ( post treatment value- pre treatment value ) was significant at p<0.05 changes ( post treatment value- pre treatment value ) was significant at p<0.01 changes ( post treatment value- pre treatment value ) was significant at p<0.001 comparing changes between groups was significant at p<0.05 comparing changes between groups was significant at p<0.01 ferriman - gallway score as well as placebo , the groups treated with metformin , flutamide , and metformin+flutamide showed significant reduction in all antropometric indices following 6 months in comparison to their baseline ( p<0.01 ) except hc in flutamide group which was not significant . in the glucose profile ,
the fbs initially demonstrated significant reduction within metformin+flutamide group and then within placebo group before and after treatment , respectively ( p<0.001 ) ( p<0.05 ) .
however , the fasting insulin showed no further modification after treatment compared to baseline except within metformin+flutamide group ( p<0.001 ) .
in the lipid profile , ldl had significant reduction in all groups except metformin+ flutamide following the treatment compared to baseline ( metformin ; p<0.001 ) , ( flutamide ; p<0.01 ) ( placebo ; p<0.05 ) . in sex hormones
, all groups demonstrated no significant reduction except dhea ( s ) in which significant reduction was seen in metformin+flutamide group and also placebo after treatment compared to the baseline .
the anthropometric indices and laboratory tests of four groups after treatment are summarized in table 2 .
parametric indices and metabolic parameters of women among the four groups under study results are expressed as meansd .
the values were evaluated with the post hoc test ; no significant differences among groups in baseline values ; difference by group p-0.05 ; ns = non significant > 0.05 ; met = metformin ; flu = flutamide ; p = placebo the difference between groups ( in a row ) is significant ferriman - gallway score there were no significant differences in the baseline values in our study . in anthropometric indices ,
significantly greater reductions were observed in bmi , wc and hc in the metformin group after treatment in comparison to other groups ( p < 0.001 ) . in sugar profile ,
the post treatment fasting blood sugar and fasting insulin were diminished significantly in metformin+flutamide group compared to other groups after treatment ( p<0.001 ) , while in the lipid profile , metformin+flutamide revealed reduction in tg and placebo reduced ldl significantly after treatment compared to other groups ( p<0.001 ) . in sex hormone profiles ,
the flutamide group was superior to others in reduction of total testosterone ( p<0.01 ) and in the placebo , the reduction of dhea(s ) was observed after treatment ( p<0.05 ) ( table 2 ) .
it should be mentioned that , throughout the study , markers of liver dysfunction such as transaminases and lactate dehydrogenase were checked monthly and they remained unaltered except among 3 women .
the result of our study indicates that the use of metformin and flutamide improves anthropometric indices and laboratory tests in obese / over - weight pcos women under hypocaloric diet .
generally , in obese women with anovulatory infertility , weight loss makes spontaneous ovulation facile and improves the chance of spontaneous conception ( 24 ) . those patients who ovulate and conceive while remaining obese will encounter predictable risks during pregnancy and post - pregnancy .
since pre - pregnancy weight loss reduces the incidence of gestational diabetes in these women ( 25 ) , most therapists encourage pcos women to reduce weight before pregnancy .
the findings of the current study are consistent with that of morin - papunen et al . who found metformin is able to decrease glucose disposal in skeletal muscle ( 26 ) .
also , a number of studies have found the reduction in weight and bmi by metformin ( 7 , 27 , 28 ) , however , there are many conflicting ideas about the effect of metformin on weight and bmi .
tang et al . concluded that metformin is less effective in very obese anovulatory women and a higher dose instead of routinely prescribed doses and a longer duration of therapy are necessary for these patients ( 29 ) .
in addition , nieuwenhuis - ruifrok in his systematic review concluded that addition of metformin treatment does not lead to greater weight loss in patients who are on a diet or who follow a lifestyle program ( 8) . a possible explanation for those might be that regarding our patients mean bmi ( 32 k / m ) , no further doses were needed for them .
our unanticipated finding shows that the combination of the two drugs as a part of polytherapy provides beneficial effects on glucose reduction .
wadden concluded that more weight loss is achieved by combination of a lifestyle modification program with drug therapy in comparison to a lifestyle program alone ( 30 ) .
's research hypocaloric diet alone has a main role in improving insulin resistance and hyperinsulinaemia .
gambineri also conducted another study on pcos patients during 12 months and concluded metformin alone decreased glucose - stimulated insulin but the combination of both drugs had no additive effect .
he explained that some therapeutic effects would not be present during the first six months of treatment ( 18 ) though , in this paper this incidence took place within 6 month .
our interesting finding was that metformin+ flutamide reduced tg more than other medicines except hypocaloric diet .
this finding is not in agreement with gambineri et al.s findings which showed none of the active treatment groups differed in changes of lipid concentrations after 6 months of treatment , whereas they observed a greater reduction in ldl cholesterol after 12 months in the metformin+flutamide group .
maybe the initial results of ldl reduction in our study relates to the lesser weights of our patients in comparison to the patients in their study ( 18 ) .
one of the limitations of our study was small sample size of the obese women which overlapped with overweight women , so the effect of medicine on them versus overweight women could not be evaluated . in our study , the menstrual pattern of our patients showed no significant differences with taking medicines or diet before and after treatment , whereas metformin further increased frequency of menstruation .
reported that flutamide therapy showed a significant enhancement in the percentage of ovulation cycles and regulated the menstrual profile in their pcos patients .
also , gambineri reported that metformin further increased frequency of menstruation compared with placebo after 6 months ( 18 , 32 ) .
maybe , by dividing our patients menstruation pattern to regular and irregular , further beneficial findings could be offered .
well designed clinical trials on the current topic are therefore recommended , especially use of flutamide and metformin and also hypocaloric diet and determining their effect on clinical and biochemical characteristics of pcos versus non pcos patients can be an important area for investigation .
it causes improvement in their general health and prevents long term consequences . also , different beneficial treatment options according to our desired outcomes in the diet of overweight / obese pcos women would help the experts to plan and treat patients according to each of their profile disturbance ( any of the 4 groups ) .
considering the beneficial effects of hypochaleric diet compared to the medicine , life style and nutrition modification in pcos patients was also effective in our study .
of course , considering findings about metformin and flutamide versus diet alone , it is supposed that our conclusions should be considered with caution and judiciously and they require more attention before clinical recommendations .
the most obvious finding of this study is that the use of metformin and flutamide improves and accelerates normalizing the anthropometric indices and laboratory tests in obese / overweight pcos women under hypocaloric diet .
Output:
| backgroundthis study was designed to investigate the effect of metformin and flutamide alone or in combination with anthropometric indices and laboratory tests of obese / overweight pcos women under hypocaloric diet.methodsthis single blind clinical trial was performed on 120 pcos women . at the beginning ,
hypocaloric diet was recommended for the patients .
after one month while they were on the diet , the patients were randomly divided in 4 groups ; metformin ( 500 mg , 3/day ) , flutamide ( 250 mg , 2/day ) , combined , metformin ( 500 mg , 3/day ) with flutamide ( 250 mg , 2/day ) and finally placebo group .
the patients were treated for 6 months .
anthropometric indices and laboratory tests ( fasting and glucose - stimulated insulin levels , lipid profile and androgens ) were measured . a one - way anova ( post hoc ) and paired t - test
were performed to analyze data .
a p 0.05 was considered statistically significant.resultsafter treatment , reduction in weight , bmi , hip circumference was significantly greater in the metformin group in comparison to other groups ( p<0.05 ) .
in addition , the fasting insulin was significantly greater in metformin group and flutamide group in comparison to metformin+flutamide and placebo groups after treatment ( p<0.05 ) . within groups ,
insulin level showed significant changes ( before and after treatment ) in metformin+flutamide group and ldl reduction was significant in flutamide group before and after treatment .
post hoc tukey and two - tailed with p0.05 were used to define statistical significance.conclusionusing combination of metformin and flutamide improves anthropometric indices and laboratory tests in obese / overweight pcos women under hypocaloric diet . |
PubmedSumm8801 | ***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: oryzias latipes belongs to the order of beloniformes and adrianichthyidae , and is known to be distributed in japan , china , and korea . in south korea , oryzias latipes are often found in freshwater areas ( e.g. , nakdong - river as well as other rivers flow into the east sea ) yet they are also discovered around brackishwater areas .
oryzias latipes are characterized with 1 ) small size , 2 ) short generation , 3 ) high resistance against water temperature , salinity , water quality , pollution , and oxygen content , and 4 ) ease of laboratory breeding hence they are widely utilized for study purposes such as genetics , physiology , and development researches ( kim & kim , 1993 ) .
there are several domestic / international studies investigated regarding taxonomy and distribution of oryzias latipes in the yunnan region of china ( chen et al . , 1989 ) , distribution areas and karyotypes of indian oryzias latipes ( uwa , 1986 ) , coefficient / measuring characteristics , and karyotypes of oryzias latipes found in southern / island areas of south korea ( kim & moon , 1987 ; magtoon & uwa , 1985 ; uwa & jeon , 1987 ) , chromosomes of oryzias latipes ( levan et al . , 1964 ) ,
two distinct population of korean oryzias latipes ( sakaizumi & jeon , 1987 ) , and list of subspecies for novel korean oryzias latipes sinensis ( kim & lee , 1992 ) ; however there is scant investigation in reference to spawning habits as well as developmental characteristics of larvae and juvenile oryzias latipes . in the present , therefore , the authors investiaged the morphology of larvae and juvenile oryzias latipes in their egg development and growth phases as a part of basic biological studies for the development of ornamental fishes , protection of oryzias latipes , and to provide preliminary data for taxonomic studies .
adult oryzias latipes and eggs laid on weeds were collected from a river in shinduck - dong , yeosu - si , jeollanam - do utilizing skimming nets ( mesh , 5.5 mm ) and dredge from may 2011 ( fig .
collected eggs were observed using a universal projector for egg sizes ( i.e. , the diameter of eggs ) while their morphological traits were investigated with a stereoscopic microscope .
hatched larvae were subsequently fed with water flea and feeding stuff for fish culture in the glass water tank ( 305030 cm ) while the temperature was maintaining 20.0~25.4c ( average 23.0c ) ; rearing water was daily changed ( morning and afternoon ; 1/2 per each time , respectively ) . in order to monitor morphological development of larvae and juvenile oryzias latipes , each part of body was observed and measured utilizing the stereoscopic microscope and universal projector from hatching to 35 days after hatching ; in each day , an average of ten fishes was anesthetized with ice and ms-222 sandoz ( tricaine methane sulfonate ) for measurements and developmental stages were determined as described elsewhere russell ( 1976 ) .
the earliest event for naturally hatched eggs was the formation of blastodisc was observed ( fig .
2 , b ) , and subsequently reached to the 4-cell stage at 1 hour 37 minutes ( fig .
the embryo reached at 8-cell stage and 32-cell stage after 2 hours 27 minutes and 3 hours 27 minutes of the blastodisc formation ( fig .
2 , g ) after 8 hours 39 minutes and 23 hours 37 minutes from the blastodisc , respectively . in turn
22 minutes of the formation of blastodisc , an elongated embryo was formed on the side of york ( fig .
2 , i ) , and then optic vesicle , kupffer 's vesicle , and myotome were formed in the embryo at 75 hours 57 minutes ( fig .
2 , j ) . the prototype of pectoral fin was form after 143 hours 37 minutes of blastodisc formation while the tail was split ; in this , the embryo started to move intermittently ( fig .
the embryo broke through the egg membrane and started to hatching from the head after 167 hours 27 minutes of formation of blastodisc ( fig .
the total length of hatched larvae was approximately 5.01 mm and swimming in a crowd near the bottom of water tank .
right after hatching , the total length of larvae was 4.95~5.10 mm ( average 5.01 mm ,
when hatched , most york was absorbed and the myotome was approximately 26~28 ( 8~9 + 18~19 ) and oil droplets were placed in the middle of the york ; dorsal fin , anal fin and the caudal fin were connected via membranes and the prototype of caudal fin was observed .
chromophores were slightly precipitated on eyes while melanophores were found on the upper part of head , back side of eyes , sides of embryo , and the air bladder with a shape of stars and dots . in this stage ,
larvae did not actively swim yet started to swim vigorously after 3~5 hours of hatching utilizing the caudal fin ( fig .
3 days after hatching , the total length of larvae was around 5.25~5.53 mm ( average 5.35 mm , n = 10 ) and active intake activities were observed ; the york was completely absorbed and the fishes were shifted to the post - larvae stage . in this stage , as the gastrointestinal tract was being developed , the anus was placed on the position of approximately 40% of the total length and a little in front of the lateral side .
while chromophores were precipitated on eyes , more melanophores were found on the head and air bladder ; these were shown along with the lateral side with shapes of stars and dots .
the caudal fin had three stems and the terminal notochord started to being bending ( fig .
, the post larvae had the total length of 5.45~5.60 mm ( average 5.52 mm , n = 30 ) with eight stems formed on the caudal fin . on the front lateral side
the post larvae represented the total length of 6.61~6.87 mm ( average 6.73 mm , n = 30 ) while melanophores were getting more clear and obvious on the head as well as air bladder .
the prototypes of pectoral fin and anal fin were shown , and rod - shaped bones on tail were developed ( fig .
the total length of post - larvae was 8.94~10.30 mm ( average 9.51 mm , n = 30 ) and 3 stems on the dorsal fin were formed .
the prototype was appeared on the ventral fin and melanophores were getting clearer along with the back side of fishes ( fig .
after 22 days of hatching , the post larvae had the 10.81~12.80 mm of the total length ( average 11.58 mm , n = 30 ) and dorsal fin as well as anal fin were being formed ; there were 6~7 stems of dorsal fin , 15~18 stems of anal fin , and 17~20 stems of caudal fin were formed ( fig .
the total length of post larvae was 11.50~13.50 mm ( average 12.47 mm , n = 30 ) and the ventral fin was being formed yet the primordial finfold was remained ( fig .
after 35 days of hatching , the total length of the post larvae was 13.95~15.30 mm ( average 14.64 mm , n = 30 ) .
all fins and numbers of fins were fixed , indicating that the juvenile stage was reached .
the earliest event for naturally hatched eggs was the formation of blastodisc was observed ( fig .
2 , b ) , and subsequently reached to the 4-cell stage at 1 hour 37 minutes ( fig .
the embryo reached at 8-cell stage and 32-cell stage after 2 hours 27 minutes and 3 hours 27 minutes of the blastodisc formation ( fig .
2 , g ) after 8 hours 39 minutes and 23 hours 37 minutes from the blastodisc , respectively . in turn
22 minutes of the formation of blastodisc , an elongated embryo was formed on the side of york ( fig .
2 , i ) , and then optic vesicle , kupffer 's vesicle , and myotome were formed in the embryo at 75 hours 57 minutes ( fig .
2 , j ) . the prototype of pectoral fin was form after 143 hours 37 minutes of blastodisc formation while the tail was split ; in this , the embryo started to move intermittently ( fig .
the embryo broke through the egg membrane and started to hatching from the head after 167 hours 27 minutes of formation of blastodisc ( fig .
the total length of hatched larvae was approximately 5.01 mm and swimming in a crowd near the bottom of water tank .
right after hatching , the total length of larvae was 4.95~5.10 mm ( average 5.01 mm , n = 10 ) while both anus and mouth were opened . when hatched , most york was absorbed and the myotome was approximately 26~28 ( 8~9 + 18~19 ) and oil droplets were placed in the middle of the york ; dorsal fin , anal fin and the caudal fin were connected via membranes and the prototype of caudal fin was observed .
chromophores were slightly precipitated on eyes while melanophores were found on the upper part of head , back side of eyes , sides of embryo , and the air bladder with a shape of stars and dots . in this stage ,
larvae did not actively swim yet started to swim vigorously after 3~5 hours of hatching utilizing the caudal fin ( fig .
3 days after hatching , the total length of larvae was around 5.25~5.53 mm ( average 5.35 mm , n = 10 ) and active intake activities were observed ; the york was completely absorbed and the fishes were shifted to the post - larvae stage . in this stage , as the gastrointestinal tract was being developed , the anus was placed on the position of approximately 40% of the total length and a little in front of the lateral side .
while chromophores were precipitated on eyes , more melanophores were found on the head and air bladder ; these were shown along with the lateral side with shapes of stars and dots .
the caudal fin had three stems and the terminal notochord started to being bending ( fig .
the post larvae had the total length of 5.45~5.60 mm ( average 5.52 mm , n = 30 ) with eight stems formed on the caudal fin .
the post larvae represented the total length of 6.61~6.87 mm ( average 6.73 mm , n = 30 ) while melanophores were getting more clear and obvious on the head as well as air bladder .
the prototypes of pectoral fin and anal fin were shown , and rod - shaped bones on tail were developed ( fig .
the total length of post - larvae was 8.94~10.30 mm ( average 9.51 mm , n = 30 ) and 3 stems on the dorsal fin were formed .
the prototype was appeared on the ventral fin and melanophores were getting clearer along with the back side of fishes ( fig .
after 22 days of hatching , the post larvae had the 10.81~12.80 mm of the total length ( average 11.58 mm , n = 30 ) and dorsal fin as well as anal fin were being formed ; there were 6~7 stems of dorsal fin , 15~18 stems of anal fin , and 17~20 stems of caudal fin were formed ( fig .
the total length of post larvae was 11.50~13.50 mm ( average 12.47 mm , n = 30 ) and the ventral fin was being formed yet the primordial finfold was remained ( fig .
the total length of the post larvae was 13.95~15.30 mm ( average 14.64 mm , n = 30 ) .
all fins and numbers of fins were fixed , indicating that the juvenile stage was reached .
when it comes to fish , morphological changes , observed in the development of larvae and juvenile fishes , have been widely utilized as important traits to identify classification such as family and genus ( okiyama , 1979 ) .
oryzias latipes is one of two fishes ( the other is oryzias sinensis ) that belongs to the oryzias genus ; these fishes are very similar yet no study has been done in regards to their spawning habits and early life history .
embryos of o. latipes are spherical transparent separate demersal eggs ; there are short hairs as well as a bunch of long hairs on the membrane ; these hairs stick together , working as sticking thread , thereby aiding to stick on weeds . in the present study ,
the average size of o. latipes eggs was ranging 1.29~1.40 mm ( average 1.35 mm , n = 50 ) which was slightly smaller than the observation of kim & kim ( 1993 ) while bigger than those of o. latipes sinensis ( 1.10~1.20 mm , average 1.15 mm ) .
also when it compares other freshwater fish , zacco koreanus with 3.090.07 mm diameter ( lee et al . ,
2013 ) showed the big difference with o. sinensis , the egg size of pseudogobio esocinus was 1.980.19 mm ( lee et al . , 2008 ) , the diameter of fertilized egg of luciogobius grandis was 2.060.23 mm ( yun et al .
, 2011 ) so that egg diameter of was smaller than other freshwater fish . in comparison with the saltwater fish , cinnamon clownfish ( amphiprion melanopus ) s fertilized size was 2.40.1 mm ( noh et al . , 2011 ) , so there was no difference , and scomber japonicus , otherwise , was smaller than o. latipes as the diameter 0.950.03 mm ( park et al . , 2008 ) .
on the other hand , we found that time took for hatching was approximately 167 hours 27 minutes from the formation of blastodisc ; this results is somewhat different compared to other study . in the study of kim & kim ( 1993 ) , it took approximately 9~10 days for hatching and such inconsistency might be due to the difference in water temperature .
the egg development of z. koreanus was completed around 68 hours after fertilization ( lee et al . , 2013 ) ,
the hatching time of p. esocinus was 164 hours ( lee et al . , 2008 ) , it was similar to o. latipes , and l. grandis was 120 hours 54 minutes ( yun et al . , 2011 ) , so it was earlier than o. latipes s hatching time .
cinnamon clownfish ( a. melanopus ) , saltwater aquarium fish , was 168 hours ( noh et al . , 2011 ) and it was also similar to o. latipes , in saltwater fish case , the time for hatching of s. japonicus was far faster than o. latipes , as 51 hours ( park et al . , 2008 ) .
right after the hatching , the total length of larvae was 4.95~5.10 mm ( average 5.01 mm , n=10 ) with opened anus and mouth . in the juvenile stage
was reached after the 35 days from hatching ; in this , the total length was found to be 14.64 mm .
freshwater fish , z. koreanus , the total length of larvae right after the hatching was 10.300.40 mm , in the juvenile stage was reached after the 13 days from hatching as the total length 16.980.56 mm ( lee et al . , 2013 ) , it was faster than o. latipes .
total length of larvae of p. esocinus was 4.610.83 mm , 16.220.65 mm after the 42 days from hatching was reached in the juvenile stage ( lee et al . , 2008 ) .
it showed similar to o. latipes , and l. grandis was 3.300.07 mm for larvae after hatching , 11.460.12 mm for juvenile after the 29 days ( yun et al . , 2011 ) .
saltwater aquarium fish , a. melanopus , showed larvae of average 3.50.3 mm , it was developed like adult after the 90 days as 41.00.3 mm ( noh et al . , 2011 ) .
the development was slower than o. latipes . in s. japonicus case , on the other hand ,
right after the hatching , the total length of larvae was average 2.750.04 mm , in the juvenile stage was reached after the 25 days from hatching ( average 55.956.74 mm ) ( park et al . , 2008 ) , so that there was difference from o. latipes .
Output:
| in order to monitor the developmental features of embryos , larvae , and juveniles of oryzias latipes ( temminck and schlegel ) , oryzias latipes was caught in river of shinduck - dong , yeosu - si , jeollanam - do , on may 2011 , and experiments were carried out in ichthyology laboratory at chonnam national university .
the blastodisc step was the first level for natural spawning .
the optic vesicle , kupffer 's vesicle , myotome began to appear 75 hours 57 minutes later .
after blastodisc development , the pectoral fins were made at 143 hours 37 minutes and the tail was separated started at the same time .
hatching was observed at 167 hours 27 minutes after blastodisc .
the total length of the hatched larvae was 4.95~5.10 mm ( mean , 5.01 mm ) , the mouth and anus were opened .
larvae used yolk completely after 3 days after hatching .
the total length larvae was 5.45~5.56 mm ( mean , 5.52 mm ) after 8 days after hatching , and appeared the stems for tail . the stems pectoral , anal fin were showed after 14 days and the stems dorsal , ventral fin were appeared after 19 days . for 35 days after hatching , the total length of larvae 13.95~15.30 mm ( mean , 14.64 mm ) , and at this time , fins and body were transferred like the adult oryzias latipes . |
PubmedSumm8802 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: bilateral renal lymphoma frequently presents as an acute kidney injury ( aki ) 3 . with systematic chemotherapy for renal lymphoma
however , in the case we describe herein , the patient 's kidney function greatly recovered after an open renal biopsy and before systematic chemotherapy . here , we review and discuss this unique case .
a 64yearold japanese man was referred to our clinic with gross hematuria , hypertension ( blood pressure 180/75 mmhg ) , and kidney insufficiency ( serum creatinine [ cr ] 2.17 mg / dl ) .
magnetic resonance imaging ( mri ) demonstrated multiple bilateral renal tumor lesions , with a low intensity on t1 and t2weighted images ( fig .
1 ) . the serum soluble interleukin2 receptor was elevated to 870 u / ml ( normal range 145519 u / ml ) .
mri showing kidney enlargement and bilateral renal multiple tumors , with low intensity on t1 and t2weighted images .
2 ) . f2fluoro2deoxyglucose positron emission tomography / computed tomography ) fdgpet / ct showed intense uptake in bilateral kidneys , a paraaortic lymph node , and the right atrial appendage .
we suspected malignant lymphoma and performed an open right kidney biopsy for a histopathologic diagnosis .
the kidney was hard and massively swelled , and the tumor lesions could not be distinguished from the normal renal parenchyma .
we freed the entire kidney from gerota 's fascia and made 1cm incisions in the renal capsule and obtained first and secondcuneiform specimens which were insufficient for diagnosis because of the inadequate number of infiltrating lymphocytes .
the third tissue specimen enabled the diagnosis : nonhodgkin 's lymphoma ( diffuse large bcell lymphoma / barkitt lymphoma ) ( fig .
( a ) renal biopsy showed diffuse interstitial infiltration by lymphocytes ( hematoxylineosin stains [ he ] 100 ) , ( b ) diffuse immunoreactivity of lymphocytes to cd10 , ( c ) no immunoreactivity of lymphocytes to cd3 ( he 200 ) .
after the open renal biopsy , the aki was unexpectedly getting better and the patient was withdrawn from hemodialysis ( fig .
he was treated with doseadjusted systemic chemotherapy ( the rchop protocol : rituximab , cyclophosphamide , doxorubicin , vincristine , and prednisone ) .
the patient was discharged after the 1st cycle of chemotherapy , and the systemic chemotherapy was continued .
renal involvement is common in hematologic malignancies and lymphomas , and it is observed in approximately 34% of patients in advanced stages of these cancers 4 . however , primary renal lymphoma ( prl ) is relatively rare , with only a few welldocumented cases reports in the literature 1 , 2 . the term prl is usually defined as when the disease is limited to the renal parenchyma and has not invaded from an adjacent lymphomatous mass 2 .
therefore , the status of prl as a primary disease or the first manifestation of a rapidly progressive disease is controversial 2 .
proposed the following diagnostic criteria for prl : ( 1 ) renal failure as the initial presentation ; ( 2 ) enlargement of the kidneys without obstruction and without other organ or nodal involvement ; ( 3 ) the diagnosis is made only by renal biopsy ; ( 4 ) absence of other causes of renal failure ; and ( 5 ) the rapid improvement of renal function after radiotherapy or systemic chemotherapy 5 .
our patient 's case matched almost all of these criteria , but he could not be diagnosed as having prl due to the involvement of the lymph node and the right atrial appendage .
there is no difference in its gender distribution , and the patients ' ages at onset have ranged from 2 to 90 years 7 , 8 .
the symptoms of prl are abdominal pain , gross hematuria , fever , and weight loss 7 , 8 .
ultrasonography and ct show kidney enlargement and hypovascular tumors . according to cohan et al .
, four patterns of renal lymphoma can be identified on ct : ( 1 ) the singlemass type ; ( 2 ) the multiplemass type ; ( 3 ) invasion of the contiguous retroperitonealmass type ; and ( 4 ) the perinephricmass type 9 .
mri shows renal tumors with low or isointensity on t1weighted images and low intensity on t2weighted images 10 . in histopathologic sections of renal lymphoma ,
the prognosis of prl is usually poor , with a 1year mortality rate of 75% 11 .
many reported cases show renal insufficiency by lymphomatous infiltration of the kidney 3 , 5 , 6 , 12 . according to tornroth et al .
, 3 acute renal failure or nephroticrange proteinuria was the principal indication for percutaneous kidney biopsy in 48 ( 87% ) of their 55 patients with bilateral renal lymphoma .
they also proposed a mechanism of acute kidney injury in which an interstitial proliferation of lymphoma increases the interstitial pressure without much destruction of renal parenchymal elements 3 .
increased pressure , however , could cause renal insufficiency by tubular obstruction , compression of the peritubular capillaries with increased postglomerular vascular resistance , or modulation of the tubuloglomerular feedback mechanism 3 .
in many reports , renal insufficiency by lymphomatous infiltration recovered rapidly after treatment 3 , 11 , 12 , 13 , 14 . in our patient 's case ,
hemodialysis and multiple incisions of the renal capsule for biopsy may have led to his kidney function recovery ; the treatment also recovered his kidney function as described .
to the best of our knowledge , the recovery of kidney function before systematic chemotherapy for a lymphoma has not been reported . in our patient , the dissection of the renal capsule , by chance , may have decreased in the renal internal pressure
this case supported the theory of renal insufficiency by compression of the peritubular capillaries with increased postglomerular vascular resistance or moderation of the tubuloglomerular feedback mechanism by a lymphomatous infiltration of the kidney . both needle biopsies and open biopsies
are used for the diagnosis of renal lymphoma 1 , 12 . in our patient , since his aki worsened rapidly and the flow cytometry for the current precise diagnosis of lymphoma required a substantial amount of malignant cells , we chose an open biopsy .
in fact , we needed to cut out renal tissue specimens three times to obtain the final diagnosis , since lymphoma cells infiltrated heterogeneously into the renal parenchyma . based on these observations
, we recommended an open biopsy rather than a needle biopsy for the precise and accurate diagnosis if a renal lymphoma is suspected .
this case supported the theory that renal insufficiency by lymphomatous infiltration of kidney is caused by compression of peritubular capillaries with increased postglomerular vascular resistance , or modulation of the tubuloglomerular feedback mechanism .
rapid diagnosis and treatment initiation are essential to preserve renal function and improve the prognosis .
informed consent was obtained from the patient for publishing this case report and accompanying images .
we declare that there is no conflict of interests regarding the publication of this article .
Output:
| key clinical messagerenal lymphoma as an initial lesion is relatively rare .
bilateral renal lymphoma frequently presents as acute kidney injury . with systematic chemotherapy for the lymphoma
, patients usually recover their kidney function .
however , in the case we describe here , the patient 's kidney function recovered greatly after an open renal biopsy . here , we review and discuss this unique case . |
PubmedSumm8803 | ***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:
| lipocortins are structurally related , glucocorticoid - inducible proteins that inhibit phospholipase a2 ( pla2 ) , thereby reducing the liberation of arachidonic acid from phospholipids and so limiting the synthesis of eicosanoid inflammatory mediators .
this study is the first demonstration of one lipocortin , lipocortin 1 ( lc 1 ; 37 kda ) , in human lung lavage supernatants . in lavage fluid from healthy volunteers , a higher percentage ( greater than 70% ) of the detected lc 1 was in its native form , compared to that from patients with abnormal lungs . in patients ' lavage fluids , lc 1 was more likely to be partially degraded ( 34 kda ) . in abnormal bronchoalveolar lavage fluid ( balf ) , the more polymorphonuclear neutrophils ( pmn)/lavage , the lower the proportion of lc 1 in the native ( 37 kda ) form ( n = 7 pairs , rs = -0.8214 , p less than 0.05 ) .
furthermore , when balf cells were cultured and the harvested conditioned media incubated with pure human recombinant lc 1 , degradation of the 37 kda form increased with the percentage of pmn ( n = 10 pairs , s = -0.7200 after 1 hr ; n = 6 pairs , rs = -0.9241 after 6 hr ) .
these results suggest that factors released from the pmn are responsible for lc 1 degradation in man . when recombinant human lc 1 was incubated with human neutrophil elastase , the enzyme degraded lc 1 in a dose - dependent way , suggesting that neutrophil elastase may be one such factor . since pmns are ubiquitous at sites of inflammation , it is possible that lc 1 degradation is a permissive mechanism , which ensures that sufficient inflammation occurs to destroy the provocative stimulus
.
however , it is equally possible that , in some circumstances , the mechanism may be pathological and that the inactivation of lc 1 leads to chronic , uncontrolled inflammation.imagesfigure 3figure 4.figure 4 . |
PubmedSumm8804 | ***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: vertebrate animals affiliate in multiple contexts , but sexual behavior is likely the only context of affiliation that is nearly ubiquitous across vertebrate species .
thus , the various forms of social contact that we observe across species are subject to independent evolution in different taxa , although some forms are conserved across very large clades .
the provision of maternal care to offspring post - hatching or post - parturition is a good example .
this kind of behavior typifies most mammals and most birds , but mammals and birds have evolved extended maternal care independently ( alcock , 2009 ; goodenough et al . , 2010 ) .
studies of many vertebrate taxa demonstrate that the neural mechanisms of sexual behavior are strongly conserved ( goodson , 2005 ; martinez - garcia et al .
, 2008 ) , and limited evidence suggests that mechanisms of parental care are at least grossly similar in mammals and birds , as well ( buntin et al . , 2006 ) .
however , almost no generalizations can be made regarding the mechanisms of evolutionarily labile aspects of social behavior , such as cooperative breeding , mating systems , and grouping .
these variables represent major defining features of species - specific social structures and have therefore garnered an extraordinary amount of attention from evolutionary biologists and behavioral ecologists .
however , evolutionarily labile behaviors pose fairly extreme challenges for comparative neurobiology , largely for reasons of feasibility .
for instance , after two decades of intensive research , the neural mechanisms of selective partner preference ( a hallmark of monogamy ) , paternal care , and alloparental care are reasonably well understood for only a single species , the monogamous prairie vole ( microtus ochrogaster ) , and we know a limited amount about the critical variables that differentiate prairie voles from other non - monogamous vole species ( carter et al . , 2008 ;
donaldson and young , 2008 ; aragona and wang , 2009 ; ross and young , 2009 ; mcgraw and young , 2010 ) .
what we do not yet know is whether neural mechanisms have evolved convergently in other monogamous or alloparental species , although this is a matter of substantial current interest ( fink et al . , 2006 ;
this example points out a fundamental difference in the approaches to social organization that are employed by evolutionary biologists and neuroethologists .
evolutionary biologists can often bring extensive information to bear on a given question , perhaps using data from dozens or hundreds of species , and analyze it in a phylogenetically corrected way that allows the extrapolation of general patterns . to some extent
, neurobiologists can employ similar techniques if they are based on anatomical characteristics or genes ( northcutt , 2008 ; pollen and hofmann , 2008 ) .
nonetheless , we can not make any strong claims about evolutionary patterns of regulation if the experimental approaches of behavioral neuroscience are not employed , and it simply not feasible to replicate experiments in dozens or hundreds of species .
for this reason , neuroethological approaches to questions about evolutionarily labile behaviors will likely continue to be somewhat different from evolutionary biological approaches , even when both are employed by the same investigators
. however , if neuroethologists want to establish predictive validity for other species , comparative experimentation focused on divergent and convergent evolution is essential . in the sections that follow ,
we describe a quasi - experimental approach that we have taken to study convergent and divergent evolution in grouping behavior within the estrildid finch family .
although only five species have been used ( table 1 ) , they have been carefully selected and our findings should therefore have good predictive validity for other estrildid finches . whether our findings can be extrapolated to other vertebrate taxa is a matter of greater speculation , and a topic that we will return to in the section conclusion .
behavioral and ecological characteristics of estrildid finch species that have been used for studies of grouping behavior . for relevant references , see footnote 1 .
the genus uraeginthus contains three species of blue waxbill that are each known by multiple common names .
thus , although u. angolensis is most typically referred to as simply blue waxbill , we have referred to this species as angolan blue waxbill in our publications in order to clearly differentiate them from other species .
this species is commonly encountered in the scientific literature , but under a variety of common names , including spotted munia , nutmeg mannikin , and spice finch .
sociality sensu stricto , as defined by grouping behavior ( alexander , 1974 ) , has broad influences on other important variables such as reproductive behavior , disease transmission , resource exploitation , and defense ( moller and birkhead , 1993 ; krause and ruxton , 2002 ; silk , 2007 ) , but has not previously been examined in neurobiological studies , likely because grouping is difficult to isolate from other aspects of ecology and behavior , such as mating system and patterns of parental care .
for instance , rodent species that differ in their grouping behavior also differ in whether they are monogamous or polygamous , and whether the father contributes to parental care ( king , 1968 ; tamarin , 1985 ) .
however , if we want to examine the neural mechanisms that titrate species - typical group - size preferences , control for such variables is very important , given that shared mechanisms ( particularly neuroendocrine mechanisms ) often regulate numerous aspects of social behavior ( e.g. , pair bonding , parental care , and affiliation ) and related aspects of physiology ( e.g. , hormone levels and stress physiology ; carter et al .
birds offer excellent opportunities to study grouping , since we can identify closely related species that are virtually identical in most aspects of behavior and ecology , but that nonetheless exhibit extreme variation in sociality , ranging from territorial pairs to massive flocks .
the majority of estrildid species ( approximately 141 total ; clements , 2007 ) form small groups of about 612 birds when they are not breeding , and then loosely distribute themselves for nesting without strong territoriality .
defense of a breeding territory has evolved in five to six species across three genera .
colonial breeding has also evolved in several genera , although most colonies are small ( perhaps 510 breeding pairs ) .
available evidence suggests that all estrildids exhibit biparental care and long - term ( typically life - long ) , socially monogamous pair bonds ( immelmann , 1965 ; goodwin , 1982 ) . we have collected five estrildid finch species that exhibit large and seasonally stable differences in grouping , but are otherwise closely matched in behavior and ecology ( table 1 ) .
in addition to being socially monogamous and biparental , as already noted , all of these species live in arid or semi - arid grassland scrub and breed opportunistically or semi - opportunistically in relation to rainfall ( skead , 1975 ; goodwin , 1982 ; zann , 1996 ; goodson et al . , 2006 ) .
these include two territorial african species that live as male female pairs year - round ( violet - eared waxbill , uraeginthus granatina , and melba finch , pytilia melba ) ; two highly gregarious , colonially breeding species that exhibit modal group sizes of approximately 100 ( zebra finch , taeniopygia guttata , and spice finch , lonchura punctulata ) ; and a moderately gregarious species , the angolan blue waxbill ( uraeginthus angolensis ) , which exhibits a modal group size of approximately 20 .
the two territorial species have evolved their territorial behavior independently and the two colonial species have also evolved their extreme sociality independently ( goodson et al . , 2006 ) .
the gregarious angolan blue waxbill is sympatric with both the melba finch and violet - eared waxbill , and our laboratory population of these three species has been established through the breeding of birds that were caught from a single location in the kalahari thornscrub of south africa in 2001 .
we have obtained zebra finches and wild - caught spice finches ( likely of an indian subspecies ) from commercial suppliers .
the inclusion of the zebra finch is an important asset to our research program because domestic zebra finches are both behaviorally robust and readily available , which makes them an ideal species for extensive laboratory studies .
domestic zebra finches are behaviorally indistinguishable from wild - caught zebra finches ( morris , 1958 ) and virtually their full range of social behavior can be observed in the lab .
for instance , we are able to quantify over 20 behaviors while zebra finches are interacting in a colony environment , and can readily track the natural formation of monogamous pair bonds ( goodson et al . , 1999 ;
vertebrates possess a core social behavior network within the basal ( limbic ) forebrain and midbrain ( figure 1 ) that is evolutionarily conserved across all taxa , but is particularly stable across the amniote clades giving rise to birds and mammals , as demonstrated by a wide range of functional and anatomical studies .
this network includes the medial extended amygdala ( including the medial bed nucleus of the stria terminalis , bstm ) , lateral septum ( ls ) , anterior hypothalamus ( ah ) , ventromedial hypothalamus ( vmh ) , midbrain central gray ( cg ; or periaqueductal gray ) , and the ventral tegmental area , although these structures are not strictly social in function and contribute to other core networks for the regulation of behavior and physiology .
all of these areas express high densities of sex steroid receptors , and in contrast to most other areas of the brain that influence social behavior , they are absolutely essential for basic functions such as the expression of sexual , aggressive , and parental behaviors , and also for the regulation of anxiety , social recognition , and approach avoidance processes ( newman , 1999 ; goodson , 2005 ) . an evolutionarily conserved suite of brain regions that regulate vertebrate social behavior .
( a ) the core components of the social behavior network include numerous areas of the basal forebrain the medial extended amygdala ( medial amygdala , mea , or taenial amygdala , tna , plus the medial bed nucleus of the stria terminalis , bstm ) , medial preoptic area ( mpoa ) , anterior hypothalamus ( ah ) , ventromedial hypothalamus ( vmh ) , and lateral septum ( ls ) , as well as areas of the midbrain , most notably the central gray ( cg ; or periaqueductal gray , pag ) and the ventral tegmental area ( vta ) .
( b ) a photomontage of a female zebra finch brain at the level of the anterior commissure ( ac ) .
immunocytochemical triple - labeling for vasoactive intestinal polypeptide ( vip ) , neuropeptide y ( npy ) , and tyrosine hydroxylase ( th ) shows the location of the ah and multiple zones of the ls , bst , and vmh .
. scale bar = 200 m . modified from goodson , 2005 .
other abbreviations : bstl , lateral bed nucleus of the stria terminalis ; hp , hippocampus ; lh , lateral hypothalamus ; lsc , caudal division of the lateral septum ( dorsal , ventrolateral , and ventral zones denoted as lsc.d , lsc.vl , and lsc.v , respectively ) ; lsr , rostral division of the lateral septum ; me , median eminence ; ms , medial septum ; msib , internal band of the medial septum ; ot , optic tract ; om , occipitomesencephalic tract ; pvn , paraventricular nucleus of the hypothalamus ; sh , septohippocampal septum ; v , lateral ventricle .
birds exhibit mammal - like patterns of immediate early gene ( ieg ) induction in this network across a variety of social contexts , including territorial aggression , a context that is strongly relevant to species differences in sociality .
ieg proteins such as fos and egr-1 are rapidly inducible transcription factors that are proxy markers of neuronal activity . following resident
intruder encounters in territorial rodents ( kollack - walker et al . , 1997 ; motta et al . , 2009 ) and
simulated territorial intrusion ( sti ; playback of song and presentation of a caged decoy male ) in male song sparrows , significant activation is observed in forebrain areas such as the bstm , ls , paraventricular nucleus of the hypothalamus ( pvn ) , ah , and the lateral portion of the vmh ( goodson and evans , 2004 ; goodson et al . , 2005b ) , as well as midbrain areas such as the cg ( maney and ball , 2003 ) .
ieg results are extensively comparable in winter and summer sparrows ( goodson and evans , 2004 ; goodson et al .
notably , ieg responses of the ah , pvn , and multiple zones of the ls correlate negatively with aggression ( goodson et al . , 2005b ) , and the case is much the same in hamsters and mice , such that fighting - induced fos expression is higher in subordinate versus dominant animals ( kollack - walker et al . , 1997 ; motta et al . , 2009 ) .
this applies to most aggression - related areas in the brain , and we have obtained very similar results in the territorial violet - eared waxbill ( j. l. goodson , s. e. schrock , and m. a. kingsbury , unpublished observations ) .
neural circuitry that regulates grouping is substantially less well known . as an initial approach to this issue
, we examined the neural responses of territorial and gregarious estrildids to same - sex conspecifics ( goodson et al . , 2005a ) .
subjects were isolated in a quiet room and then exposed to a same - sex conspecific through a wire barrier .
importantly , this manipulation elicits very little overt behavior and thus species differences in neural response should primarily reflect species differences in perceptual or motivational processes . despite the simplicity of this paradigm , fos and egr-1 responses clearly distinguish the territorial from gregarious ( flocking ) species , including differences between the two sympatric uraeginthus species described in the previous section .
overall , territorial birds exhibit significantly greater ieg responses in the medial extended amygdala ( especially the bstm ) , ventrolateral ls , ah , lateral vmh , and cg ( and adjacent intercollicular territory that is now known to be homologous to the dorsal and dorsolateral cg of mammals ; goodson et al .
this pattern is virtually identical to a pattern associated with aversive social stimulation in rodents ( sheehan et al . , 2001 ; providing a good example of deep functional conservation in the social behavior circuits of vertebrate brains ) , but possible mechanisms of gregariousness were not evident at this level of analysis .
this may partially reflect the fact that functionally distinct neurons are intercalated with one another in the various brain areas that influence social behavior ( e.g. , choi et al . ,
for instance , as described in the next section , fos induction within arginine vasotocin ( vt ) neurons of the bstm is strictly associated with affiliation - related stimuli , and following same - sex exposure , the gregarious species show greater fos induction in the vt neurons than do territorial species ( goodson and wang , 2006 ) . however , as just noted , the overall fos response of the bstm is greater in the territorial birds ( goodson et al . , 2005a ) , suggesting that the vt neurons are intermingled with other neurons that exhibit opposing profiles of response .
these hypothetical aversion neurons have not yet been identified , although aromatase - expressing neurons , which are numerous in the bstm and mostly negative for vt ( kabelik et al . ,
2010 ) , are possible candidates . consistent with this idea , recent findings in mice suggest that estrogen signaling within the bstm is important for the regulation of resident intruder aggression ( trainor et al . , 2006 , 2007 ) and inhibits affiliative behavior in male prairie voles ( lei et al . , 2010 ) .
nonapeptides , are among the most interesting modulators of social behavior identified to date .
although many anatomical and functional properties of nonapeptide systems are strongly conserved across all vertebrate taxa ( and in the case of neurosecretory magnocellular neurons , perhaps across all bilaterians ; tessmar - raible et al . , 2007 ) , there is substantial diversity in receptor distributions and nonapeptides have been extensively linked to behavioral variation across individuals , sexes , and species ( goodson and bass , 2001 ; de vries and panzica , 2006 ; donaldson and young , 2008 ; goodson , 2008 ) .
duplication of the vt gene in early jawed vertebrates gave rise to two nonapeptide lineages , which include the mammalian peptides arginine vasopressin ( vp ; homolog of vt ) and oxytocin ( ot ) .
most non - mammalian vertebrates express vt and an ot - like peptide , such as isotocin , found in ray - finned fishes , or mesotocin ( mt ) , which is ubiquitously expressed in non - mammalian tetrapods ( acher , 1972 ; hoyle , 1999 ) .
all jawed vertebrates express their two nonapeptide forms in both magnocellular and parvocellular neurons of the preoptic area and hypothalamus , which in amniotes are located primarily within the supraoptic nucleus of the hypothalamus and the pvn ( moore and lowry , 1998 ; goodson , 2008 ) . in rats ,
the parvocellular neurons of the pvn give rise to widespread projections in the brain ( de vries and buijs , 1983 ) , and this is almost certainly the same in other vertebrates .
lesions of the pvn in rats virtually eliminate vp projections to the caudal brainstem , but not other areas , and eliminate ot projections throughout the brain ( de vries and buijs , 1983 ) .
thus , given the strong similarities of mt and ot systems , it is likely the case that extrahypothalamic mt projections in birds are exclusively or almost exclusively derived from the pvn .
in addition to these hypothalamic cell groups , most tetrapods exhibit a very unique vt / vp cell group of the bstm , which in some mammals extends into medial amygdala proper . with only a few exceptions , these neurons and their projections to the ls and other basal forebrain areas
have been found to be seasonally variable , exquisitely dependent on sex steroids , and sexually dimorphic ( males > females ) . in each of these respects ,
the extrahypothalamic vt / vp circuitry arising in the bstm is among the most extremely plastic systems in the brain . indeed , as demonstrated for many species of mammals , amphibians , birds , and reptiles , this circuitry typically disappears in animals that are in non - reproductive condition or otherwise deprived of sex steroids ( goodson and bass , 2001 ; de vries and panzica , 2006 ) .
however , in estrildids that exhibit opportunistic breeding and have no apparent endogenous reproductive cycles , no such collapse is observed , although basal transcriptional activity [ as measured by constitutive expression of fos protein in vt - immunoreactive ( -ir ) neurons ] is nonetheless regulated by androgens ( kabelik et al . ,
thus , of the finches that we have examined , large seasonal fluctuations in vt immunoreactivity are found only for the spice finch , a species that exhibits photorefractoriness and endogenous rhythms of reproductive physiology that correlate with monsoon cyclicity ( goodwin , 1982 ; chaturvedi and prasad , 1991 ; sikdar et al . , 1992 ;
the vt / vp neurons of the bstm project to numerous other areas of the basal forebrain where vt / vp modulates aggression , parental behavior , social recognition , and various affiliative and anxiety - like behaviors ; and at least in male prairie voles , vp release in the ventral pallidum promotes partner preference ( donaldson and young , 2008 ; veenema and neumann , 2008 ; goodson and thompson , 2010 ; insel , 2010 ) .
although these basal forebrain sites likely receive vt / vp from multiple hypothalamic cell groups in addition to the bstm population , the relative contributions of the different cell groups are difficult to ascertain , given the extensive evidence for paracrine signaling and volumetric release from dendrites and soma ( ludwig and leng , 2006 ; goodson and kabelik , 2009 ) . in order to determine the kinds of stimuli that different vt / vp cell groups respond to ( particularly those of the bstm ) , we have conducted several experiments in which we have exposed animals to social stimuli or control conditions , and then sacrificed the animals 90 min later for immunohistochemical colocalization of vt and fos ( see table 2 for a summary of studies ) .
experimental induction of fos is still robust at 90 min , but the half - life of fos protein is only 45 min ( herdegen and leah , 1998 ) , and thus if cellular activity is depressed by our social manipulations , we can detect this as a reduction in fos expression .
fos colocalization , since mt behavioral functions were unknown at the time , but we are now conducting these analyses with alternate tissue series from the same animals . a summary of main findings from studies of nonapeptide systems in territorial ( t ) , moderately gregarious ( mg ) , and highly gregarious ( hg ) species of estrildid finches . goodson and wang ( 2006 ) , also see goodson et al .
goodson ( 1998 ) , goodson and adkins - regan ( 1999 ) , goodson et al .
goodson et al . ( 2004 ) , kelly et al . ( 2011 ) .
our experiments have demonstrated a remarkable sensitivity of the bstm vt / vp cells to social valence ( figure 2 ) .
relative to handled controls , vt - ir neurons in the territorial estrildid species decrease their fos expression in response to same - sex stimuli ( exposed through a wire barrier as described above ) , but increase fos expression in response to their pairbond partner .
in contrast , in colonial birds that form mixed - sex flocks , vt - ir cells in the bstm increase their activity in response to both same - sex stimuli and competitive courtship interactions , but not following intense subjugation ( goodson and wang , 2006 ) .
no sex differences were observed in any of these results and similar effects were not observed for vt
fos colocalization in the pvn ( j. l. goodson and y. wang , unpublished observations ) .
notably , although the modestly gregarious angolan blue waxbill shows only a small ( and not significant ) increase in vt
fos colocalization following exposure to a same - sex conspecific , the response profile of this species is still significantly different from its territorial congener , the violet - eared waxbill . species differences in vt signaling may be further magnified based on vt - ir cell numbers , which are approximately 10 times more abundant in the colonial species relative to other species ( goodson and wang , 2006 ) .
finally , adding onto the remarkable response profile of this cell group , recent experiments in male zebra finches demonstrate that the bstm vt neurons increase their fos expression selectively in response to a positive social stimulus , but show no response to a positive non - social stimulus ( goodson et al .
valence sensitivity of vasotocin ( vt ) neurons in the medial bed nucleus of the stria terminalis ( bstm ) , as demonstrated by socially induced changes in the immunocytochemical colocalization of vt and the proxy activity marker fos .
( a ) representative colocalization of vt ( green ) and fos ( red ) in the bstm of a male zebra finch following a courtship interaction .
scale bar = 20 m . ( b ) in the zebra finch , which is a highly gregarious species , isolation in a quiet room followed by exposure to a same - sex conspecific through a wire barrier produces a robust increase in vt neuronal activity in both males and females .
fos colocalization in the territorial violet - eared waxbill , a species that does not naturally exhibit same - sex affiliation , but exposure to the subject 's pairbond partner ( a presumably positive stimulus ) , produces a robust increase in neuronal activity .
( d ) vt fos colocalization increases in zebra finches following competition with a same - sex individual for courtship access to an opposite - sex bird , but not if the subject is paired with a highly aggressive partner and intensely subjugated .
subjugated animals were aggressively displaced or attacked 71210 times during a 10-min interaction , demonstrating that social arousal alone does not increase vt
( 2009b ) ; ( b d ) are modified from goodson and wang ( 2006 ) .
our results in birds are consistent with other recent findings in mice , and may therefore represent a common feature of bstm vt / vp neurons across all tetrapods . in male c57bl/6j mice ,
bstm vp neurons exhibit robust fos responses to copulation ( which is clearly a positive , affiliation - related stimulus ) and very modest responses to non - aggressive same - sex chemoinvestigation , but show no greater fos response to aggressive interactions than simple chemoinvestigation ( ho et al . , 2010 ) .
notably , the sensitivity of amygdala neurons to valence has been extensively characterized through neurophysiological and neuroimaging studies in mammals ( nishijo et al . , 1988 ;
also see goodson and thompson , 2010 ) , but specific cell types that process valence have not previously been identified .
neurophysiological studies in monkeys demonstrate that neurons which exhibit stable preferences for positive or negative stimuli are intercalated ( paton et al . , 2006 ) , and thus the neurochemical identification of valence - sensitive populations represents an important step toward understanding how social value is encoded and used by the brain to regulate behavior .
species differences in the response profiles of various brain areas and specific cell group are likely coordinated , at least to an extent , by the differential expression of receptors for neuromodulators .
in fact , using the five finch species already introduced , we have obtained good evidence that the distributions of binding sites for vasoactive intestinal polypeptide ( vip ) , vt , and mt all exhibit convergent and divergent evolution in relation to sociality ( based on quantitative autoradiography using i vip and iodinated antagonists of ot and v1a receptors ; goodson et al . , 2006 , 2009c )
. remarkably , binding sites for all three peptides exhibit sociality - related evolution within the ls , indicating that the ls plays a special role in grouping . in order to be interpreted as sociality - related ,
we require that binding densities differ significantly between the two territorial and three flocking species ( defined as contrast a ) and differ significantly between the two territorial and two colonial species ( contrast b ) , with the modestly gregarious species being intermediate or falling in line with the two colonial species .
the most convincing comparisons are those that meet these criteria , with additional significant differences between the territorial and gregarious uraeginthus species , which are sympatric ( contrast c ) .
figure 3 shows one such pattern for the density of v1a - like receptor density in the dorsal ls , and similar abc species differences are observed in several other ls zones for both v1a - like , ot - like and vip binding sites ( goodson et al . , 2006 , 2009c ) .
binding densities are mostly biased toward the gregarious species , although sociality - related differences in ot - like binding densities reverse along a dorso - ventral gradient , and the relative density between the pallial and subpallial ls provides the clearest differentiation of territorial and flocking species ( goodson et al . ,
2009c ; figure 4 ) , suggesting that sociality is reflected in a complex neuromodulatory balance across the ls subnuclei .
outside of the ls , sociality - related differences in the finches are observed for vip binding in the bstm , which are biased toward the gregarious species ( goodson et al . , 2006 ) .
v1a antagonist binding in the lateral septum ( ls ) reflect evolutionary convergence and divergence in flocking and territoriality .
( a e ) representative i v1a antagonist binding in the ls of the territorial melba finch [ mf ; ( a ) ] , territorial violet - eared waxbill [ vew ; ( b ) ] , moderately gregarious angolan blue waxbill [ abw ; ( c ) ] , colonial spice finch [ sf ; ( d ) ] , and colonial zebra finch [ zf ; ( e ) ] .
the scale bar in ( e ) corresponds to 500 m in ( a e ) .
( f , g ) representative sections for a male angolan blue waxbill and male spice finch ( colonial ) , respectively , showing species differences in binding for the nidopallium ( n ) and other areas of the forebrain .
the scale bar in ( g ) corresponds to 1 mm in ( f , g ) .
v1a antagonist binding in the dorsal ( pallial ) portion of the ls , shown as decompositions per min / mg ( dpm / mg ; means sem ) .
different letters above the error bars denote significant species differences ( fisher 's plsd following significant anova ; p < 0.0001 ) .
abbreviations : e , entopallium ; ha , apical part of the hyperpallium ; lsc , caudal division of the lateral septum ( dorsal , ventrolateral , and ventral zones denoted as lsc.d , lsc.vl , and lsc.v , respectively ) ; lsr , rostral division of the lateral septum ; lst , lateral striatum ; ms , medial septum ; n , nidopallium ; sh , septohippocampal septum ; teo , optic tectum .
species - specific distributions of oxytocin - like binding sites reflect evolutionary convergence and divergence in flocking and territoriality .
( a c ) representative autoradiograms of i ot antagonist binding sites in the caudal ls ( lsc ) in two sympatric , congeneric finches the territorial violet - eared waxbill ( a ) and the gregarious angolan blue waxbill ( b ) , plus the highly gregarious zebra finch ( c ) .
( d ) densities of binding sites in the dorsal ( pallial ) lsc of two territorial species ( melba finch , mf , and violet - eared waxbill , vew ) , a moderately gregarious species ( angolan blue waxbill , abw ) , and two highly gregarious species ( spice finch , sf , and zebra finch , zf ) .
different letters above the boxes denote significant species differences ( mann whitney p <
( e ) binding densities tend to reverse in the subpallial lsc ( p = 0.06 ) , suggesting that species differences in sociality are most closely associated with the relative densities of binding sites along a dorso - ventral gradient , as confirmed in the bottom ( f ) using a dorsal : ventral ratio .
abbreviations : hp , hippocampus ; lsc.d , dorsal zone of the lsc ; lsc.v , vl , ventral , and ventrolateral zones of the lsc ; n , nidopallium ; plh , posterolateral hypothalamus ; teo , optic tectum .
densities of nonapeptide receptors in the ls are also highly variable in mammals , although the relevance of these species differences to behavior has largely been a matter of speculation ( insel et al .
however , recent findings suggest that ot receptor densities may reflect species differences in the provision of alloparental care by juvenile females , and alloparental care in female prairie voles is negatively correlated with ot receptor densities in the ls ( olazbal and young , 2006 ) . in male prairie voles , social investigation behavior is positively correlated with v1a receptor densities and negatively with ot receptor densities in the ls ( ophir et al . ,
the relevance of nonapeptide receptors to grouping behavior has been directly confirmed by a series of recent experiments using central antagonist and antisense manipulations in zebra finches . based on the well known effects of ot and ot receptors on affiliation in mammals ( carter et al . , 2008 ; goodson and thompson , 2010 ) , we began by blocking ot - like receptors ( as in mammals , a single ot - like receptor has been identified in birds , vt3 ; baeyens and cornett , 2006 ) . using the choice apparatus shown in figure 5a , in which subjects can choose between groups of 10 or 2 same - sex conspecifics ( or not spend time near either )
, we first showed that subcutaneous and lateral ventricle infusions of an ot antagonist reduce preferences for the larger group ( figures 5b e ) without influencing the amount of time that subjects spent in close proximity to other birds ( hereafter contact time ) .
the peripheral effect was female - specific and ventricular infusions of mt produced a female - specific increase in the amount of time that subjects spent with large group , again with no effect on contact time .
infusions of the ot antagonist directly into the ls replicated the peripheral and ventricular antagonist effects in females , whereas control infusions into the medial striatum ( adjacent to the ventricle ) did not ( goodson et al .
a 1-m wide testing cage was subdivided into zones by seven perches ( thin lines ) .
subjects were considered to be within close proximity when they were within 6 cm of a stimulus cage ( i.e. , on the perches closest to the sides of the testing cage ) .
( b e ) relative to vehicle treatments , subcutaneous ( s.c . ) or intracerebroventricular ( i.c.v . )
nh2 , d(ch2)5[tyr(me ) , thr]ovt ( ota ; 250 ng ) , reduce the amount of time that zebra finches spend in close proximity to the large group ( b , c ) and increase time in close proximity to the small group ( d , e ) . *
p < 0.05 , * * * p < 0.001 , main effect of treatment ; # p < 0.5 sex*treatment ; n = 12 m , 12 f. letters above the error bars denote significant within - sex effects . modified from goodson et al .
as described in the previous sections , gregarious species show a relatively greater social induction of fos within vt neurons , more vt - ir neurons in the bstm , and a higher density of vt v1a - like receptors in the ls than do territorial species ( goodson and wang , 2006 ; goodson et al . , 2006 ) , suggesting the hypothesis that vt projections from the bstm to the ls promote sociality .
indeed , recent experiments in male zebra finches demonstrate that knockdown of vt production in the bstm by antisense oligonucleotides potently reduces gregariousness relative to subjects infused with scrambled oligonucleotides , with a median reduction of 80% .
gregariousness in this experiment was defined as the percent of contact time that was spent next to a group of 10 conspecifics versus a group of 2 ( kelly et al . , 2011 ) .
surprisingly , this same manipulation increased contact time modestly relative to scrambled oligonucleotide controls ( median difference of 25% ) , although intraseptal infusions of a v1a antagonist produce no effects on contact time ( and convincingly so ) .
as with the vt antisense , intraseptal v1a antagonist infusions virtually eliminated subjects preferences for the large group while concomitantly increasing the amount of time that subjects spent with the small group .
we have further replicated this effect in both males and females using a novel v1a antagonist that crosses the blood brain barrier ( jnj-17308616 ; j. l. goodson and s. e. schrock , unpublished observations ) . in conjunction with both the antisense and central antagonist studies , we also conducted tests of anxiety - like behavior ( novelty - suppressed feeding and exploration of a novel environment ) , which produced particularly intriguing results : whereas septal vp is usually found to be anxiogenic in rodents , it appears to be strongly anxiolytic in zebra finches ( kelly et al . , 2011 )
whether this difference is the result of unique receptor distributions and/or is an important factor in the social evolution of zebra finches remains to be determined .
however , it is interesting in this light to note that septal vp may promote active stress coping in rats ( ebner et al . , 1999 ) , which are more social than laboratory mice and hamsters .
using five finch species that are all socially monogamous and biparental , we have shown that ( 1 ) receptor distributions for multiple neuropeptide systems ( vt / mt , vip , and crf ) exhibit divergent and convergent evolution in relation to species - typical group size , particularly within the ls , ( 2 ) vt cells in the bstm exhibit an exquisite sensitivity to the valence of social stimuli , thereby creating differences between gregarious and territorial species in the response of their bstm vt neurons to same - sex conspecifics , ( 3 ) endogenous nonapeptide signaling via v1a- and ot - like receptors in the ls promotes preferences for larger groups in zebra finches without effects on social contact time , and ( 4 ) in male zebra finches , antisense knockdown of vt production in the bstm profoundly reduces gregariousness . although not discussed above , we have also found that the three flocking finch species exhibit relatively more dopamine neurons than do territorial species in a caudal subpopulation of cells in the ventral tegmental area that has also been implicated in appetitive courtship behavior ( goodson et al . , 2009a ) .
all of the neurochemical systems just mentioned influence myriad behavioral and physiological functions , thus we might expect that those systems may not evolve in relation to grouping , and in an estrildid - like manner , if other species - specific behavioral and physiological functions constrain the evolutionary process .
this may occur if a given neural mechanism is under strong selection in relation to something other than grouping . at the same time , nonapeptides influence basic social behaviors across a wide range of vertebrates , suggesting that they may be common or even ubiquitous targets of selection during social evolution .
the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
Output:
| species - typical patterns of grouping have profound impacts on many aspects of physiology and behavior . however , prior to our recent studies in estrildid finches , neural mechanisms that titrate species - typical group - size preferences , independent of other aspects of social organization ( e.g. , mating system and parental care ) , have been wholly unexplored , likely because species - typical group size is typically confounded with other aspects of behavior and biology .
an additional complication is that components of social organization are evolutionarily labile and prone to repeated divergence and convergence .
hence , we can not assume that convergence in social structure has been produced by convergent modifications to the same neural characters , and thus any comparative approach to grouping must include not only species that differ in their species - typical group sizes , but also species that exhibit convergent evolution in this aspect of social organization . using five estrildid finch species that differ selectively in grouping ( all biparental and monogamous )
we have demonstrated that neural motivational systems evolve in predictable ways in relation to species - typical group sizes , including convergence in two highly gregarious species and convergence in two relatively asocial , territorial species .
these systems include nonapeptide ( vasotocin and mesotocin ) circuits that encode the valence of social stimuli ( positive negative ) , titrate group - size preferences , and modulate anxiety - like behaviors .
nonapeptide systems exhibit functional and anatomical properties that are biased toward gregarious species , and experimental reductions of nonapeptide signaling by receptor antagonism and antisense oligonucleotides significantly decrease preferred group sizes in the gregarious zebra finch . combined , these findings suggest that selection on species - typical group size may reliably target the same neural motivation systems when a given social structure evolves independently . |
PubmedSumm8805 | ***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 identification is one of the most challenging tasks one has been confronted with whenever a catastrophe strikes .
identification of the victims of the disaster is mandatory from a judicial point of view for settlement of wills , insurance payments and disposal of deceased estate as well as from a humanitarian point of view for the relatives to claim the body for last rites according to their religious beliefs . in order to establish a positive identification ,
procedures such as dna fingerprinting , dental analysis , identification using scars , tattoos , recognition using clothes and belongings , autopsy findings , analysis of skeletal remains can all be used to identify an individual .
forensic odontology has played a pivotal role in identification of persons in various scenarios like in mass disasters , crime investigations , ethnic studies as well as in cases of decomposed , and disfigured remains in traffic accidents , fires , and bomb blasts .
the reason why dentition is used so often in identification is because dental tissue is amongst the hardest structures in the human body which is resistant to a number of adverse conditions such as incineration , immersion , trauma , mutilation , and putrefaction .
due to its durability and ability to withstand very high temperatures without appreciable loss of microstructure , it can survive long after the soft and skeletal tissues have been destroyed .
furthermore , because of their impervious nature , they serve as an excellent source of dna , which can ascertain the identification in catastrophic conditions .
calcification and eruption are the two developmental factors that are considered while estimating the age from dentition , while a combination of odontometric dimensions can be used for estimation of sex accurately . apart from its application in anthropological studies
, tooth can be a valuable source of toxicological information , for it is an imperative site of deposit of exogenous substances , which may be accumulated in the pulp or calcified tissues . with an overview of the diverse applications of teeth in forensic medicine , the present report discusses the importance of enamel hypoplasia in identification .
enamel hypoplasia appears as scars on the teeth and can provide valuable information in identification of the deceased . however , description of this entity is limited in forensic literature .
the present article reviews the literature on the enamel hypoplasia and discusses its utility in the identification of individuals in forensic examinations .
their life cycle is divided into six stages that include morphogenetic , organizing , formative , maturative , protective , and desmolytic .
amelogenesis that refers to the formation of enamel occurs during the formative and maturative stages of the ameloblasts .
enamel matrix is secreted in the formative stage where as mineralization of the enamel matrix occurs in the maturation stage .
enamel hypoplasia occurs if matrix formation is affected and may manifest as pitting , grooving or even total absence of enamel .
hypomineralization results when maturation is disturbed and is manifested in the form of opaque or chalky areas on normally contoured enamel surfaces .
thus , disturbance either in matrix formation or in calcification can occur depending chiefly on the stage of tooth formation at the time of injury .
development defects of enamel ( dde ) comprise of mainly dental defects such as hypoplasia and diffuse and demarcated opacities ; fluorosis and amelogenesis imperfecta .
enamel hypoplasia , thus , is a surface defect of the tooth crown that is caused by a disturbance of enamel matrix secretion , defective calcification or defective maturation .
enamel hypoplasia or hypo mineralization may be caused by hereditary factors and environmental factors that include systemic factors such as nutritional factors , exanthematous diseases like measles and chicken pox , congenital syphilis , hypocalcemia , birth injury or premature birth , fluoride ingestion or idiopathic causes , and local factors such as infection or trauma from a deciduous tooth .
it is transmitted in the family as a mendelian dominant trait which affects enamel of all the teeth , deciduous as well as permanent .
environmental enamel hypoplasia / hypo mineralization of systemic or local origin is also termed as chronologic hypoplasia .
this lesion is found in areas of those teeth where the enamel was being formed during the systemic or local disturbance . since the formation of enamel extends over a long period and the systemic or local disturbance , in most cases are of short duration , the defect is limited to a circumscribed area of the affected teeth or tooth . thus knowing the chronologic development of deciduous and permanent teeth will make it possible to determine from the location of the defect , the approximate time at which the injury occurred .
the basic pathology in dde is the result of abrupt , short - term or long - term ameloblastic insults during the secretory or maturation phase of the development of tooth ; any systemic illness , disturbance , deficiency or prematurity of neonate or local trauma can lead to dde .
enamel hypoplasia can also be seen in other pediatric conditions in which hypocalcemia is a major sign as in rickets , prematurity and neonatal tetany .
furthermore , disturbances in the development of the enamel of permanent teeth can result from trauma to the primary teeth because of the close proximity of the root of the primary teeth to their permanent successors .
enamel hypoplasia may be inherited or may result from an illness , malnutrition , trauma or due to fluorosis . although it can occur in any permanent tooth , the most commonly involved sites of hypoplasia are the permanent first molars and incisors with specific areas of defect and well - demarcated areas of hypomineralization .
the secretory phase for development of the permanent incisors and first molars begins in utero whereas the maturation process begins at birth and thus any trauma of inadequate mineralization can result in dde .
( mih ) , is a more specific form of dde characterized by hypomineralization due to systemic illness , which can be seen as translucency in the enamel .
environmental enamel hypoplasia / hypomineralization due to systemic factors are commonly manifested in the first permanent molars and incisors .
clinical studies indicate that enamel hypoplasia involve those teeth that form within the 1 year of birth .
when presented clinically these hypomineralized defects frequently break down because of the masticatory pressure and are seen as mixed areas of hypoplasias and hypomineralizations .
premolars and 2 , 3 molars are seldom affected , since their formation does not begin until age of 3 years or later .
environmental enamel hypoplasia / hypomineralization due to local factors is also called as turners hypoplasia / hypomineralization seen most commonly in permanent maxillary incisors or upper lower premolars .
turner 's hypoplasia usually manifests as a portion of missing or diminished enamel , which affects one or more than one permanent tooth in the oral cavity .
any degree of defects ranging from mild brownish discoloration of enamel ( hypomineralization ) to severe pitting and irregularity of tooth crown ( hypoplasia ) depending on severity of infection [ figure 1 ] .
similarly , when a deciduous tooth has been driven into the alveolus and has disturbed the permanent bud , it can manifest as a yellowish or brownish stain or pigmentation of the enamel usually on the labial surface or a true hypoplastic pitting defect or deformity .
radiograph showing turner 's hypoplasia of upper first premolar different types of enamel hypoplasia have been identified such as pit type , plane type , and linear enamel type . in mih
, there is a definite correlation between the color , histology , porosity and mineral content .
yellow - brown defects are deeper , extending from the dento - enamel junction to the enamel surface , whereas white creamy defects are usually less porous and vary in depth and are typically limited to the inner enamel .
biochemically , it is found that , hypomineralized enamel had a higher content of carbon and lower levels of calcium and phosphorous as compared to the normal enamel .
forensic odontology has been playing a significant role in the identification of unknown , dismembered and commingled human remains .
dental restorations , diseased conditions , disorders , prostheses and radiological examinations of the teeth may help in identification of the victims of mass disasters .
the reports suggest that various kinds of dental characteristics helped in identification process in the recently experienced disasters . according to a communication ,
about 80% of the non - thai victims were identified by dental characteristics in phuket , thailand when a powerful tsunami hit south - east asia in december 2004 .
all the dental characteristics including the information pertaining to the conditions of the teeth are entered in a standardized dental disaster victim identification ( dvi ) protocol(dvi form of the interpol ) and then matched with the available antemortem data .
the process of comparison involves certain important features of the teeth which are individualistic to a person , and include dental fillings , dental enamel hypoplasia , extractions , missing teeth , extra teeth , rotations , supernumerary cusps , features of the occlusal aspect of the teeth , various other dental anomalies and special characteristics as the taurodontism and carabelli cusps , etc .
enamel defects have been widely used by anthropologists for the investigation of growth disruptions in the past populations as they provide a permanent record for disturbances during much of a child 's developmental period . to the best of our knowledge ,
there is no reported case of enamel hypoplasia being used for identification in forensic investigation . the fact that these defects are a reflection of the events in utero as well as after birth means that their unique profile can help in identification of victims of mass disasters as well as the bodies of those which are completely charred , putrefied and mutilated and
it is suggested that dental practitioners make a note of these defects in their routine practice so that the information is available for matching dental records during forensic investigations .
Output:
| identification of individuals is the mainstay of any forensic investigation especially in cases of mass disasters when mutilated remains are brought for examination
. dental examination helps in establishing the identity of an individual and thus , has played a vital role in forensic investigation process since long . in this
regard , description on the role of enamel hypoplasia is limited in the literature .
the present article reviews the literature on the enamel hypoplasia and discusses its utility in forensic identification .
enamel hypoplasia is a surface defect of the tooth crown caused by disturbance of enamel matrix secretion .
enamel defects can be congenital or acquired . in cases of mass disasters , or when the body is completely charred , putrefied and mutilated beyond recognition , the unique dental features can help in identification of the victims . |
PubmedSumm8806 | ***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: brucellosis is a worldwide bacterial zoonosis posing hazards to the public health and causing economic losses for livestock production industry [ 13 ] .
animal brucellosis is mainly characterized by reproductive involvement resulting in abortion and infertility , whereas human brucellosis is a febrile illness known as undulant fever which can lead to chronic debilitating complications [ 3 , 4 ] .
the disease results from facultative intracellular bacteria belonging to the genus brucella which are gram - negative , nonspore - forming and noncapsulated coccobacilli [ 3 , 5 , 6 ] . currently , the genus consists of 10 species classified based on their host preferences and phenotypic differences [ 2 , 7 ] .
three species are also divided into biovars which are b. abortus , b. melitensis , and b. suis with 7 , 3 , and 5 biovars , respectively . in sheep and goats
, brucellosis is primarily due to b. melitensis which is the most pathogenic species for human beings , responsible for the main proportion of human cases in endemic regions including mediterranean and middle east countries [ 1 , 3 , 810 ] .
humans catch the disease via direct contact with infected animals , their vaginal discharges , and aborted fetuses ; dealing with pure cultures ; and consumption of unpasteurized contaminated milk and milk products [ 3 , 6 , 11 ] .
the latter is the major way through which b. melitensis is transmitted to people in endemic areas [ 1 , 5 ] .
identification of b. melitensis biovars involved in small ruminant brucellosis is a critical component of epidemiological surveys required for designing proper preventive and control strategies . in iran , due to the existence of other related factors including illegal livestock import from neighboring countries where b. melitensis is also prevalent and uncontrolled animal movements ,
it was considered necessary to study changes in the epidemiologic distribution of different biovars in order to determine introduction of new biovars and evaluate the success of ongoing control measures .
therefore , the present study was performed to renew our knowledge about the current prevalence status of b. melitensis biovars causing abortion in sheep and goats in iran .
the present cross - sectional study was carried out from 2007 to 2009 . according to iranian veterinary organization classification
, all country provinces were divided into 3 categories with low ( < 2% ) , intermediate ( 2 - 3% ) , and high ( > 3% ) brucellosis prevalence .
this classification is based on a seroepidemiological survey carried out in 2003 using conventional rose bengal , serum agglutination , and 2-mercaptoethanol tests .
two provinces were then selected from each category based on geography and availability of a central laboratory in the provincial veterinary general office with skilled personnel for bacterial isolation .
the selected provinces were kerman and markazi ; ilam and khorasan razavi ; chehar - mahal bakhtiari and mazandaran from low , intermediate , and high prevalence categories , respectively .
all small ruminant aborted fetuses referred to the central laboratory of the provincial veterinary general office during the study period were cultured for brucella isolation .
brucella isolates were sent to brucellosis department of razi vaccine and serum research institute to be identified at species and biovar levels .
specimens obtained from liver , lungs , spleen , and fetal stomach content of referred aborted fetuses were cultured on brucella agar ( bd , usa ) containing 5% ( v / v ) inactivated horse serum , 2% ( w / v ) dextrose , and brucella selective supplement ( oxoid , uk ) according to the manufacturer 's instruction .
tissue specimens were first decontaminated using ethanol and flame and then homogenized in sterile normal saline by means of a grinder . for each specimen ,
two sets of 3 agar plates were inoculated and incubated at 37c with one set in the air having 10% co2 .
inoculated plates were monitored every 2 days to detect any colonial growth , and in the case of no colony observation , they were kept at most for 35 days .
suspected colonies based on their morphological characteristics were subcultured on brucella agar slopes for further evaluation and biovar identification .
brucella isolates , confirmed by microscopic characterization using gram stain and results of catalase , oxidase , and urease tests , were examined for biotyping according to the standard methods described by alton et al . .
briefly , biovars were identified based on agglutination with a and m monospecific antisera , co2 requirement for growth , h2s production , lysis by tbilisi ( tb ) and berkeley ( bk2 ) phages , and growth on media containing 20 g / ml basic fuchsin and thionin dyes [ 1215 ] .
in the present survey , a total number of 851 aborted sheep and goat fetuses were cultured microbiologically and 265 brucellae were isolated .
biotyping of these 265 isolates showed that 246 ( 92.8% ) were b. melitensis biovar 1 .
eighteen isolates ( 6.8% ) were identified as b. melitensis biovar 2 ; and interestingly , one isolate ( 0.4% ) , which was obtained from mazandaran province , was determined as b. abortus biovar 3 .
table 1 illustrates numbers of brucella isolates attained in different provinces and results of their biotyping .
b. melitensis biovar 3 was isolated in none of the six provinces during the study period , and b. melitensis biovar 2 was only isolated in two provinces which are khorasan razavi and kerman belonging to intermediate and low prevalence categories , respectively .
small ruminant brucellosis is still a major animal and public health burden in many parts of the world particularly in the middle east and mediterranean region [ 1 , 6 , 8 , 10 ] .
sheep and goats are primarily infected by b. melitensis as its preferential hosts [ 8 , 18 ] .
regarding the public health , b. melitensis is the most important zoonotic pathogen amongst the brucella spp .
[ 1 , 3 , 5 ] , accounting for the vast majority of human cases all around the world .
in endemic areas , it is transmitted to people mostly through consumption of unpasteurized milk and milk products from sheep and goats [ 3 , 5 , 19 ] .
b. melitensis is divided into three biovars which are differentiated using conventional laboratory methods such as agglutination with a and m monospecific antisera and lysis by brucella phages [ 12 , 13 ] .
determination of biovars involved in animal brucellosis is an important step for epidemiologic characterization of the disease in any country and a preliminary requirement for designing control and eradication programs .
additionally , owing to the ability of brucellae to adapt to new environments and its re - emergence [ 3 , 5 , 6 ] , revealing changes in epidemiologic features of brucella species / biovars can help to unravel complexity of interactions between the organism , animals , and humans . in iran , the first b. melitensis isolation from an aborted sheep fetus was reported in 1950 [ 16 , 17 ] .
thereafter it has been widely isolated in different parts of the country mainly from sheep and goats but also occasionally from cattle , camel , and sheepdogs [ 17 , 20 ] .
all biovars of b. melitensis exist in iran among which biovar 1 is known as the most widespread .
table 2 summarizes biotyping results of iranian b. melitensis isolates during two periods of time from 1971 to 2000 .
immunization of host species with b. melitensis strain rev.1 has been the main strategy for the control of small ruminant brucellosis in iran since 1960s . during 19832003 ,
a test - and - slaughter campaign was also conducted in adult sheep and goats using rose bengal , serum agglutination , and 2-mercaptoethanol tests , while vaccination was limited to young animals . from 2003 ,
control program has been based on mass vaccination using full doses ( containing 13 10 bacteria per dose ) of rev.1 vaccine in lambs and kids at 47 months of age , and its reduced doses ( containing 0.52 10 bacteria per dose ) in adult female animals .
in addition to the mass vaccination , other measures including public education , promotion of sanitary husbandry practices , and microbiological evaluation of abortion outbreaks have been implemented . as a result ,
the number of new human cases reported annually dropped from 39 in 2005 - 2006 to 15.9 in 2010 - 2011 per one hundred thousand people in the country ( unpublished data ) .
our survey showed that b. melitensis biovar 1 is the most frequent cause of clinical brucellosis in small ruminant populations of the provinces included .
this finding is in agreement with the results of the previous studies in the country [ 16 , 17 ] .
isolation of b. abortus biovar 3 , which is an enzootic etiologic agent of bovine brucellosis [ 17 , 21 , 22 ] , from an aborted sheep fetus in our study suggests the possibility of cross - species transmission of the pathogen from cattle .
b. abortus has been sporadically identified and reported as a causative agent for sheep brucellosis in iran [ 17 , 21 ] .
are present , and cattle and small ruminants are raised in close contact , transmission to nonpreferred hosts may occur [ 17 , 21 , 23 ] .
this should be taken into account while implementing control measures . whereas the estimation of disease prevalence was not the aim of this study
, the results showed that in spite of implementing vaccination and other control measures for years , small ruminant brucellosis in clinical form still persists in various parts of the country .
nevertheless , there is a need for country - wide investigations covering the whole target population including traditionally and nomadically reared flocks to ascertain geographical distribution of different biovars region by region .
it will also help trace potential outbreaks , especially in provinces neighboring western and eastern borders .
for this purpose , using geographic information system ( gis ) will be helpful in analyzing interactions between animal and human brucellosis .
the present study revealed that b. melitensis biovar 1 remains the most prevalent cause of clinical form of small ruminant brucellosis in various provinces of iran .
however , more studies are required to determine current status of the disease throughout the country and the evaluation of its impact on human health .
further control and prevention measures can be implemented to curtail the human and animal disease incidence to a greater extent .
Output:
| to determine the most prevalent biovar responsible for brucellosis in sheep and goat populations of iran , a cross - sectional study was carried out over 2 years in six provinces selected based on geography and disease prevalence .
specimens obtained from referred aborted sheep and goat fetuses were cultured on brucella selective media for microbiological isolation .
brucellae were isolated from 265 fetuses and examined for biovar identification using standard microbiological methods .
results showed that 246 isolates ( 92.8% ) were b. melitensis biovar 1 , 18 isolates ( 6.8% ) were b. melitensis biovar 2 , and , interestingly , one isolate ( 0.4% ) obtained from mazandaran province was b. abortus biovar 3 . in this study ,
b. melitensis biovar 3 was isolated in none of the selected provinces , and all isolates from 3 provinces ( i.e. , chehar - mahal bakhtiari , markazi , and ilam ) were identified only as b. melitensis biovar 1 . in conclusion , we found that b. melitensis biovar 1 remains the most prevalent cause of small ruminant brucellosis in various provinces of iran . |
PubmedSumm8807 | ***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 44-year - old woman developed intermittent exercise - induced headaches with chest tightness over a period of 10 months .
cardiac catheterization followed by acetylcholine provocation demonstrated a right coronary artery spasm with chest tightness , headache , and ischemic effect of continuous electrocardiography changes .
a coronary angiogram with provocation study revealed variant angina and cardiac cephalalgia , as per the international classification of headache disorders ( code 10.6 ) .
we report herein a patient with cardiac cephalalgia that manifested as reversible coronary vasospasm following an acetylcholine provocation test .
headache as a symptom of myocardial ischemia has been reported previously.1,2 the convergence of cardiac nerve fibers on central pathways receiving somatic afferents from the head is likely to be responsible for the perception of cardiac ischemic pain as headache.1 several reports have implicated headache , both with3 - 5 and without4,6 chest pain , as a clinical manifestation of coronary ischemia . in all previous reports , effect of continuous electrocardiography ( ecg)-based testing was abnormal .
the neuroanatomical substrates of headache induction by coronary ischemia are not well understood , although mechanisms involving increased intracranial pressure4 and convergence or overflow of somatic inputs from lower cervical levels into second - order neurons within the caudal trigeminal nucleus have been proposed.6
a 44-year - old woman was admitted with exertional headache that had developed over the previous 10 months .
her headache was located on the bifrontal area and was associated with substernal chest tightness after the onset of 5 - 10 minutes of exercise .
her headache gradually resolved over a period of minutes to an hour after the cessation of exercise and was not associated with aura , nausea , vomiting , photophobia , phonophobia , palpitation , or diaphoresis .
also , the headache was not provoked by cough , sneeze , or straining during bowel movement .
the patient had suffered a severe headache 4 days before her admission to hospital that was biparietally and bioccipitally located , bursting in onset , and which was improved by laying down and resting . on a few occasions ,
her history was negative for hypertension , diabetes , and heart disease , and she did not smoke . neurological examination , routine laboratory tests , transcranial doppler , brain imaging studies ( brain ct , mri , and magnetic resonance angiogram ) , ecg , eeg , and spinal tapping with cerebrospinal fluid studies produced normal results .
the findings of a 24-hour holter monitoring study were occasional periventricular complexes and one episode of nonsustained supraventricular tachycardia . during treadmill exercise stress testing , the patient simultaneously suffered severe headache with chest tightness and st - segment depression on ecg .
termination of the exercise - stress test was followed by resolution of her headache , chest pain , and ecg change .
a coronary angiogram was performed the next day , revealing coronary artery spasm following an acetylcholine provocation study during which chest tightness , headache , and ischemic ecg changes appeared ( fig .
the symptoms completely disappeared after the patient was administered nitroglycerine by intra - arterial injection . because of the reversible coronary changes on coronary angiogram ( the headache and chest tightness disappeared after intra - arterial nitroglycerine injection ) , the patient was diagnosed as having variant angina .
after 5 days of nitrate and calcium - channel - blocker medication , the patient was discharged without headache or adverse medication effect .
organic causes of exertional headache usually result from intracranial structural lesions , but may also occur in association with myocardial ischemia.7 headache as a rare symptom of myocardial infarction , and cardiac cephalalgia has been reported previously.2,7 - 9 cardiac cephalalgia has only recently been recognized as a distinct entity , being first proposed as ' cardiac cephalgia ' by lipton et al.4 in 1997 .
headache attributed to disorder of homeostasis , ' which is coded and named ' 10.6 cardiac cephalalgia ' in the second edition of the international classification of headache disorders ( ichd - ii).3 the diagnostic criteria are as follows:3
headache , which may be severe , aggravated by exertion , and accompanied by nausea , and fulfilling criteria c and d.acute myocardial ischemia occurs.headache develops concomitantly with acute myocardial ischemia.headache resolves and does not recur after effective medical therapy for myocardial ischemia or coronary revascularization .
headache , which may be severe , aggravated by exertion , and accompanied by nausea , and fulfilling criteria c and d. acute myocardial ischemia occurs .
headache resolves and does not recur after effective medical therapy for myocardial ischemia or coronary revascularization .
our patient experienced cardiac cephalalgia showing a reversible coronary vasospasm in coronary angiogram according to the ichd - ii : 10.6 .
the concomitant occurrence of headache and myocardial ischemia is the key criterion ( criterion c ) for diagnosis .
the proposed headache features ( criterion a ) are not generally satisfactory ; in particular , nausea was the least commonly fulfilled criterion in the review study of the literature with the new ichd - ii criteria revisited,10 in which the proposed mechanisms of cardiac cephalalgia are described .
because fibers from these ganglia also supply the structures of the eye , face , neck , and cerebrovasculature , referral of pain along these pathways might account for headache symptoms .
a second possible mechanism is that the decrease in cardiac output and increase in left - ventricular and right - atrial pressures associated with angina pectoris causes a decrease in venous return from the brain and subsequently an increase in intracranial pressure .
a sudden and transient increase in intracranial pressure is also proposed as an explanation for cough headache .
a third explanation posits an as yet unidentified mediator that is released secondary to cardiac ischemia and which might act on intracranial pain - sensitive structures .
serotonin , bradykinin , histamine , and substance p have been proposed as mediators of ischemic pain and might also have distant intracranial effects .
the increase in intracardiac pressure associated with angina may also induce the release of atrial natriuretic peptide ( anp ) and brain natriuretic peptide ( bnp ) , a response to increased right - atrial and left - ventricular pressures .
anp and bnp are potent vasodilators and thus could produce headache by dilation of the cerebrovasculature.4 the differential diagnosis with migraine is crucial to avoid the administration of vasoconstrictors .
in addition , exercise - induced headache relieved by rest should raise a high suspicion of the headache 's cardiac cause .
response of a headache to nitrates provides a strong clue as to the myocardial ischemic cause of the symptom.11
Output:
| backgroundunder certain conditions , exertional headaches may reflect coronary ischemia.case reporta 44-year - old woman developed intermittent exercise - induced headaches with chest tightness over a period of 10 months .
cardiac catheterization followed by acetylcholine provocation demonstrated a right coronary artery spasm with chest tightness , headache , and ischemic effect of continuous electrocardiography changes .
the patient 's headache disappeared following intra - arterial nitroglycerine injection.conclusionsa coronary angiogram with provocation study revealed variant angina and cardiac cephalalgia , as per the international classification of headache disorders ( code 10.6 ) .
we report herein a patient with cardiac cephalalgia that manifested as reversible coronary vasospasm following an acetylcholine provocation test . |
PubmedSumm8808 | ***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: noninvasive mechanical ventilation ( nimv ) refers to the application of artificial ventilation without an invasive access to the airway ( i.e. , without using an endotracheal or tracheostomy tube ) .
the increased popularity of nimv among clinicians and researchers alike is justified by the fact that it spares the patient the complications associated with invasive mechanical ventilation ( imv ) like nosocomial pneumonia ( 21% ) , sinusitis ( 5 - 25% ) , and other airway problems .
this , coupled with the availability of better and more accessible interfaces , has greatly increased the usage of nimv over the last decade .
its success or failure is essentially determined by appropriate patient selection , correct choice of interface , its correct application , and proper patient monitoring .
nimv has assumed a prominent role in the management of acute respiratory failure , and its success in various conditions is supported by literature .
the benefits of nimv have been studied most extensively in hypercapnoeic respiratory failure associated with ae - copd by means of multiple , well - designed , randomized controlled trials .
other less extensively studied conditions of hypercapnoeic respiratory failure with weaker recommendations in favor of nimv usage include neuromuscular diseases , chest - wall deformities , acute asthma , acute respiratory failure in obstructive sleep apnea / obesity - hypoventilation syndrome , and interstitial lung disease ( ild ) .
nimv has also been found to be beneficial in carefully selected patients of hypoxemic respiratory failure , particularly cardiogenic pulmonary edema , and less so in community acquired pneumonia ( cap ) , acute respiratory distress syndrome ( ards ) , and chest trauma with flail chest , among others .
the variability in the success of using nimv in different clinical conditions prompted us to conduct this study with the objective of evaluating the feasibility , efficacy , and outcome of using nimv in tertiary care centres .
this observational , retrospective study was conducted over an 18-month period ( between november 1 , 2009 and april 30 , 2011 ) in two tertiary level referral medical institutions in north india .
a total of 184 consecutive subjects who were treated with nimv ( irrespective of indication ) during the study period were included .
criteria of inclusion were patients of respiratory failure with ( a ) respiratory rate > 25/min ; ( b ) signs of increased work of breathing ; ( c ) arterial blood gas ( abg ) analysis showing ph < 7.35 or partial pressure of carbon dioxide ( paco2 ) > 45 mmhg , partial pressure of oxygen ( pao2 ) < 60 mmhg .
the exclusion criteria were the same as the contraindications to nimv application , namely cardiac / respiratory arrest , severe encephalopathy ( glasgow coma scale score < 10 ) , severe upper gastrointestinal bleeding , hemodynamic instability , unstable arrhythmias , facial surgery / trauma / deformity , upper airway obstruction , inability to cooperate / protect airway / clear secretions , and high risk for aspiration .
all patients were grouped according to the underlying clinical condition that prompted the application of nimv .
nimv was started by pulmonologists in the emergency department and , if required , patients were shifted to intensive respiratory care unit ( ircu ) .
bilevel positive airway pressure ( bipap ) system ( resmed , vpap iii sta ) with a full - face mask was used to apply nimv using st mode .
the outcome of nimv usage in each group was measured in terms of the number of patients cured by nimv and those who failed on nimv .
patients who failed on nimv were further evaluated regarding requirement of intubation and those who subsequently survived or expired .
the other variables collected in the study included abg parameters ( ph , paco2 , and pao2 ) and the mean duration of nimv application . paired t test and analysis of variance ( anova )
the outcome of nimv usage in each group was measured in terms of the number of patients cured by nimv and those who failed on nimv .
patients who failed on nimv were further evaluated regarding requirement of intubation and those who subsequently survived or expired .
the other variables collected in the study included abg parameters ( ph , paco2 , and pao2 ) and the mean duration of nimv application . paired t test and analysis of variance ( anova )
out of a total of 184 patients who were included in the study , most of the patients belonged to the age group 41 - 59 years ( 78 patients , 42.39% ) [ table 1 ] .
the number of male patients ( 95 patients , 51.6% ) slightly exceeded the number of female patients ( 89 patients , 48.4% ) .
the most common indication for application of nimv in our centers was acute exacerbation of copd ( 148 patients , 80.43% ) .
other less common indications for nimv were cap ( consolidation ) , ards , pulmonary edema , bronchiectasis , ild , asthma , and kyphoscoliosis . demographic characteristics of study subjects in copd patients , the change in ph , paco2 , and pao2 from baseline to after 24 h and at the time of discharge was significant ( p < 0.0001 by paired t test and anova ) . however , in non - copd patients , the change in ph and paco2 from baseline to after 24 h and at the time of discharge was not significant , but the change in pao2 values from the baseline to at the time of discharge was significant ( p < 0.00001 by paired t test and anova ) [ table 2 ] .
abg trends in copd and non - copd patients at admission , after 24 h of nimv application , and at discharge the mean duration of nimv usage in ae - copd patients was 8.35 5.98 days [ table 3 ] .
patients with underlying ild required the maximum duration of nimv support ( 17 8.48 days ) ; 134 of the 148 patients with underlying copd ( 90.54% ) were improved with nimv .
all patients with underlying cap ( 8 numbers ) , pulmonary edema ( 6 numbers ) , bronchiectasis ( 6 numbers ) , or kyphoscoliosis ( 2 numbers ) were benefitted with nimv , while none of the patients with ards ( 6 numbers ) showed any improvement . among ild and asthma patients ,
50% ( 2 out of 4 ) patients showed improvement with nimv and 13.04% ( 24 out of 184 ) patients on nimv required intubation and mechanical ventilation .
most of the complications were in the form of worsening respiratory distress despite nimv application , which necessitated endotracheal intubation and invasive ventilation .
the latter brought along associated complications like ventilator - associated pneumonia , sepsis , and cardiac arrest .
the most promising use of nimv appears to be in patients of ae - copd with hypercapnoeic respiratory failure who are on standard medical treatment .
the results of our study strongly support and encourage the use of nimv as the first - line ventilatory treatment in this group of patients .
these patients showed significant improvement in abg parameters at the time of discharge as compared to the baseline values . in this
regard , numerous randomized controlled trials have been conducted in the past that highlight the benefits of nimv usage in this group of patients in terms of reduced rate of endotracheal intubation and mortality , shortened length of icu and hospital stay , and reduction of complications like nosocomial pneumonia .
meta - analyses of these trials have also confirmed benefits of nimv in ae - copd .
studies have also found that early initiation of nimv is associated with better outcome compared to delayed initiation . even in sick patients who required immediate intubation ,
nimv was shown to avoid intubation in almost 50% of the patients in a prospective randomized controlled trial by conti et al .
nimv was not found to be beneficial in copd patients with mild exacerbation . in this study ,
copd patients were the ones who most commonly presented with type 2 respiratory failure ( respiratory acidosis ) .
nimv application facilitated co2 wash - out in these patients and helped regain normocapnea ( from 66.48 16.24 at baseline to 56.37 12.37 at discharge , p < 0.0001 ) [ table 2 ] and a normal ph ( from 7.334 0.08 at baseline to 7.421 0.062 at discharge , p < 0.0001 ) [ table 2 ] .
non - acidotic copd patients were also benefited by nimv as it helped decrease the respiratory rate by resting the respiratory muscles and thereby reducing the work of breathing , improving patient comfort , and possibly preventing the onset of frank respiratory failure and acidosis . regarding patients of cap , our results differ from those of previous studies in that all our 8 patients of cap
this could possibly be attributed to the fewer number of cap patients in our study .
previous published studies on the use of nimv in hypoxemic respiratory failure in cap have shown conflicting results .
some of these have shown no major benefit of nimv in this group of patients .
on the other hand , a randomized controlled trial done on patients with severe cap and hypoxemic respiratory failure in a subgroup of copd patients has demonstrated major benefit of nimv . however , these studies largely lead to the conclusion that nimv may be useful in carefully selected cap patients , particularly those with concomitant copd
. whatever may be the reason , a trial of nimv may not prove harmful , if not useful , in this group of patients . in our study , none of the patients having ards could be benefitted by nimv and mortality rate following intubation was nearly 67% .
usefulness of nimv in ards is questionable , as suggested by the limited studies available . in a study by rocker et al .
two other studies that included ards patients in comparing nimv with a conventional approach found that the rate of endotracheal intubation in ards patients randomized to nimv was 40% and the mortality rate in these patients was 35% .
it may be concluded that nimv should be very carefully applied to ards patients who are preferably hemodynamically stable , in an intensive care setting .
a beneficial outcome was seen in all 6 patients of pulmonary edema in whom nimv was applied in the present study . among the causes of hypoxemic respiratory failure
, nimv has been found to be very effective in patients of cardiogenic pulmonary edema in previous studies . a study by nava et al .
, revealed that , in these patients , nimv , in comparison to medical therapy plus oxygen , resulted in an improvement of pao2/fio2 ratio , respiratory rate , and dyspnea , but had no beneficial effect on intubation rate , hospital mortality , and duration of hospital stay .
thus , in addition to standard medical therapy , nimv appears to be a feasible supplementary treatment in acutely decompensated patients of cardiogenic pulmonary edema . among asthmatics ,
as far as the use of nimv in bronchial asthma is concerned , the evidence is inconclusive .
a retrospective analysis shows rapid improvement of blood gases and less hypercapnea in asthmatics treated with nimv .
a randomized controlled trial showed beneficial effect of nimv in selected patients of asthma in terms of improved lung function , faster alleviation of symptoms , and reduced need of hospitalization .
thus , nimv may be tried in those asthmatics that respond inadequately to medical therapy and have no contraindication for nimv usage , preferably in the icu .
no randomized controlled trials have examined the effect of nimv in patients of chest wall deformity like kyphoscoliosis and neuromuscular diseases . only some retrospective case series suggest that nimv alleviates gas exchange abnormalities and avoids intubation in this group of patients who present with respiratory failure .
thus , nimv may be beneficial in these patients when they present with acute - on - chronic respiratory failure .
to conclude , this study demonstrates the feasibility and efficacy of nimv applied in regular clinical practice .
the results strongly support and encourage the use of nimv as a first - line ventilatory treatment in ae - copd patients with respiratory failure .
nimv should also be considered in other causes of respiratory failure as a promising step toward prevention of mechanical ventilation .
Output:
| background : noninvasive mechanical ventilation ( nimv ) is the delivery of positive pressure ventilation through an interface to upper airways without using the invasive airway .
use of nimv is becoming common with the increasing recognition of its benefits.objectives:this study was done to evaluate the feasibility and outcome of nimv in tertiary care centres.materials and methods : an observational , retrospective study conducted over a period of 18 months in two tertiary level hospitals of north india on 184 consecutive patients who were treated by nimv , regardless of the indication .
nimv was given in accordance with the arterial blood gas ( abg ) parameters defining respiratory failure ( type 1/type 2).results : the most common indication of nimv in our hospitals was acute exacerbation of chronic obstructive pulmonary disease ( ae - copd 80.43% ) , and 90.54% ae - copd patients were improved by nimv .
application of nimv resulted in significant improvement of ph and blood gases in copd patients , while non - copd patients showed significant improvement in partial pressure of oxygen ( pao2 ) alone .
the mean duration of nimv was 8.35 5.98 days , and patients of interstitial lung disease ( ild ) were on nimv for the maximum duration ( 17 8.48 days ) .
none of the patients of acute respiratory distress syndrome were cured by nimv ; 13.04% patients on nimv required intubation and mechanical ventilation.conclusion:this study demonstrates and encourages the use of nimv as the first - line ventilatory treatment in ae - copd patients with respiratory failure .
it also supports nimv usage in other causes of respiratory failure as a promising step toward prevention of mechanical ventilation . |
PubmedSumm8809 | ***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: stainless steel crowns are the most commonly used treatment modality for full - coverage restoration of primary molar teeth .
american academy of pediatric dentistry recommends stainless steel crowns ( ssc ) treatment for cases with extensive and multi - surface caries . despite many advantages ,
the metal appearance of these crowns is unpleasant to the parents and children and they prefer tooth - colored restorations to silver - colored fillings regardless of location of restorations [ 13 ] . considering the increasing demand for esthetic restorations , several treatment options have been proposed for primary teeth to overcome this shortcoming such as open face sscs ( ofsscs ) , strip crowns , preveneered sscs ( pvsscs ) and zirconia crowns . the ofsscs benefit from the durability of sscs while having an esthetic appearance .
however , their facing may detach and the metal margin around composite in this type of restoration may have an unpleasant appearance .
they need a clean , dry surface and sufficient tooth structure in order to have retention . in pvsscs ,
consequently , they are more difficult to crimp and fit compared to sscs and require greater tooth preparation .
susceptibility to fracture , chipping and separation of the veneer and high cost are among other disadvantages of these crowns .
they highly resemble tooth color and have very high fracture toughness and biocompatibility . however , high cost , greater thickness than sscs and inability to crimp are among the drawbacks of these crowns . considering these shortcomings
, attempts have been made to find a more esthetic method with the advantages of sscs .
chair - side veneering of well - adjusted sscs using composite ( first defined by weildenfield et al , in 1995 ) can be a suitable approach to achieve esthetic goals in addition to durability and strength , given that a durable bond is obtained .
mechanical and chemical methods are used to enhance composite resin bond to metals . in this study , we roughened the surface of sscs by diamond bur and sandblasting ( mechanical methods ) and then used two bonding systems ( chemical methods ) .
this study aimed to compare the sbs of composite to sscs using two methods of mechanical surface treatments ( mst ) and two different bonding systems .
in this in vitro study , 84 pre - crimped pre - contoured sscs ( 3 m espe , st .
paul , mn , usa ) of primary mandibular left second molar ( size 5 ) were divided into six groups of 14 sscs based on the type of mst and bonding system ( table 1 ) .
descriptive data of different groups based on the type of mst and bonding system the sscs were mounted in cubic acrylic molds measuring 72030 mm in such a way that the lingual surface of crowns was completely accessible for bond to composite .
the two types of mst in this study were performed as follows : using a round diamond bur , two vertical and two horizontal grooves were created on the lingual surface of sscs .
the grooves were 4 mm long and had 1 mm distance from one another ( fig .
ssc surface ; ( a ) after roughening by diamond bur , ( b ) after sandblasting for sandblasting of the surface of sscs , 50m aluminum oxide particles were used for 20 seconds in such a way that the lingual surface of sscs was completely sandblasted ( fig .
after mst , specimens were etched with 9.6% hydrofluoric ( hf ) acid for 20 seconds . by doing so , the metal surface was cleansed .
next , the following two bonding systems along with the composite resins recommended by the manufacturers were applied :
1- scotchbond universal adhesive ( scotchbond universal adhesive , 3 m espe , seefeld , germany).2- alloy primer ( kuraray , okayama , japan ) plus clearfil se primer and bond ( kuraray , okayama , japan )
1- scotchbond universal adhesive ( scotchbond universal adhesive , 3 m espe , seefeld , germany ) .
2- alloy primer ( kuraray , okayama , japan ) plus clearfil se primer and bond ( kuraray , okayama , japan ) according to the manufacturer s instructions , the bonding agent was applied to the ssc surface using a micro - brush ; 10 seconds time was allowed and after gentle air spray , it was cured for 15 seconds . next , filtek z250 composite resin ( 3 m espe , st .
paul , mn , usa ) was applied to a transparent prefabricated cylindrical mold ( measuring 33 mm ) .
the composite was condensed and light cured for 40 seconds using a light curing unit ( fig .
2 ) . composite bonded to the ssc surface : ( a ) frontal view , ( b ) superior view according to the manufacturer s instructions , alloy primer was applied to the lingual surface of sscs using a micro - brush .
next , the primer of clearfil se bond was applied and after 10 seconds of waiting , it was gently air - dried .
finally , the bonding agent of clearfil se bond was applied and after 10 seconds of waiting , it was gently air - dried and light cured for 15 seconds .
clearfil ap - x composite ( kuraray , okayama , japan ) was then applied to a prefabricated cylindrical mold ( measuring 3 mm in diameter and 3 mm in height ) .
the mold was positioned at the center of the lingual surface of sscs and after condensing the composite , it was cured for 40 seconds .
after preparation of all six groups , the specimens were subjected to thermocycling for 1500 cycles between 555c ( each cycle for 30 seconds ) .
then , the sbs of specimens was measured using a universal testing machine ( zwick roell , ulm , germany ) in newton ( n ) .
shear load was applied by a blade to the composite - ssc interface at a crosshead speed of 0.5mm / min until fracture .
the load at fracture in n was converted to megapascals ( mpa ) by dividing it by the surface area ( fig .
the mode of failure in all specimens was determined by two calibrated observers blinded to the group allocation of specimens using a5 magnifier and classified into adhesive , cohesive and mixed types .
the mean shear bond strength of the six groups in mpa along with 95% ci the data were analyzed using spss version 21 . the mean and standard deviation ( sd ) of sbs
two - way anova was used to assess the effect of mst and type of bonding system on the sbs .
considering the significant interaction effect of the above - mentioned two factors ( p<0.001 ) , comparison of the means was performed separately for each factor .
t - test was applied to compare bonding systems in each mst group while one - way anova was used for the comparison of mean sbs values with each method of mst separately for each bonding system . for pairwise comparison of groups after applying anova , tukey s test or dunnett s t3 test was used depending on the homogeneity or non - homogeneity of variances .
using a round diamond bur , two vertical and two horizontal grooves were created on the lingual surface of sscs .
the grooves were 4 mm long and had 1 mm distance from one another ( fig .
. ssc surface ; ( a ) after roughening by diamond bur , ( b ) after sandblasting
for sandblasting of the surface of sscs , 50m aluminum oxide particles were used for 20 seconds in such a way that the lingual surface of sscs was completely sandblasted ( fig .
after mst , specimens were etched with 9.6% hydrofluoric ( hf ) acid for 20 seconds . by doing so , the metal surface was cleansed .
next , the following two bonding systems along with the composite resins recommended by the manufacturers were applied :
1- scotchbond universal adhesive ( scotchbond universal adhesive , 3 m espe , seefeld , germany).2- alloy primer ( kuraray , okayama , japan ) plus clearfil se primer and bond ( kuraray , okayama , japan )
1- scotchbond universal adhesive ( scotchbond universal adhesive , 3 m espe , seefeld , germany ) .
2- alloy primer ( kuraray , okayama , japan ) plus clearfil se primer and bond ( kuraray , okayama , japan )
according to the manufacturer s instructions , the bonding agent was applied to the ssc surface using a micro - brush ; 10 seconds time was allowed and after gentle air spray , it was cured for 15 seconds .
paul , mn , usa ) was applied to a transparent prefabricated cylindrical mold ( measuring 33 mm ) .
the composite was condensed and light cured for 40 seconds using a light curing unit ( fig .
2 ) . composite bonded to the ssc surface : ( a ) frontal view , ( b ) superior view
according to the manufacturer s instructions , alloy primer was applied to the lingual surface of sscs using a micro - brush .
next , the primer of clearfil se bond was applied and after 10 seconds of waiting , it was gently air - dried .
finally , the bonding agent of clearfil se bond was applied and after 10 seconds of waiting , it was gently air - dried and light cured for 15 seconds .
clearfil ap - x composite ( kuraray , okayama , japan ) was then applied to a prefabricated cylindrical mold ( measuring 3 mm in diameter and 3 mm in height ) .
the mold was positioned at the center of the lingual surface of sscs and after condensing the composite , it was cured for 40 seconds .
after preparation of all six groups , the specimens were subjected to thermocycling for 1500 cycles between 555c ( each cycle for 30 seconds ) .
then , the sbs of specimens was measured using a universal testing machine ( zwick roell , ulm , germany ) in newton ( n ) .
shear load was applied by a blade to the composite - ssc interface at a crosshead speed of 0.5mm / min until fracture .
the load at fracture in n was converted to megapascals ( mpa ) by dividing it by the surface area ( fig .
the mode of failure in all specimens was determined by two calibrated observers blinded to the group allocation of specimens using a5 magnifier and classified into adhesive , cohesive and mixed types .
the data were analyzed using spss version 21 . the mean and standard deviation ( sd ) of sbs
two - way anova was used to assess the effect of mst and type of bonding system on the sbs .
considering the significant interaction effect of the above - mentioned two factors ( p<0.001 ) , comparison of the means was performed separately for each factor .
t - test was applied to compare bonding systems in each mst group while one - way anova was used for the comparison of mean sbs values with each method of mst separately for each bonding system . for pairwise comparison of groups after applying anova , tukey s test or dunnett s t3 test was used depending on the homogeneity or non - homogeneity of variances .
based on the results , no significant difference ( p=0.503 ) was found in sbs of the two bonding systems between the two groups of msts ( groups n+u and n+a ) . in groups r+u and r+a ( mst with a round diamond bur ) , a significant difference was noted in sbs between the two bonding systems and the mean sbs in group r+u was significantly higher than that in group r+a ( p<0.001 ) . in groups s+u and s+a ( mst with sandblasting ) , no significant difference ( p=0.103 ) was noted in sbs between the two bonding systems ( table 2 ) .
comparison of mst methods based on the type of bonding system revealed that groups n+u , r+u and s+u ( using scotchbond universal adhesive with different msts ) were significantly different ( p<0.001 ) in terms of sbs ( table 3 ) .
shear bond strength of composite resin to sscs in the six groups in mpa and comparison of the two bonding systems used based on the method of mst comparison of shear bond strength of the six groups ( mpa ) based on the type of bonding system used groups n+a , r+a and s+a ( using alloy primer with different msts ) were also significantly different ( p<0.001 ) in terms of sbs ( table 3 ) .
pairwise comparison of groups in terms of sbs based on the type of bonding system used revealed significant differences in sbs of groups n+u and r+u and also n+u and s+u ( p<0.001 ) .
based on table 4 , a significant difference was noted in the mean sbs of groups r+a and s+a ( p=0.02 ) .
pairwise comparison of groups s+a and n+a revealed a significant difference in sbs ( p=0.01 ) .
pairwise comparison of shear bond strength of the six groups ( mpa ) based on the type of bonding system used adhesive fracture was the most frequent in groups n+u and n+a while mixed fracture was the most common in groups r+u and s+u .
the frequency distribution of mode of failure in groups r+a and s+a was not significantly different from that in groups r+u and s+u and also n+u and n+a ( table 5 ) . the frequency distribution of mode of failure in the six groups
most previous studies have evaluated the effect of msts or chemical methods on sbs . however , we evaluated the interaction effect of two msts and two bonding systems on the sbs of composite to sscs .
the manufacturers of the two bonding systems used in this study claim that these systems provide adequate resin - metal bond . based on the results ,
the highest sbs was obtained in s+u group ( 9.992.59 mpa ) while the lowest value was obtained in n+u group ( 3.341.72 mpa ) .
considering the significant interaction effect of mst and type of bonding system on sbs , the results are discussed separately for each factor .
different mechanical methods have been used to enhance composite bond to metal such as sandblasting , surface roughening by diamond bur , air abrasion , ultra - violet radiation and spot welding .
some studies have shown that sandblasting increases the composite bond to sscs . in the process of sandblasting ,
a specific boundary can not be outlined for sandblasting and particles may be propelled beyond the surface area specified for veneering .
thus , aside from sandblasting , surface roughening by diamond bur was also evaluated in the current study as an affordable , easy to perform mst and the result was compared with that of sandblasting .
based on the results , in groups without mst , no significant difference was noted between the two bonding systems . also , the sbs values were the lowest in n+u and n+a groups .
the low sbs values obtained in these two groups were probably attributed to the lack of mst and application of bonding agents to a completely smooth surface with no mechanical retention / interlocking . also , the sbs of groups that were sandblasted was not significantly different from that of other groups .
this finding indicates increased sbs due to creation of a rough surface and increased surface area by sandblasting . in groups where surface roughening was performed by a diamond bur ,
the sbs was significantly different between the two bonding systems and the sbs in r+u group was higher than that in r+a group .
it appears that surface roughening by diamond bur improves the sbs when scotchbond universal adhesive is used .
the reason may be that in alloy primer bonding system , primers and the bonding agent are applied in three steps and the degree of roughness created by diamond bur may not be sufficient for this purpose ; whereas , scotchbond universal adhesive is applied in one step . in groups where sandblasting was performed for mst ,
no significant difference was noted in sbs and this value was 9.992.59 mpa in group s+u and 8.023.21 mpa in group s+a .
it appears that in both groups , sandblasting increased the sbs by creating a rough surface and increasing the surface area .
hattan et al , in their study used sandblasting for mst and reported higher sbs of composite to sscs in scotchbond universal adhesive group compared to adper and prime & bond nt groups ; this result was in accordance with our finding .
the manufacturer of adper and prime & bond nt do not claim an optimal bond to metal . also , the values obtained in their study were higher than our obtained values ( 17.624.22 mpa ) and the reason may be conduction of thermocycling with lower number of thermal cycles in their study ( 500 thermal cycles in their study versus 1500 cycles in ours ) .
both alloy primer and scotchbond universal adhesive used in the current study have mdp monomer in their composition .
presence of mdp monomer along with silane in the composition of bonding agent increases the bond strength of resin to metal , alumina , zirconia and ceramic .
mdp monomer chemically bonds to non - precious metals from its phosphoric acid group end ; while , the double bond in the other end of the molecule is copolymerized with resin monomers .
based on our results , the highest sbs belonged to s+u group while the lowest was observed in n+s group . in groups where universal scotch bond was used as the bonding agent
, significant differences were noted in sbs among different msts and the sbs in s+ u and r+u groups was significantly higher than that in n+u group .
it appears that both msts can adequately enhance the sbs probably by increasing the surface area and creating a macro - retentive surface . in groups where alloy primer was used for bonding
, significant differences were noted in sbs among groups with different msts and s+a group had significantly higher sbs than r+a and n+a groups .
the difference between sandblasting and surface roughening by diamond bur may be due to the different surface area receiving the mst . in the sandblasting method ,
the entire surface area of the interface between the ssc and composite is sandblasted by aluminum oxide particles .
but , in surface roughening by diamond bur , surface roughening is performed in only a portion of the surface area .
considering the fact that roughening by bur did not result in a significant improvement in sbs compared to no mst group for this specific bonding agent , it appears that sandblasting in conjunction with the application of alloy primer is the method of choice for achieving a higher sbs of composite to sscs .
salama and el - mallakh reported that sandblasting provided higher sbs compared to no mst in bond of compomer to sscs ( 9.512.47 versus 2.991.38 ) ; this finding was similar to our result .
although they did not perform thermocycling , they obtained sbs values close to ours for scotchbond multi purpose plus tm ( 9.373.7 ) and dyract psa prime / adhesive ( 9.522.46 ) .
al - shalan et al , found no significant difference in sbs of composite to sscs between surface roughening by bur and no mst .
their results were similar to our findings regarding surface roughening by bur followed by the application of alloy primer .
but , the results of the two studies were different for surface roughening followed by the application of scotchbond universal adhesive .
this difference may be explained by the different bonding systems used or the technique of surface roughening .
ajami et al , found no significant difference in sbs of composite to sscs using ( a ) single bond , ( b ) all bond and ( c ) panavia f2 and three methods of surface preparation namely acidic gel , sandblasting and surface roughening by fissure bur .
no difference was reported in sbs between surface roughening by bur and sandblasting and this result is in line with our findings in groups where scotchbond universal adhesive was used . however , our findings in alloy primer groups were not in accordance with those of ajami et al , . in our study , significant differences existed among groups in terms of mode of failure .
most fractures were of adhesive type in n+u and n+a groups ; whereas , in s+u and r+u groups , mixed fractures had a higher frequency . in groups
no cohesive fracture occurred in our specimens . in the study by hattan et al ,
. this difference may be due to errors in observation or variable definitions of cohesive fractures .
many previous studies have reported the sbs of bonding systems to dentin to be in the range of 1012 mpa .
moreover , the minimum required clinical bond strength for bracket bonding to permanent teeth has reported to be 68 mpa . based on our results ,
also , considering the single step application of scotchbond universal adhesive compared to the three - step alloy primer and also higher sbs values obtained in the scotchbond universal adhesive groups , scotchbond universal adhesive seems to be a more suitable bonding system for bonding of composite to sscs . since both surface roughening by bur and sandblasting followed by scotchbond universal adhesive application yielded high sbs values
considering the lack of a significant difference between the two methods of mst and lower cost of surface roughening by diamond bur compared to sandblasting , surface roughening by diamond bur may be preferred to sandblasting in the clinical setting .
chair - side bonding of composite to sscs not only improves their esthetic appearance , but also can be used for repair of pvsscs .
last but not least , it should be noted that this study had an in - vitro design and this indicates the need for future in vivo studies to assess the validity of the clinical application of these techniques and the durability of composite bond to sscs using these methods .
different mechanical methods have been used to enhance composite bond to metal such as sandblasting , surface roughening by diamond bur , air abrasion , ultra - violet radiation and spot welding .
some studies have shown that sandblasting increases the composite bond to sscs . in the process of sandblasting ,
a specific boundary can not be outlined for sandblasting and particles may be propelled beyond the surface area specified for veneering .
thus , aside from sandblasting , surface roughening by diamond bur was also evaluated in the current study as an affordable , easy to perform mst and the result was compared with that of sandblasting .
based on the results , in groups without mst , no significant difference was noted between the two bonding systems . also , the sbs values were the lowest in n+u and n+a groups .
the low sbs values obtained in these two groups were probably attributed to the lack of mst and application of bonding agents to a completely smooth surface with no mechanical retention / interlocking . also , the sbs of groups that were sandblasted was not significantly different from that of other groups .
this finding indicates increased sbs due to creation of a rough surface and increased surface area by sandblasting . in groups where surface roughening was performed by a diamond bur ,
the sbs was significantly different between the two bonding systems and the sbs in r+u group was higher than that in r+a group .
it appears that surface roughening by diamond bur improves the sbs when scotchbond universal adhesive is used .
the reason may be that in alloy primer bonding system , primers and the bonding agent are applied in three steps and the degree of roughness created by diamond bur may not be sufficient for this purpose ; whereas , scotchbond universal adhesive is applied in one step . in groups where sandblasting was performed for mst ,
no significant difference was noted in sbs and this value was 9.992.59 mpa in group s+u and 8.023.21 mpa in group s+a .
it appears that in both groups , sandblasting increased the sbs by creating a rough surface and increasing the surface area .
hattan et al , in their study used sandblasting for mst and reported higher sbs of composite to sscs in scotchbond universal adhesive group compared to adper and prime & bond nt groups ; this result was in accordance with our finding .
the manufacturer of adper and prime & bond nt do not claim an optimal bond to metal . also , the values obtained in their study were higher than our obtained values ( 17.624.22 mpa ) and the reason may be conduction of thermocycling with lower number of thermal cycles in their study ( 500 thermal cycles in their study versus 1500 cycles in ours ) .
both alloy primer and scotchbond universal adhesive used in the current study have mdp monomer in their composition .
presence of mdp monomer along with silane in the composition of bonding agent increases the bond strength of resin to metal , alumina , zirconia and ceramic .
mdp monomer chemically bonds to non - precious metals from its phosphoric acid group end ; while , the double bond in the other end of the molecule is copolymerized with resin monomers . based on our results ,
the highest sbs belonged to s+u group while the lowest was observed in n+s group . in groups where universal scotch bond was used as the bonding agent
, significant differences were noted in sbs among different msts and the sbs in s+ u and r+u groups was significantly higher than that in n+u group .
it appears that both msts can adequately enhance the sbs probably by increasing the surface area and creating a macro - retentive surface . in groups where alloy primer was used for bonding
, significant differences were noted in sbs among groups with different msts and s+a group had significantly higher sbs than r+a and n+a groups .
the difference between sandblasting and surface roughening by diamond bur may be due to the different surface area receiving the mst . in the sandblasting method ,
the entire surface area of the interface between the ssc and composite is sandblasted by aluminum oxide particles .
but , in surface roughening by diamond bur , surface roughening is performed in only a portion of the surface area .
considering the fact that roughening by bur did not result in a significant improvement in sbs compared to no mst group for this specific bonding agent , it appears that sandblasting in conjunction with the application of alloy primer is the method of choice for achieving a higher sbs of composite to sscs .
salama and el - mallakh reported that sandblasting provided higher sbs compared to no mst in bond of compomer to sscs ( 9.512.47 versus 2.991.38 ) ; this finding was similar to our result .
although they did not perform thermocycling , they obtained sbs values close to ours for scotchbond multi purpose plus tm ( 9.373.7 ) and dyract psa prime / adhesive ( 9.522.46 ) .
al - shalan et al , found no significant difference in sbs of composite to sscs between surface roughening by bur and no mst .
they used five different bonding systems in their study . also , they roughened the surface using # 4 round diamond bur .
their results were similar to our findings regarding surface roughening by bur followed by the application of alloy primer .
but , the results of the two studies were different for surface roughening followed by the application of scotchbond universal adhesive . this difference may be explained by the different bonding systems used or the technique of surface roughening .
ajami et al , found no significant difference in sbs of composite to sscs using ( a ) single bond , ( b ) all bond and ( c ) panavia f2 and three methods of surface preparation namely acidic gel , sandblasting and surface roughening by fissure bur . no difference was reported in sbs between surface roughening by bur and sandblasting and this result is in line with our findings in groups where scotchbond universal adhesive was used .
however , our findings in alloy primer groups were not in accordance with those of ajami et al , . in our study , significant differences existed among groups in terms of mode of failure .
most fractures were of adhesive type in n+u and n+a groups ; whereas , in s+u and r+u groups , mixed fractures had a higher frequency . in groups s+a and r+a , most fractures were of adhesive type .
no cohesive fracture occurred in our specimens . in the study by hattan et al ,
. this difference may be due to errors in observation or variable definitions of cohesive fractures .
many previous studies have reported the sbs of bonding systems to dentin to be in the range of 1012 mpa .
moreover , the minimum required clinical bond strength for bracket bonding to permanent teeth has reported to be 68 mpa .
also , considering the single step application of scotchbond universal adhesive compared to the three - step alloy primer and also higher sbs values obtained in the scotchbond universal adhesive groups , scotchbond universal adhesive seems to be a more suitable bonding system for bonding of composite to sscs . since both surface roughening by bur and sandblasting followed by scotchbond universal adhesive application yielded high sbs values
, the authors believe that both methods of msts are suitable for bond enhancement . considering the lack of a significant difference between the two methods of mst and lower cost of surface roughening by diamond bur compared to sandblasting , surface roughening by diamond bur may be preferred to sandblasting in the clinical setting .
chair - side bonding of composite to sscs not only improves their esthetic appearance , but also can be used for repair of pvsscs .
moreover , it enables the use of ssc for an abutment tooth in splinting . however , addition of composite to ssc increases the treatment time .
last but not least , it should be noted that this study had an in - vitro design and this indicates the need for future in vivo studies to assess the validity of the clinical application of these techniques and the durability of composite bond to sscs using these methods .
with the use of alloy primer , sandblasting provided higher sbs of composite to sscs compared to no mst and roughening by diamond bur . with the use of scotchbond universal adhesive ,
both sandblasting and surface roughening by bur provided higher sbs of composite to sscs compared to no mst . both scotchbond universal adhesive and alloy primer in conjunction with sandblasting provided adequate sbs of composite to sscs .
Output:
| objectives : this study aimed to compare the shear bond strength ( sbs ) of composite to stainless steel crowns ( ssc ) using two mechanical surface treatments ( msts ) and two bonding systems.materials and methods : eighty - four sscs were divided into six groups of 14 ; group1 : no mst+scotchbond universal adhesive ( n+u ) , group 2 : surface roughening by a diamond bur+scotchbond universal adhesive ( r+u ) , group 3 : sandblasting+scotchbond universal adhesive ( s+u ) , group 4 : no mst+alloy primer+clearfil se primer and bond ( n+a ) , group 5 : surface roughening by a diamond bur+alloy primer+clearfil se primer and bond ( r+a ) , group 6 : sandblasting+alloy primer+clearfil se primer and bond ( s+a ) . after mst and bonding procedure ,
composite cylinders were bonded to the lingual surface of sscs , then the sbs of composite to sscs was measured using a universal testing machine following thermocycling.results:the sbs of groups r+u and s+u was significantly higher than that of group n+u . no significant difference was noted in sbs of groups r+u and s+u .
the sbs of group s+a was significantly higher than that of groups n+a and r+a .
no significant difference was noted in the sbs of groups n+a and r+a ( p>0.05).conclusions : in scotchbond universal adhesive groups , sandblasting and surface roughening by diamond bur significantly increased the sbs of composite to sscs compared to no mst . in alloy primer groups , sandblasting significantly increased the sbs of composite to ssc compared to surface roughening with diamond bur and no mst . |
PubmedSumm8810 | ***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: palisaded encapsulated neuroma ( pen ) is a benign neural tumor , which usually presents as small , solitary , asymptomatic , firm , skin - colored , or pink papule , or nodule , almost always present on the face or close to a mucocutaneous junction .
palisaded encapsulated neuroma ( pen ) is a distinctive benign neural tumor , which usually presents as small , solitary , asymptomatic , firm , rubbery , skin - colored or pink papule or nodule , almost always present on the face or close to a mucocutaneous junction .
it commonly occurs in middle - aged adults with female to male ratio of 1:1 .
rarely it can present with multiple lesions . despite the fact that it is not uncommon ,
clinically , pen is most commonly confused with neurofibroma , basal cell carcinoma , nevus , or skin appendage tumor .
pen has histological appearance between that of a neurofibroma and a schwannoma situated predominantly in the dermis .
differentiation from neurofibromas is essential , because the latter is often associated with neurofibromatosis , and has a propensity for malignant transformation .
pen has no association with neurofibromatosis or multiple endocrine neoplasia syndrome type 2b ( men 2b ) .
even after incomplete excision pen does not recur , a fact supporting a reactive rather than a neoplastic origin . here , we present a rare case of multiple cutaneous pen in a dermatomal distribution on the face not associated with neurofibromatosis or men 2b .
a 30-year - old female patient presented to us with asymptomatic skin lesions on the face of 4 years duration .
these lesions began as pinhead sized elevations and gradually grew in size to the present state . on examination , lesions were multiple , discrete , mostly multi - lobulated , flesh colored , soft to firm , papules , and nodules arranged in a curvilinear fashion on the face [ figure 1 ] starting from tip of the nose and gradually deviating to the left along the nose , left eyebrow , and forehead region along the distribution of the ophthalmic division of the trigeminal nerve .
routine blood investigations , chest x - ray , ultrasonography of the whole abdomen were normal .
skin biopsy specimen showed a tan granular surface of the base and histopathological examination revealed a normal epidermis . in the dermis
, there was a partially encapsulated , well - circumscribed nodule [ figure 2 ] composed of fascicles of small spindle cells with wavy nuclei interlaced with small slits and clefts [ figure 3 ] .
we had sent the patient to the plastic surgery out patient departmentfor excision of the lesion .
multiple , discrete , flesh colored , soft to firm , papules and nodules arranged in a curvilinear fashion on the face multiple partially encapsulated , well - circumscribed nodules in the dermis ( h and e , 40 ) fascicles of small spindle cells with wavy nuclei interlaced with small slits and clefts ( h and e , 100 ) tumor mass showing positive s-100 ( immunohistochemical staining , 100 )
pen of the skin was first described by reed et al . in 1972 .
it is an infrequent , benign cutaneous neural tumor , clinically misdiagnosed as a neurofibroma , basal cell carcinoma , melanocytic nevus , epidermal cyst , or skin appendage tumor , with a histological appearance between that of a neurofibroma and a schwannoma .
common differentials of papule / nodules on the face are presented in table 1 . despite the relatively high - incidence of this tumor ,
common differentials of papule / nodules on the face pen clinically presents as solitary , asymptomatic , firm , sessile , immobile , rubbery , skin - colored or pink dome - shaped papule or nodule , commonly present on the face or close to a mucocutaneous junction .
the lesions have also been found on the trunk , shoulder , arm , oral mucosa , eyelid , and glans penis .
it is usually found in middle - aged adults with equal incidence in both sexes .
clinically , it is difficult to differentiate pen from neurofibroma because of their similar clinical presentation ; though the lesions of pen are commonly present on the face , usually firm with absence of buttonhole sign ; whereas in neurofibroma the lesions are mostly present on the trunk , usually soft where buttonhole sign can be elicited .
they are composed of a partially encapsulated mass of schwann cells arranged in interlacing fascicles separated by small clefts , interspersed with a variable amount of tiny axons .
although the nodular growth pattern is most frequently encountered , other types include epithelioid , plexiform , multi - nodular and fungating .
immunohistochemical analyses reveal that tumor cells stain positively for s100 protein , collagen type iv and vimentin characteristic of schwann cell differentiation .
the capsule is composed of elongated perineural cells that stain positively for epithelial membrane antigen .
the histological differential diagnosis for pen includes neurofibroma , schwannoma , traumatic neuroma and leiomyoma . unlike pen ,
neurofibromas lack a capsule , contain mucopolysaccharide ground substance , and have fewer axons with myelin sheaths .
schwannomas are typically found subcutaneously , contain antoni a and b type tissue with verocay bodies , and do not have axons .
overall , the pen accounts for approximately 25% of all nerve sheath tumors of the dermis .
traumatic neuromas have axonal and schwann cell proliferation , however , scarring and inflammatory cells are evident as well .
leiomyomas are spindle cell tumors composed of muscle cells readily differentiated by immunohistochemistry where they are consistently positive for desmin .
so patients can be reassured that excision is curative with a minimum possibility of recurrence , which reduces unnecessary further testing or concern to search for systemic diseases or malignancy .
a similar presentation of linearly arranged papules , and nodules on the neck and forehead with diagnosis of collagenoma was reported .
clinicians should include pen in the differential diagnosis of fleshy papules presenting on the nose and forehead for the purpose of obtaining wider recognition of the tumor , which responds well to excision .
multiple cutaneous pen in a dermatomal distribution on the face in a middle aged female is a very rare presentation .
Output:
| palisaded encapsulated neuroma ( pen ) is an infrequent benign cutaneous neural tumor , which usually presents as solitary , asymptomatic , papule or nodule , often localized on the faces , around the orifices , in middle age with no sex preponderance .
rarely , it can be multiple .
both solitary and multiple lesions are not associated with neurofibromatosis or multiple endocrine neoplasica syndrome type 2b ( men 2b ) .
we hereby report , a rare case of multiple cutaneous pen in a 30-year - old female who presented with multiple asymptomatic soft - to - firm papules and nodules in a dermatomal distribution on the face along the supply of the ophthalmic division of the trigeminal nerve with no signs of neurofibromatosis or men 2b . |
PubmedSumm8811 | ***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: myocardial function of the heart relies on rhythmic and effective cardiac contraction and relaxation , which depends on the appropriately timed generation and spread of cardiac electrical activity itself . at the cellular level , excitation - contraction
( e - c ) coupling is initiated by action potential depolarization resulting , via a cascade of events , in an increase in intracellular calcium concentration , which ultimately leads to muscle contraction ; subsequent removal of intracellular calcium via a number of mechanisms results in relaxation .
thus , this process involves multiple trans - membrane ( e.g. , ion channels ) and intracellular proteins ( e.g. , ca handling and sarcomeric proteins ) and is highly regulated by multiple extra- and intra - cellular signaling pathways .
recent work by us and others has laid the groundwork for elucidating key functional roles for p21 activated kinase 1 ( pak1 ) in this process including following aspects : the expression of pak1 as well as its isoforms pak2 and pak3 in cardiac tissues has been investigated in several species .
the protein level of pak1 is high in all regions of the heart such as the sino - atrial node ( san ) , atrial and ventricular tissue , whereas pak2 is expressed at low or modest levels in cardiac tissues , and there is little expression of pak3 in the heart . at the cellular level
, it is localized to z - disc , cell and nuclear membrane and intercalated disc of ventricular myocytes .
distinct subcellular distribution patterns have also revealed , for example , in guinea pig san cells , we found pak1 was evenly expressed in central nodal cells , whereas it demonstrated a clear striation patterns in peripheral nodal cells ( fig . 1 ) .
( a ) western blot detection of pak1 expression in san , left atrial ( la ) and ventricular tissues ( v ) .
pak1 expression pattern was examined by immunocytochemical staining in ( b ) adult rat cardiomyocyte ( green , anti - pak1 ; red , rhodamine - conjugated phalloidin ) , in ( c ) guinea pig senatorial node ( san ) cells ( adapted from refs . 3 and 4 ) . in cells pak1 activation
requires not only the gtpases ( cdc42 and rac ) , but also the tyr - kinase etk and the sh3 adaptor proteins such as pak - interacting exchange factor ( pix ) and non - catalytic region of tyrosine kinase adaptor protein ( nck ) , which directly interact with pak1 ( for detail , see parrini in this issue ) .
furthermore , pak1 is directly activated by a group of small molecules including c2/c6 ceramide and fty720 .
sphingosine also stimulates auto - phosphorylation of pak2 at the same sites as cdc42 and rac do .
however , it is still unclear whether sphingosine activates pak1 from the gtpase - binding domain or not .
early studies indicate that cdc42/rac and sphingosine share the same molecular mechanism in the activation of pak1 .
however , more recent studies indicate that these gtpases and sphingosine activate pak1 in a synergetic way .
pak1 can also be activated by some other signal transducers that have prominent functional effects in the heart .
for example , it was found that receptors coupled to the inhibitory g proteins gi , such as bradykinin and acetylcholine , were able to activate pak1 indirectly .
excellent evidence to support this comes from the observation that constitutively active pak1 and ligands stimulating these receptors produce the same cytoskeletal re - organization in mammalian cells .
interestingly , recent studies have indicated that pak1 is activated by a variety of growth factors such as egf and other extracellular factors such as angiotensin ii and isoproterenol ( iso ) .
these observations reflect the complexity of pak1 upstream signaling pathways that are still not well understood .
the potential role of pak1 in the regulation of ion channel activities was first demonstrated by us in isolated guinea pig san preparations and single san pacemaker cells . in san expressing the constitutively active ( ca ) pak1 , responses to iso stimulation manifested by the frequency of electrical impulse firing were significantly lower compared with those of controls .
we also characterized the beating rate of cultured san cells infected with adpak1 or the control adlacz . in the control san cells infected with adlacz , 5 nm iso increases the beating rate by 40 - 50% .
however , this iso - induced increase in beating rate is diminished , when they express the ca - pak1 , clearly indicating that pak1 antagonizes iso .
whole cell patch clamping demonstrated that both l - type ca current and the delayed rectifier k current had a repressed response to iso in cells expressing the ca - pak1 ( fig .
2 ) . in the san cells , ca - pak1 redirects intracellular localization of protein phosphatase 2a ( pp2a ) .
a recent study further demonstrated pak1 regulation of connexion ( cx ) 43 phosphorylation in both isolated rabbit ventricular myocytes and hek cells expressing cx43 is likely through the pp2a activity .
( a and b ) representative l - type ca current recordings from cultured san cells infected with ad - lacz or ad - pak1 in the absence and presence of 100 nmol / l iso for 5 min
. currents were recorded during 200-ms step depolarizations from a holding potential of -50 mv to a range of potentials between -40 and + 50 mv .
( c and d ) current - voltage relationship of ical in cells infected with ad - lacz or ad - pak1 , in the absence and presence of iso ( adapted from ref .
, we suggested that there is a dynamic balance between the kinase and the phosphatase activity in controlling l - type ca channel as well as delayed rectifier k channel activity in heart cells .
the balance between these kinase and phosphatase actions may be of importance in controlling cardiac pacemaker activity in response to autonomic and humoral stimulation .
the importance of this balance is highlighted by a recent report by vinogradova et al .
that a high basal pka - dependent phosphorylation in san pacemaker cells drives rhythmic internal ca store oscillations and spontaneous beating of these cells . alterations of pak1 activity may lead to the alteration of the dynamic regulatory processes and balance between kinase and phosphatase activity in cardiac cells and thus result in change in various ion channel activity .
it will be important to further investigate the regulatory role of pak1 on ion channels in the heart under physiological and pathological conditions .
a recent study by us also presented a novel evidence for the regulatory role of pak1 on ca handling in cardiac myocytes .
specifically , we examined the effects of constitutively active ( ca)-pak1 on [ ca]i transients and shortening of electrically stimulated ventricular myocytes under basal and -adrenergic - stimulated conditions ( fig . 3 ) .
under basal conditions , a change in the [ ca]i characteristics consisting of a significantly slower rate of ca decline in single adult rat ventricular myocytes expressing ca - pak1 than in control cells , concurrent with longer time for cellular re - lengthening .
there was no change in adpak1 cell sarcoplasmic reticulum ( sr ) ca content as assessed by caffeine , consistent with the lack of change in phospholamban ( plb ) phosphorylation .
this indicates ca - pak1 slows the intracellular ca decay rate independently of plb , although the exact mechanism remains to be determined .
there was also a significant reduction in the amplitude of spontaneous ca sparks in ca - pak1 compared with the control cells but no change in the frequency of occurrence .
they suggested that lower amplitude may be in part due to the slight decrease in sr .
line - scan images and whole cell - width line plots of fluo-4 fluorescence recorded parallel to the longitudinal axis of the cell from representative field - stimulated adult rat ventricular myocytes expressing lacz [ blue trace , ( a ) ] or ca - pak1 [ red trace , ( b ) ] under control conditions and during steady - state stimulation with 100 nm iso .
( c ) average intracellular ca concentration ( [ ca]i ) transient amplitudes in lacz ( 875 153 and 1,889 286 nm without and with iso , respectively ) and ca - pak1 ( 845 99 and1,299 138 nm without and with iso , respectively ) cells .
( d ) average time constant for [ ca]i transient decay ( decay ) for lacz ( 276 8 and 149 6 ms without and with iso , respectively ) and ca - pak1 ( 308 10 and 180 10 ms without and with iso , respectively ) cells .
values are means se * , statistically significant difference between lacz and ca - pak1 . , statistically significant difference between iso and + iso ( adapted from ref .
20 ) . under -adrenergic stimulation by treatment of the cells with iso , a significant blunting of
iso induced increases in [ ca]i transient amplitude , sr ca content and cell shortening was observed in ca - pak1 myocytes .
propagation of spontaneous ca waves resulting from sr ca overload was significantly slower in ca - pak1 myocytes .
thus pak1 activity may alter ryanodine receptor ( ryr ) 2 gating via dephosphorylation by pp2a , but a full characterization is required .
the level of plb phosphorylation at ser16 and thr17 was not significantly different between ca - pak1 and control myocytes , nor was cardiac troponin i ( ctni ) phosphorylation at ser significantly different .
alternatively , the lower spark amplitude in ca - pak1 myocytes may suggest that the ryr channel po may be lower , so that fewer ryrs are gating within a cluster .
the spatial spread of the sparks was reduced , but the temporal duration was unchanged , suggesting that fewer channels opened but the kinetics of opening and closing were the same .
the slower propagation velocity of spontaneous ca waves indicates a resistance to activation of adjacent ryr clusters by cytosolic ca in ca - pak1 cells . as well as a regulator of electrical activity and
ca handling in myocytes , pak1 is emerging as a potent modulator of cardiac contractility .
activation of pak1 appears likely to alter the sarcomeric response to ca by modification of phosphorylation of contractile proteins . the phosphorylation state of myofilament regulatory proteins such as ctni , cardiac tnt ( ctnt ) , myosin binding protein c
( mybp - c ) and tropomyosin are critical in regulation of contractility and are major determinants of myofilament ca sensitivity and cross - bridge cycling kinetics . in our previous study , we compared the phosphorylation levels of both ctni and mybp - c between the control and ca - pak1 myocytes .
measurement of ca tension relations in single myocytes demonstrated that this reduction in their phosphorylation was associated with the predicted increase in sensitivity to ca .
pak1 is emerging as a potent regulator of cardiac contractility not only through pp2a - mediated dephosphorylation of ctni and mybp - c but may also through modification of the cellular proteins that regulate ca fluxes .
as previously discussed , the potential targets for the pak1-pp2a signaling module in intracellular ca regulation include l type - ca channels , ryr and plb in control of sarcoplasmic reticulum ca - atpase ( serca ) activity .
the expression of pak1 as well as its isoforms pak2 and pak3 in cardiac tissues has been investigated in several species .
the protein level of pak1 is high in all regions of the heart such as the sino - atrial node ( san ) , atrial and ventricular tissue , whereas pak2 is expressed at low or modest levels in cardiac tissues , and there is little expression of pak3 in the heart . at the cellular level
, it is localized to z - disc , cell and nuclear membrane and intercalated disc of ventricular myocytes .
distinct subcellular distribution patterns have also revealed , for example , in guinea pig san cells , we found pak1 was evenly expressed in central nodal cells , whereas it demonstrated a clear striation patterns in peripheral nodal cells ( fig . 1 ) .
( a ) western blot detection of pak1 expression in san , left atrial ( la ) and ventricular tissues ( v ) .
pak1 expression pattern was examined by immunocytochemical staining in ( b ) adult rat cardiomyocyte ( green , anti - pak1 ; red , rhodamine - conjugated phalloidin ) , in ( c ) guinea pig senatorial node ( san ) cells ( adapted from refs . 3 and 4 ) . in cells pak1 activation
requires not only the gtpases ( cdc42 and rac ) , but also the tyr - kinase etk and the sh3 adaptor proteins such as pak - interacting exchange factor ( pix ) and non - catalytic region of tyrosine kinase adaptor protein ( nck ) , which directly interact with pak1 ( for detail , see parrini in this issue ) .
furthermore , pak1 is directly activated by a group of small molecules including c2/c6 ceramide and fty720 .
sphingosine also stimulates auto - phosphorylation of pak2 at the same sites as cdc42 and rac do .
however , it is still unclear whether sphingosine activates pak1 from the gtpase - binding domain or not .
early studies indicate that cdc42/rac and sphingosine share the same molecular mechanism in the activation of pak1 .
however , more recent studies indicate that these gtpases and sphingosine activate pak1 in a synergetic way .
pak1 can also be activated by some other signal transducers that have prominent functional effects in the heart .
for example , it was found that receptors coupled to the inhibitory g proteins gi , such as bradykinin and acetylcholine , were able to activate pak1 indirectly .
excellent evidence to support this comes from the observation that constitutively active pak1 and ligands stimulating these receptors produce the same cytoskeletal re - organization in mammalian cells .
interestingly , recent studies have indicated that pak1 is activated by a variety of growth factors such as egf and other extracellular factors such as angiotensin ii and isoproterenol ( iso ) .
these observations reflect the complexity of pak1 upstream signaling pathways that are still not well understood .
the potential role of pak1 in the regulation of ion channel activities was first demonstrated by us in isolated guinea pig san preparations and single san pacemaker cells . in san expressing the constitutively active ( ca ) pak1 , responses to iso stimulation manifested by the frequency of electrical impulse firing were significantly lower compared with those of controls .
we also characterized the beating rate of cultured san cells infected with adpak1 or the control adlacz . in the control san cells infected with adlacz , 5 nm iso increases the beating rate by 40 - 50% .
however , this iso - induced increase in beating rate is diminished , when they express the ca - pak1 , clearly indicating that pak1 antagonizes iso . whole cell patch
clamping demonstrated that both l - type ca current and the delayed rectifier k current had a repressed response to iso in cells expressing the ca - pak1 ( fig . 2 ) .
in the san cells , ca - pak1 redirects intracellular localization of protein phosphatase 2a ( pp2a ) .
a recent study further demonstrated pak1 regulation of connexion ( cx ) 43 phosphorylation in both isolated rabbit ventricular myocytes and hek cells expressing cx43 is likely through the pp2a activity .
( a and b ) representative l - type ca current recordings from cultured san cells infected with ad - lacz or ad - pak1 in the absence and presence of 100 nmol / l iso for 5 min
. currents were recorded during 200-ms step depolarizations from a holding potential of -50 mv to a range of potentials between -40 and + 50 mv .
( c and d ) current - voltage relationship of ical in cells infected with ad - lacz or ad - pak1 , in the absence and presence of iso ( adapted from ref .
4 ) . based on these results , we suggested that there is a dynamic balance between the kinase and the phosphatase activity in controlling l - type ca channel as well as delayed rectifier k channel activity in heart cells .
the balance between these kinase and phosphatase actions may be of importance in controlling cardiac pacemaker activity in response to autonomic and humoral stimulation .
the importance of this balance is highlighted by a recent report by vinogradova et al .
that a high basal pka - dependent phosphorylation in san pacemaker cells drives rhythmic internal ca store oscillations and spontaneous beating of these cells . alterations of pak1 activity may lead to the alteration of the dynamic regulatory processes and balance between kinase and phosphatase activity in cardiac cells and thus result in change in various ion channel activity .
it will be important to further investigate the regulatory role of pak1 on ion channels in the heart under physiological and pathological conditions .
a recent study by us also presented a novel evidence for the regulatory role of pak1 on ca handling in cardiac myocytes .
specifically , we examined the effects of constitutively active ( ca)-pak1 on [ ca]i transients and shortening of electrically stimulated ventricular myocytes under basal and -adrenergic - stimulated conditions ( fig . 3 ) .
under basal conditions , a change in the [ ca]i characteristics consisting of a significantly slower rate of ca decline in single adult rat ventricular myocytes expressing ca - pak1 than in control cells , concurrent with longer time for cellular re - lengthening .
there was no change in adpak1 cell sarcoplasmic reticulum ( sr ) ca content as assessed by caffeine , consistent with the lack of change in phospholamban ( plb ) phosphorylation .
this indicates ca - pak1 slows the intracellular ca decay rate independently of plb , although the exact mechanism remains to be determined .
there was also a significant reduction in the amplitude of spontaneous ca sparks in ca - pak1 compared with the control cells but no change in the frequency of occurrence .
they suggested that lower amplitude may be in part due to the slight decrease in sr .
line - scan images and whole cell - width line plots of fluo-4 fluorescence recorded parallel to the longitudinal axis of the cell from representative field - stimulated adult rat ventricular myocytes expressing lacz [ blue trace , ( a ) ] or ca - pak1 [ red trace , ( b ) ] under control conditions and during steady - state stimulation with 100 nm iso .
( c ) average intracellular ca concentration ( [ ca]i ) transient amplitudes in lacz ( 875 153 and 1,889 286 nm without and with iso , respectively ) and ca - pak1 ( 845 99 and1,299 138 nm without and with iso , respectively ) cells .
( d ) average time constant for [ ca]i transient decay ( decay ) for lacz ( 276 8 and 149 6 ms without and with iso , respectively ) and ca - pak1 ( 308 10 and 180 10 ms without and with iso , respectively ) cells .
values are means se * , statistically significant difference between lacz and ca - pak1 .
a significant blunting of iso induced increases in [ ca]i transient amplitude , sr ca content and cell shortening was observed in ca - pak1 myocytes .
propagation of spontaneous ca waves resulting from sr ca overload was significantly slower in ca - pak1 myocytes . thus pak1 activity may alter ryanodine receptor ( ryr ) 2 gating via dephosphorylation by pp2a , but a full characterization is required .
the level of plb phosphorylation at ser16 and thr17 was not significantly different between ca - pak1 and control myocytes , nor was cardiac troponin i ( ctni ) phosphorylation at ser significantly different .
alternatively , the lower spark amplitude in ca - pak1 myocytes may suggest that the ryr channel po may be lower , so that fewer ryrs are gating within a cluster .
the spatial spread of the sparks was reduced , but the temporal duration was unchanged , suggesting that fewer channels opened but the kinetics of opening and closing were the same .
the slower propagation velocity of spontaneous ca waves indicates a resistance to activation of adjacent ryr clusters by cytosolic ca in ca - pak1 cells .
as well as a regulator of electrical activity and ca handling in myocytes , pak1 is emerging as a potent modulator of cardiac contractility .
activation of pak1 appears likely to alter the sarcomeric response to ca by modification of phosphorylation of contractile proteins .
the phosphorylation state of myofilament regulatory proteins such as ctni , cardiac tnt ( ctnt ) , myosin binding protein c ( mybp - c ) and tropomyosin are critical in regulation of contractility and are major determinants of myofilament ca sensitivity and cross - bridge cycling kinetics . in our previous study
, we compared the phosphorylation levels of both ctni and mybp - c between the control and ca - pak1 myocytes .
measurement of ca tension relations in single myocytes demonstrated that this reduction in their phosphorylation was associated with the predicted increase in sensitivity to ca .
pak1 is emerging as a potent regulator of cardiac contractility not only through pp2a - mediated dephosphorylation of ctni and mybp - c but may also through modification of the cellular proteins that regulate ca fluxes .
as previously discussed , the potential targets for the pak1-pp2a signaling module in intracellular ca regulation include l type - ca channels , ryr and plb in control of sarcoplasmic reticulum ca - atpase ( serca ) activity .
hypertrophy is defined as proliferation - independent cardiomyocyte growth , which bears some similarity to tumor growth . in response to acute or chronic insults the heart initially undergoes hypertrophic growth as an adaptive response to normalize ventricular wall stress
; however , the capacity of this compensation is limited , prolonged application of deleterious stimuli eventually causes decompensated remodeling , such as chamber dilation , reduced contractile function , interstitial fibrosis and myocyte loss .
these maladaptive effects subsequently lead to heart failure , a devastating condition currently affecting millions people world - wide . since hypertrophy is generally regarded as a determinant of heart failure ; studies to discover molecular and cellular mechanisms underlying hypertrophic remodeling and to identify potential therapeutic approaches for treating heart failure are of paramount importance . to date , many oncogenes have been demonstrated to positively regulate cardiac hypertrophy .
similarly , aberrant activation of raf is a step in the development of many types of cancers .
moreover , transgenic mice with cardiac - specific expression of a dominant - negative ( dn ) form of raf-1 or cardiac - specific raf-1 knockout mice demonstrate resistance to stresses inducing cardiac hypertrophy . in line with these observations , a recent study by oceandy et al .
revealed that the tumor suppressor rassf1a ( ras - association domain family 1 isoform a ) inhibits pressure overload - induced hypertrophy in mice .
, patients with noonan or costello syndrome in which a number of mutations occur in genes of the ras signaling pathway develop both tumors and hypertrophic cardiomyopathy .
thus , above evidence indicates that the oncogenic signaling programs may be closely related to the programs that control the growth of post - mitotic adult cardiomyocytes .
thus , we predicted that pak1 , which is activated by ras and in turn activates raf and is responsible for the growth of more than 70% of human cancers , may exert a similar function to that of the ras - raf pathway in facilitating cardiac hypertrophy .
however , to our surprise , our recent study using primary cardiomyocytes and cardiomyocyte - specific pak1 knockouts ( pak1 ) revealed an anti - hypertrophic function of pak1 .
we found in cultured neonatal rat cardiomyocytes ( nrcms ) with overexpression of constitutively active pak1 attenuated phenylephrine - induced hypertrophic responses , whereas knockdown of pak1 in nrcm caused a greater hypertrophy after phenylephrine stimulation .
this anti - hypertrophic property of pak1 was further substantiated by the study of pak1 mice .
the pak1 mice manifested cardiac hypertrophy greater than controls with evident apoptosis following two weeks of pressure overload , and a rapid progression to heart failure after five weeks of load stress ( fig . 4 ) .
we found that pak1 activates another kinase called jnk ( c - jun n - terminal kinase ) which in turn phosphorylates and inactivates a transcription factor called nfat , which is essential for activation of the hypertrophic genes such as atrial natriuretic peptide ( anp ) , brain natriuretic peptide ( bnp ) .
thus , the loss of pak1 would lead to inactivation of this jnk signaling cascade and an enhancement of nfat ( fig .
application of fty720 ( a synthetic analog structurally similar to sphingosine ) induced pak1 activation and restrained the development of cardiac hypertrophy in pressure overload stressed - wild type mice , but not in pak1 mice , suggesting the anti - hypertrophic effect of fty720 was likely due to its function on activation of pak1 .
furthermore , a recent examination of pak1 global knockout mice revealed a similar phenotype as that in pak1 mice .
absence of pak1 in the whole heart rendered mice more capable of hypertrophic growth under a condition of iso stimulation .
overall , these data demonstrate that pak1 plays differing roles in promoting the malignant cell growth and in cardiac hypertrophy and pak1 activators , which could be oncogenic , may thus be potential therapeutics for the cardiac hypertrophy .
figure 4 . exacerbated cardiac hypertrophy in pak1 mice after 5 weeks transverse aortic constriction ( tac ) .
( a ) heart weight / tibia length ( hw / tl ) ratios of pak1 and pak1 mice ( upper panel ) .
morphometry demonstrates greater hypertrophy in pak1-tac mice ( lower panel , scale bar : 2 mm ) .
( b ) measurements of mean cross - sectional areas ( upper panel ) and hematoxylin and eosin staining of heart cross - sections ( lower panel , scale bar : 20 m ) ( adapted from ref .
, pak1 regulates activities of ion channels and myofilaments through pp2a activation . cardiac hypertrophy induced under pathological conditions
acute myocardial ischemia - reperfusion injury is the major pathophysiological manifestation of ischemic heart disease ( i.e. , coronary heart disease ) .
interestingly , the heart has ability to render itself resistant to ischemia / reperfusion injury , such phenomenon was first discovered by murry et al . to describe as ischemic preconditioning .
conditioning the heart to tolerate the effects of acute ischemia - reperfusion injury can be initiated through inducing brief non - lethal episodes of ischemia and reperfusion to the heart either prior to , during , or even after an episode of sustained lethal myocardial ischemia - a phenomenon termed ischemic preconditioning ( ipc ) , preconditioning or post - conditioning , respectively . to date , at least three different cardio - protective protein kinase programs have been proposed to be initiated by different g - protein coupled receptors including the adenosine , bradykinin , opioid , protease activated receptor 2 ( par2 ) and sphingosine-1-phosphate ( s1p ) receptors , etc .
the activation of these cell - surface receptors activates several intracellular signaling cascades including akt and erk1/2 components of the reperfusion injury salvage kinase ( risk ) pathways , which then activate downstream targets that terminate at the level of the mitochondria .
s1p has been shown to be an important mediator ( through s1p receptor signaling ) of cardiac ischemic pre- and post - conditioning in both pharmacological and knockout animal studies .
fty720 demonstrated a protective effect on preventing organ ischemia / reperfusion ( i / r ) injury in animal models . in our recent study
, we demonstrated that prevention of arrhythmias by fty720 in i / r model was attributed to the activation of pak1/akt .
fty720 is able to stimulate the auto - phosphorylation of both pak1 and akt and their kinase activities in cardiomyocytes .
akt is a well - established regulator of myocardial growth and survival , contractile function and coronary angiogenesis . using both gain- and loss - of - function approaches in vitro and in vivo , mao et al
the functional significance of this pak1-akt signaling is underscored by the observation that the pro - survival effect of pak1 is diminished by akt inhibition .
the pak1-conferred protection was blocked by the akt inhibitor x ( a selective akt phosphorylation inhibitor ) , suggesting that the protective effect of pak1 is mediated , at least in part , by akt signaling .
our more recent study also demonstrated that pak1 improves cardiac contractile function in the i / r model of pak1 global ko mice through regulation of troponin - t and myosin light chain 2 phosphorylation .
our further experiments on a mouse model of cardiac - specific deletion of pak1 demonstrate a crucial role of pak1 in cardiac protection against i / r injury .
the recognition of the functional significance of pak1 in preventing arrhythmogenesis associated with i / r injury may lead to the development of more potent therapeutics for treating i / r injury induced ventricular arrhythmias .
hypertrophy is defined as proliferation - independent cardiomyocyte growth , which bears some similarity to tumor growth . in response to acute or chronic insults the heart initially undergoes hypertrophic growth as an adaptive response to normalize ventricular wall stress
; however , the capacity of this compensation is limited , prolonged application of deleterious stimuli eventually causes decompensated remodeling , such as chamber dilation , reduced contractile function , interstitial fibrosis and myocyte loss .
these maladaptive effects subsequently lead to heart failure , a devastating condition currently affecting millions people world - wide . since hypertrophy is generally regarded as a determinant of heart failure ; studies to discover molecular and cellular mechanisms underlying hypertrophic remodeling and to identify potential therapeutic approaches for treating heart failure are of paramount importance . to date , many oncogenes have been demonstrated to positively regulate cardiac hypertrophy .
similarly , aberrant activation of raf is a step in the development of many types of cancers .
moreover , transgenic mice with cardiac - specific expression of a dominant - negative ( dn ) form of raf-1 or cardiac - specific raf-1 knockout mice demonstrate resistance to stresses inducing cardiac hypertrophy . in line with these observations , a recent study by oceandy et al .
revealed that the tumor suppressor rassf1a ( ras - association domain family 1 isoform a ) inhibits pressure overload - induced hypertrophy in mice .
, patients with noonan or costello syndrome in which a number of mutations occur in genes of the ras signaling pathway develop both tumors and hypertrophic cardiomyopathy .
thus , above evidence indicates that the oncogenic signaling programs may be closely related to the programs that control the growth of post - mitotic adult cardiomyocytes .
thus , we predicted that pak1 , which is activated by ras and in turn activates raf and is responsible for the growth of more than 70% of human cancers , may exert a similar function to that of the ras - raf pathway in facilitating cardiac hypertrophy .
however , to our surprise , our recent study using primary cardiomyocytes and cardiomyocyte - specific pak1 knockouts ( pak1 ) revealed an anti - hypertrophic function of pak1 .
we found in cultured neonatal rat cardiomyocytes ( nrcms ) with overexpression of constitutively active pak1 attenuated phenylephrine - induced hypertrophic responses , whereas knockdown of pak1 in nrcm caused a greater hypertrophy after phenylephrine stimulation .
this anti - hypertrophic property of pak1 was further substantiated by the study of pak1 mice .
the pak1 mice manifested cardiac hypertrophy greater than controls with evident apoptosis following two weeks of pressure overload , and a rapid progression to heart failure after five weeks of load stress ( fig . 4 ) .
we found that pak1 activates another kinase called jnk ( c - jun n - terminal kinase ) which in turn phosphorylates and inactivates a transcription factor called nfat , which is essential for activation of the hypertrophic genes such as atrial natriuretic peptide ( anp ) , brain natriuretic peptide ( bnp ) .
thus , the loss of pak1 would lead to inactivation of this jnk signaling cascade and an enhancement of nfat ( fig .
application of fty720 ( a synthetic analog structurally similar to sphingosine ) induced pak1 activation and restrained the development of cardiac hypertrophy in pressure overload stressed - wild type mice , but not in pak1 mice , suggesting the anti - hypertrophic effect of fty720 was likely due to its function on activation of pak1 .
furthermore , a recent examination of pak1 global knockout mice revealed a similar phenotype as that in pak1 mice .
absence of pak1 in the whole heart rendered mice more capable of hypertrophic growth under a condition of iso stimulation .
overall , these data demonstrate that pak1 plays differing roles in promoting the malignant cell growth and in cardiac hypertrophy and pak1 activators , which could be oncogenic , may thus be potential therapeutics for the cardiac hypertrophy .
figure 4 . exacerbated cardiac hypertrophy in pak1 mice after 5 weeks transverse aortic constriction ( tac ) .
( a ) heart weight / tibia length ( hw / tl ) ratios of pak1 and pak1 mice ( upper panel ) .
morphometry demonstrates greater hypertrophy in pak1-tac mice ( lower panel , scale bar : 2 mm ) .
( b ) measurements of mean cross - sectional areas ( upper panel ) and hematoxylin and eosin staining of heart cross - sections ( lower panel , scale bar : 20 m ) ( adapted from ref .
, pak1 regulates activities of ion channels and myofilaments through pp2a activation . cardiac hypertrophy induced under pathological conditions
acute myocardial ischemia - reperfusion injury is the major pathophysiological manifestation of ischemic heart disease ( i.e. , coronary heart disease ) .
interestingly , the heart has ability to render itself resistant to ischemia / reperfusion injury , such phenomenon was first discovered by murry et al . to describe as ischemic preconditioning .
conditioning the heart to tolerate the effects of acute ischemia - reperfusion injury can be initiated through inducing brief non - lethal episodes of ischemia and reperfusion to the heart either prior to , during , or even after an episode of sustained lethal myocardial ischemia - a phenomenon termed ischemic preconditioning ( ipc ) , preconditioning or post - conditioning , respectively . to date
, at least three different cardio - protective protein kinase programs have been proposed to be initiated by different g - protein coupled receptors including the adenosine , bradykinin , opioid , protease activated receptor 2 ( par2 ) and sphingosine-1-phosphate ( s1p ) receptors , etc .
the activation of these cell - surface receptors activates several intracellular signaling cascades including akt and erk1/2 components of the reperfusion injury salvage kinase ( risk ) pathways , which then activate downstream targets that terminate at the level of the mitochondria .
s1p has been shown to be an important mediator ( through s1p receptor signaling ) of cardiac ischemic pre- and post - conditioning in both pharmacological and knockout animal studies .
fty720 demonstrated a protective effect on preventing organ ischemia / reperfusion ( i / r ) injury in animal models . in our recent study
, we demonstrated that prevention of arrhythmias by fty720 in i / r model was attributed to the activation of pak1/akt .
fty720 is able to stimulate the auto - phosphorylation of both pak1 and akt and their kinase activities in cardiomyocytes .
akt is a well - established regulator of myocardial growth and survival , contractile function and coronary angiogenesis . using both gain- and loss - of - function approaches in vitro and in vivo , mao et al
the functional significance of this pak1-akt signaling is underscored by the observation that the pro - survival effect of pak1 is diminished by akt inhibition .
the pak1-conferred protection was blocked by the akt inhibitor x ( a selective akt phosphorylation inhibitor ) , suggesting that the protective effect of pak1 is mediated , at least in part , by akt signaling .
our more recent study also demonstrated that pak1 improves cardiac contractile function in the i / r model of pak1 global ko mice through regulation of troponin - t and myosin light chain 2 phosphorylation .
our further experiments on a mouse model of cardiac - specific deletion of pak1 demonstrate a crucial role of pak1 in cardiac protection against i / r injury .
the recognition of the functional significance of pak1 in preventing arrhythmogenesis associated with i / r injury may lead to the development of more potent therapeutics for treating i / r injury induced ventricular arrhythmias .
Output:
| our work and others over the past few years have led to the identification of new roles of pak1 in cardiac physiology , such as the regulation of cardiac ion channel and actomyosin function .
more recent studies have revealed that pak1-deficient mice were vulnerable to cardiac hypertrophy and readily progress to failure under sustained pressure overload and susceptible to ischemia / reperfusion injury .
our further study indicated that the pak1 activator fty720 was able to prevent this pressure overload - induced hypertrophy in wild - type mice without compromising their cardiac functions .
a cardiac protective effect against ischemia / reperfusion injury by fty720 was also observed in both rat and mouse models by us and others .
thus , these studies suggest that pak1 is more important in the heart than previously thought , in particular a therapeutic potential of pak1 activators . in the future , in - depth investigations are required to further substantiate our hypotheses on mechanisms for pak1 function in the heart and to explore a therapeutic potential of fty720 and other pak1 activators in heart disease conditions . |
PubmedSumm8812 | ***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: ankylosing spondylitis ( as ) is characterized by progressive ossification of the spinal column with resultant stiffness . as does not typically result in dysphagia as the syndesmophytes are marginal .
dysphagia in the elderly is more commonly associated with diffuse idiopathic skeletal hyperostosis ( dish ) .
we report the anaesthetic management of a patient with the unusual combination of a rigidly fused spine and focal exuberant anterior osteophytosis .
his past medical history was significant for as with previous anaesthetics notable for failed direct laryngoscopy and considerably difficulty with fibreoptic orotracheal intubation .
the patient 's presenting dysphagia was first evaluated by the ear nose and throat ( ent ) surgeon whose awake flexible fiberoptic nasoendoscopy revealed a significant bulging of the posterior pharyngeal wall into the airway at the level of the epiglottis . a plain x - ray and computed tomography scan of the spine demonstrated significant anterior cervical osteophytes from c3 to c5 with the largest osteophyte of size equivalent to the diameter of the vertebral body at level c3 and c4 [ figure 1a and b ] .
patient was referred to the spine surgery unit and he was scheduled to undergo removal of the exuberant anterior cervical osteophytes for symptomatic relief of his dysphagia .
the surgeons requested that an elective pre - operative tracheostomy be avoided , if possible as this would interfere with the planned surgical approach through an incision through the anterior triangle of the neck . in the pre - anaesthetic clinic , after careful evaluation and discussion with the patient , an awake fibreoptic intubation was planned .
( a ) pre - operative plain radiograph of the neck showing anterior cervical osteophytes at the level of the epiglottis , ( b ) pre - operative computerized tomogram showing the anterior cervical osteophyte at the level of the epiglottis with size equal to that of vertebral body after an appropriate period of fasting , patient was brought to the or with both the ent and spine surgery teams in attendance .
after standard monitoring was instituted , in the semi - sitting position ; airway topicalization with 2% lidocaine spray was attempted .
a right superior laryngeal nerve block and trans - tracheal injection were performed with 2 ml each of 2% lidocaine .
patient was placed supine , but as his head did not touch the mattress ( phantom pillow sign ) ; a stack of flannel in the configuration of a ramp was placed under his head , neck , and torso . a modified nasal trumpet ( mnt )
was prepared by inserting a 15 mm universal connector from a 7.0 mm i d tracheal tube into the flanged end of a 30fr nasal airway [ simulated in figure 2 ] .
oxygen ( 3 l / min ) was delivered through this airway using the anaesthetic breathing circuit and capnography confirmed a patent airway and adequate spontaneous breathing . into the other nares , the split nasopharyngeal airway ( snpa ) was inserted .
the snpa is a 32fr nasal airway , which had previously been cut spirally [ simulated in figure 2 ] .
a standard adult fibreoptic bronchoscope ( 5.5 mm ) was loaded with a size 7.0 mm i d reinforced tracheal tube ( lma fastrach tube , vitaid , toronto , canada ) .
the bronchoscope was introduced through the snpa and the large posterior pharyngeal wall bulge was evident . advancing and rotating the snpa caudad and posterior to the bony bulge was required to facilitate visualisation of the vocal cords , caudad and posterior to the bony bulge .
the vocal cords were sprayed with 2cc of 2% lidocaine and the bronchoscope passed into the trachea without resistance .
patient tolerated the procedure well and after confirmation of the appropriate position of the tracheal tube , anaesthesia was induced intravenously and then maintained with sevoflurane in an air - oxygen mixture using controlled ventilation .
simulation of the fibreoptic nasal intubation technique through split nasopharyngeal airway with a modified nasal trumpet in situ the surgeons performed a left - sided anterior neck approach to the cervical spine and then proceeded to dissect the pharynx off of the osteophytes .
after removal of the bony elements , the pharynx was once again evaluated to make sure there was no soft - tissue pathology .
all monitored parameters remained stable . at the end of surgery , the need for a definitive postoperative airway was discussed . the possibility of pharyngeal oedema and anticipated difficult airway due to the as were considered and
though leaving the trachea intubated was considered , it was decided that the patient would be best served by an elective tracheostomy .
after the oxygen delivery was reduced to fio2 of 0.3 , a tracheostomy was performed and the tracheal tube was removed .
he woke up breathing comfortably and was monitored in the post - anaesthetic care unit overnight .
the tracheostomy was decannulated on the 3 post - operative day and he was discharged on the 5 post - operative day . when followed - up 6 weeks later ,
he continued to be doing well - his dysphagia partially resolved and he was able to swallow semi - solid food .
as is a chronic , progressive autoimmune exonerative spondyloarthopathy that affects primarily the posterior articulations of the spine and adjacent tissues . as the cervical spine involvement progresses , the decreasing neck extension can progress to a
dish is a non - inflammatory enthesopathy causing ossification of the anterior and lateral elements of the spine .
interestingly , it is reported as a common cause of dysphagia and aspiration in elderly patients with good results from surgical excision of the osteophytosis . though there have been previous reports of patients with co - existent dish and as
the etiology of this patient 's focal osteophytosis is unclear although may be post - traumatic or the result of incomplete fusion of the motion segment [ figure 1a ] .
nevertheless , the dish - like presentation of this patient was taken into consideration in our airway management plan .
failure of videolaryngoscopy has been reported in dish , attributed to the disparity between size and angulation of the blade and the limited oro - pharyngeal space due to the cervical osteophytes .
our planned modified awake fibreoptic intubation and preference for the nasal route was based on these abnormalities and the radiological images .
nasotracheal intubation is useful in some anticipated difficult airways and shown to require ( and or produce ) less cervical spine movement .
nasal fibreoptic intubation has previously been recommended in patients with lesions of the cervical spine .
we believe that if only minimal movement of the neck is allowed ( or possible ) , the nasopharyngeal axis is better aligned with the laryngeal and tracheal axes . in our patient , this is evident from the radiological images [ figure 1a ] .
nasal bleeding is a concern with fibreoptic nasal intubation and it may either prevent fibreoptic view or contribute to airway obstruction .
we preferred to use the tracheal tube that is available with the lma fastrach because not only is this tube reinforced , its silicone tip is relatively soft and tends to hug the bronchoscope better .
we also used two nasopharyngeal airways - one to ensure delivery of adequate oxygen ( mnt ) and the other ( snpa ) to facilitate the fibreoptic intubation [ figure 2 ] .
the mnt allows for connection to the anaesthetic breathing circuit and thereby facilitating continuous capnographic monitoring of airway patency and breathing .
in addition , as required uninterrupted delivery of positive pressure ventilation and oro - pharyngeal suctioning can be performed while the fibreoptic intubation is being performed .
we suggest that the split be performed spirally as cutting it straight through tends to make the spna collapse in the nasopharynx .
if the spna is adequately prepared ( warm , soft , and lubricated with local anesthetic gel ) , it allows for nasal fiberoptic endoscopy to be performed with little distress to the awake patient .
most importantly , since the snpa can be peeled off the bronchoscope , nasotracheal intubation can be facilitated [ figure 2 ] .
when compared to direct nasal endoscopy , the snpa may require less anaesthetic depth and affords for the fibreoptic procedure to repeated atraumatically if required
. in our patient , the snpa additionally allowed us to navigate around the hard posterior pharyngeal bulge .
we believe the use of these two nasal airways improved the safety and success of the difficult airway in the current patient .
the role of tracheostomies in cervical spine surgery is controversial . while they may be necessary in some patients
, they may interfere with the surgical access to the spine and increase implant or surgical site infections .
airway management for the shared airway is often complicated by pre - operative abnormalities , intraoperative considerations and post - operative complications .
this patient 's case report serves to provide additional information on various aspects of airway management for cervical spine surgery .
the use of the modified nasal airways and an awake fibreoptic nasal intubation was useful in our patient and should be considered in other similar situations . in such patients with bony
hard anterior cervical osteophytes and a stiff spine from as , literally ; safe airway management may lie between a rock and a hard place .
Output:
| we report the perioperative course of a patient with long standing ankylosing spondylitis with severe dysphagia due to large anterior cervical syndesmophytes at the level of the epiglottis .
he was scheduled to undergo anterior cervical decompression and the surgical approach possibly precluded an elective pre - operative tracheostomy .
we performed a modified awake fibreoptic nasal intubation through a split nasopharyngeal airway while adequate oxygenation was ensured through a modified nasal trumpet inserted in the other nares .
we discuss the role of nasal intubations and the use of both the modified nasopharyngeal airways we used to facilitate tracheal intubation .
this modified nasal fibreoptic intubation technique could find the application in other patients with cervical spine abnormalities and in other anticipated difficult airways . |
PubmedSumm8813 | ***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 impact of coronary artery anomalies depends on the capability of anomalous arteries to provide adequate blood supply to the myocardium.[13 ] double left anterior descending coronary artery arising from the left and right coronary arteries is one of the rarest of coronary anomalies .
it is usually clinically silent but the recognition of this rare anomaly is important because it may mislead to wrong clinical diagnosis as well as surgical complications.[25 ] in this report , we present a case of double left anterior descending coronary artery with one originating from the left main stem and the second one originating from the same ostium with the right coronary artery , which is diagnosed with multislice computed tomography ( ct ) angiography .
a 36-year - old male patient was admitted to our hospital with the complaint of non - specific chest pain .
he had a history of smoking and hypertension , potential risk factors for coronary artery disease .
also his father at the age of 46 years had died suddenly with unclear etiology . at the time of the evaluation
the chest pain was not typical for angina pectoris but the patient was very nervous due to his family history .
for further evaluation an exercise test was required but this was not possible as the patient had recently undergone knee surgery for meniscopathy .
therefore , to evaluate chest pain and to detect or rule out coronary artery disease , the patient underwent computed tomography coronary angiography ( ctca ) .
ctca was performed using a 64 slice ct scanner ( siemens sensation 64 , germany ) .
scan parameters were as follows : slice collimation , 32 2 0.625 mm ; rotation time , 0.33 mins ; tube voltage , 120 kv ; tube current , 600 ma ; and pitch , 0.2 .
ct angiography was triggered automatically by the arrival of the contrast bolus ( automatic bolus tracking ) .
a prescan was taken at the level of the aortic root and a region of interest ( roi ) was placed on the ascending aorta .
as soon as the signal density level in the ascending aorta reached the predefined threshold of 120 hounsfield units ( hu ) , the scan started .
we injected 80 ml nonionic contrast medium ( iomeron 400/ml ; iomeprol , bracco , italy ) at a flow rate of 5 ml / s in the left antecubital vein .
this was followed by a 40 ml saline chaser bolus at a flow rate of 4 ml / s to wash out contrast from the right ventricle . during the scan ,
the reconstruction interval for the coronary arteries with the fewest motion artifacts was determined ( images at 75% of the r - r interval ) and used for further analysis . for reconstruction of axial images , we used a slice thickness of 0.75 mm and a slice width of 0.5 mm . a medium soft - tissue reconstruction kernel ( b30f ) was used for reconstruction . for post - processing ,
in addition to the transverse source images , multiplanar reformations ( mprs ) , curved mpr images , maximum intensity projections ( mips ) , and volume rendered ( vr ) images were utilized for the evaluation . vr reconstructions depicted the vascular anatomy well and
coronary cta demonstrated an anomalous left anterior descending artery ( lad ) arising from the same ostium with the right coronary artery , which coursed downwardly along the interventricular sulcus , and another lad arising from the left main coronary artery , which spread to the anterior wall of the left ventricle toward the left ventricular apex [ figures 1 and 2 ] . the right coronary artery ( rca ) and the left circumflex artery ( lcx ) were normal . there were no significant coronary stenoses or occlusions
however , the anomalous lad was coursing between right ventricular outflow tract and aorta which should be considered to be critical because of the potential to provoke myocardial ischemia or even sudden cardiac death [ figure 3 ] .
these ctca findings were consistent with double lad , with one vessel arising from the ostium of right coronary artery and the second one arising from the left main coronary artery .
the 3-dimensional ( 3d ) volume rendered image demonstrates both of the left anterior descending arteries ( lad ) , one originating from the left main coronary artery and the second anomalous one from the right side and spreading to the anterior wall of the left ventricle toward the left ventricular apex .
the segmented 3d image demonstrates both the left anterior descending arteries ( lad ) , their origin and course .
the curved multiplanar reformatted ( mpr ) image demonstrates the interarterial course of anomalous left anterior descending artery ( lad ) originating from the right side and passing between aorta and right ventricular outflow tract ( rvot ) .
the incidence of congenital coronary artery anomalies ranges from 0.6% to 1.3% in most of the reported series .
some of these are of clinical interest because they can cause ischemic complications or even sudden death.[13 ] however , other coronary artery anomalies do not cause symptoms and their detection during coronary angiography is an incidental finding .
double lad originating from both the right coronary and the left main coronary artery is an extremely rare congenital coronary artery anomaly with an angiographic prevalence ranging from 0.01 to 0.03% in the published studies.[37 ] according to the origin and anatomical course from the left and right coronary arteries spindola franco et al . ,
types i , ii , and iii have a similar pattern ; all of them arise separately from the proximal part of the left anterior descending artery and/or are divided into two left coronary arteries .
type iv is defined as the presence of two separate lads , a short lad arising from the left main coronary artery and a long lad arising from the right coronary artery or right sinus of valsalva . according to this classification ,
identification of the presence of a double left anterior descending artery is important both for diagnostic and therapeutic reasons.[36 ] conventional coronary angiography is still considered as the gold standard for the diagnosis of coronary artery disease .
however , detection of coronary artery anomalies is frequently difficult with conventional coronary angiography because of the lack of 3d information which is necessary to locate the origins and courses of the coronary arteries.[35 ] consequently , it is often difficult to differentiate total occlusion of the medial or distal portion of the lad from this anomaly during routine coronary angiography .
this lack of 3d orientation becomes even more important when the anomalous vessel courses between the aorta and the right ventricular outflow tract because this condition may provoke myocardial ischemia and sudden death and this information can be missed with conventional angiography.[1357 ] recognition of coronary artery anomalies prior to coronary artery by - pass surgery is of great importance .
the cardiac surgeon must be aware of the abnormal anatomy inorder to avoid accidental ligation or transection at the time of surgery.[36 ] multidetector row ct allows 3d comprehension of the coronary artery system and it is extremely useful to identify congenital coronary artery anomalies , regarding both their origins , courses and also relationships with other cardiac structures.[37 ] in our patient , ct angiography provided direct visualization of the dual lad distribution of the type iv variant of spindola - franco and colleagues classification in which first lad originated from the left main , and the second lad originated from the same ostium with the rca .
in addition , the interarterial course of the second lad arising from the right side was also clearly depicted .
in conclusion , we present a very rare coronary artery anomaly , called double lad type iv , detected during ct coronary angiography . recognition of this anomaly is important because it may lead to misinterpretation of coronary angiograms and severe intraoperative complications during coronary artery by - pass surgery such as incorrect placement of an arteriotomy , inadvertent cutting or ligation of the aberrant vessel during operation .
Output:
| double left anterior descending coronary artery arising from the left and right coronary arteries is one of the rarest of coronary anomalies . in this report , we present a case of double left anterior descending coronary artery with one originating from the left main stem and the second one originating from the same ostium with the right coronary artery , passing to the left side following an inter - arterial course between aorta and right ventricular outflow tract and spreading to the anterior wall of the left ventricle .
the diagnosis was made with multislice computed tomography angiography . to our knowledge ,
only a few such cases have been published in the literature so far . |
PubmedSumm8814 | ***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 scourge of cardiovascular diseases ( cvds ) is the most prevalent cause of death . according to national commission on macroeconomics and health ( ncmh ) , a government of india undertaking
, there would be around 62 million patients with coronary artery disease ( cad ) by 2015 in india and of these , 23 million would be patients younger than 40 years of age .
cad is due to atherosclerosis of large- and medium - sized arteries , and dyslipidemia has been found to be one of the most important contributing factors [ national cholesterol education program , the adult treatment panel iii ( ncep , atp iii ) ] . during the past three decades , dyslipidemia as a risk factor for cvd has increased markedly in india .
currently available hypolipidemic drugs ( statins ) have been associated with a number of side effects .
patients on treatment with crystalline niacin or extended - release niacin showed significant elevation in alt and risk of hepatotoxicity is much greater with slow - release niacin .
increases in plasma creatinine from 15% to 20% are common in fibrate - treated patients and more significant increases can occur in patients with underlying renal disease .
research interest has focused on various herbs that possess hypolipidemic effect that may be helpful adjunct in reducing the risks of cvd .
it has been used for centuries with claimed efficacy and safety in treatment of jaundice , liver disorders and various skin disorders .
it consists picrorrhiza kurroa ( kutki ) , terminalia chebula ( haritaki ) , terminalia bellerica ( bibhitaka ) , emblica officinalis ( amalaki ) , asphaltum ( silajatu ) , commiphora wightii ( guggulu ) , ricinus communis ( eranda ) , azadirachta indica ( neem leaves ) and metal including suddh rasa ( detoxified mercury ) , gandhaka suddha ( detoxified sulfur ) , lauha - bhasma ( iron ) , abhraka bhasma ( mica ) , tamra bhasma ( copper ) .
the findings of the study showed that arogyavardhini vati in the doses equivalent to 10 times of the human dose , administered to rats for 28 days , do not have appreciable toxicological effects on brain , liver , and kidney .
endothelial dysfunction plays a vital role in triggering ischemic events in the development of cvd .
c - reactive protein ( crp ) , an acute phase protein , has been clinically used as a sensitive marker for systemic inflammation .
therapies have been developed to lower hs - crp concentrations and reduce the potential risk factor for cvds .
there are plethora of clinical and experimental studies showing that antioxidants such as vitamin e have been shown to reduce the oxidative susceptibility of lipoproteins and may have anti - atherosclerotic effects . in hypercholesterolemic animal models ,
epidemiologic studies also indicate an inverse association between the intake of vitamin e and coronary heart disease .
hence , considering the antioxidant , anti - inflammatory and hypolipidemic property , the present study was designed to study the effect of arogyavardhini vati in triton wr-1339-induced hyperlipidemia in rats .
male wistar rats ( 150 - 200 g ) were used in the present study .
the animals were obtained from the central animal facility , all india institute of medical sciences , new delhi and stock bred in the departmental animal house .
the rats were group - housed in polyacrylic cages ( 38 23 10 cm ) with not more than four animals per cage and maintained under standard laboratory conditions with natural dark and light cycle .
they were allowed free access to standard dry diet ( ashirwad , punjab , india ) and tap water ad - libitum .
all experimental procedures described were reviewed and approved by the institutional animal ethics committee , all india institute of medical sciences , new delhi india ( 497/iaec/09 ) .
arogyavardhini vati was purchased from the gmp certified company ( maharshi ayurveda pharmaceutical limited , new delhi , india ) .
triton wr-1339 was purchased from sigma - aldrcih ( st . louis , mo , usa ) and dissolved in dmso .
the first group was given standard pellet diet , water and administered intraperitoneal injection of 4% dmso .
the second hyperlipidemic group received triton wr-1339 dissolved in 4% dmso ( 400 mg / kg body weight ) .
after 72 h of triton injection , this group received a daily dose of 4% dmso ( p.o . ) for 7 days .
third group was administered with the standard fenofibrate ( 65 mg / kg , p.o . ) for 7 days . the fourth , fifth , and sixth group was administered daily doses of arogyavrdhini vati ( 50 , 100 , 200 mg / kg , p.o . ) for 7 days , after inducing hyperlipidemia .
human equivalent rat dose of 500 , 1000 , and 2000 mg will be 50 , 100 , and 200 mg / kg ( human to rat dose conversion factor is 6 and average human body weight is 60 kg ) . the doses of arogyavardhini vati ( 50 , 100 , 200 mg / kg ) in rat was calculated by extrapolating the equivalent human dose ( therapeutic dose , sub - maximum , and maximum dose ) and was administered orally between 10 and 11 a.m. daily for 7 days , in a volume not exceeding 1 ml/100 g rat weight .
after 12 h of treatment , animals were anesthetized with diethyl ether and blood was withdrawn from retro - orbital sinus .
the blood samples were immediately centrifuged ( 3000 rpm for 10 min ) and serum was used to estimate the levels of total cholesterol , triglyceride , ldl , and hdl using semi - auto analyzer ( mini techno , newark , de 19711 , usa ) according to the instruction of manufacturer of assay kits ( logitech india pvt .
the level of serum crp was estimated by elisa , according to the instruction of manufacturer of assay kits ( life diagnostics inc .
, mill valley , ca 94941 , usa ; catalog number : 2210 - 21-hr ) .
cardiac risk was determined by estimating its atherogenic index ( ai = tc / hdl - c ) as stated by malaspina .
animals were euthanized and liver was removed to determine the levels of mda and gsh .
malondialdehyde , an indicator of lipid peroxidation was determined by the method of ohkawa et al .
glutathione was measured according to the method of ellman and concentration was expressed as mg / g - wet tissue .
a one - way analysis of variance ( anova ) , followed by tukey 's test was used for statistical analysis .
spss ( version 16 ) statistical software was used for the analysis of data and p < 0.05 was taken as the level of significance .
male wistar rats ( 150 - 200 g ) were used in the present study .
the animals were obtained from the central animal facility , all india institute of medical sciences , new delhi and stock bred in the departmental animal house .
the rats were group - housed in polyacrylic cages ( 38 23 10 cm ) with not more than four animals per cage and maintained under standard laboratory conditions with natural dark and light cycle .
they were allowed free access to standard dry diet ( ashirwad , punjab , india ) and tap water ad - libitum .
all experimental procedures described were reviewed and approved by the institutional animal ethics committee , all india institute of medical sciences , new delhi india ( 497/iaec/09 ) .
arogyavardhini vati was purchased from the gmp certified company ( maharshi ayurveda pharmaceutical limited , new delhi , india ) .
triton wr-1339 was purchased from sigma - aldrcih ( st . louis , mo , usa ) and dissolved in dmso .
the first group was given standard pellet diet , water and administered intraperitoneal injection of 4% dmso .
the second hyperlipidemic group received triton wr-1339 dissolved in 4% dmso ( 400 mg / kg body weight ) .
after 72 h of triton injection , this group received a daily dose of 4% dmso ( p.o . ) for 7 days .
third group was administered with the standard fenofibrate ( 65 mg / kg , p.o . ) for 7 days . the fourth ,
fifth , and sixth group was administered daily doses of arogyavrdhini vati ( 50 , 100 , 200 mg / kg , p.o . ) for 7 days , after inducing hyperlipidemia .
human equivalent rat dose of 500 , 1000 , and 2000 mg will be 50 , 100 , and 200 mg / kg ( human to rat dose conversion factor is 6 and average human body weight is 60 kg ) .
the doses of arogyavardhini vati ( 50 , 100 , 200 mg / kg ) in rat was calculated by extrapolating the equivalent human dose ( therapeutic dose , sub - maximum , and maximum dose ) and was administered orally between 10 and 11 a.m. daily for 7 days , in a volume not exceeding 1 ml/100 g rat weight .
after 12 h of treatment , animals were anesthetized with diethyl ether and blood was withdrawn from retro - orbital sinus .
the blood samples were immediately centrifuged ( 3000 rpm for 10 min ) and serum was used to estimate the levels of total cholesterol , triglyceride , ldl , and hdl using semi - auto analyzer ( mini techno , newark , de 19711 , usa ) according to the instruction of manufacturer of assay kits ( logitech india pvt . ltd . ,
the level of serum crp was estimated by elisa , according to the instruction of manufacturer of assay kits ( life diagnostics inc .
, mill valley , ca 94941 , usa ; catalog number : 2210 - 21-hr ) .
cardiac risk was determined by estimating its atherogenic index ( ai = tc / hdl - c ) as stated by malaspina .
animals were euthanized and liver was removed to determine the levels of mda and gsh .
malondialdehyde , an indicator of lipid peroxidation was determined by the method of ohkawa et al .
glutathione was measured according to the method of ellman and concentration was expressed as mg / g - wet tissue .
a one - way analysis of variance ( anova ) , followed by tukey 's test was used for statistical analysis .
spss ( version 16 ) statistical software was used for the analysis of data and p < 0.05 was taken as the level of significance .
the serum total cholesterol , triglycerides , ldl , and hdl levels were measured in normal and triton wr-1339-induced rats [ table 1 ] .
there was significant increase in serum total cholesterol , triglycerides , and ldl levels and decreased hdl levels in triton - induced hyperlipidemic rats .
administration of arogyavardhini vati at doses of 50 , 100 , 200 mg / kg and standard drug fenofibrate ( 65 mg / kg ) significantly decreased serum total cholesterol , triglycerides , and ldl , and increased hdl when compared with triton - induced hyperlipidemic rats ( p < 0.001 ) . there were no statistically significant differences in the level of serum total cholesterol , triglycerides , ldl , and hdl in fenofibrate - treated rats as well as normal control rats .
effect of arogyavardhini vati on serum lipid profiles and c - reactive protein in the rats crp level was increased in triton - treated rats .
fenofibrate ( 65 mg / kg ) treated rats showed significant decrease in crp levels when compared with triton - treated rats ; however levels were raised when compared with normal control .
there was no significant change in the level of crp at low dose of arogyavardhini vati ( 50 mg / kg ) when compared with triton- treated rats .
however , significant decrease in the level of crp was observed at higher doses ( 100 and 200 mg / kg ) of arogyavardhini vati ( p < 0.001 ) .
there was no statistical significant difference in the level of crp at maximum dose of arogyavardhini vati ( 200 mg / kg ) when compared with fenofibrate - treated rats [ table 1 ] .
there was significant decrease in liver mda and increased gsh level observed at all doses of arogyavardhini vati ( 50 , 100 , 200 mg / kg ) and fenofibrate ( 65 mg / kg ) treated rats when compared with triton - treated rats ( p < 0.001 ) . a significant increased mda and decreased gsh levels in liver of triton - treated rats ( p < 0.001 ) was observed when compared with normal control .
there was significant decrease in mda and increased gsh was observed in a dose - dependent manner [ table 2 ] .
effect of arogyavardhini vati on liver oxidative stress marker ( mda and reduced glutathione levels ) in the rats treatment with arogyavardhini vati ( 50 , 100 , 200 mg / kg ) in triton wr-1339-induced dyslipidemic rats significantly decreased ai level in a dose - dependent manner when compared with triton - treated rats ( p < 0.001 ) .
there was no statistically significant change in the level of ai in fenofibrate ( 65 mg / kg ) treated rats and maximum dose of arogyavardhini vati ( 200 mg / kg ) treated rats when compared with normal control [ figure 1 ] .
values are expressed as mean sem , n = 6 , p < 0.001 , a when compared with normal control ; b when compared with triton - treated group , c when compared with fenofibrate - treated group
the serum total cholesterol , triglycerides , ldl , and hdl levels were measured in normal and triton wr-1339-induced rats [ table 1 ] .
there was significant increase in serum total cholesterol , triglycerides , and ldl levels and decreased hdl levels in triton - induced hyperlipidemic rats .
administration of arogyavardhini vati at doses of 50 , 100 , 200 mg / kg and standard drug fenofibrate ( 65 mg / kg ) significantly decreased serum total cholesterol , triglycerides , and ldl , and increased hdl when compared with triton - induced hyperlipidemic rats ( p < 0.001 ) . there were no statistically significant differences in the level of serum total cholesterol , triglycerides , ldl , and hdl in fenofibrate - treated rats as well as normal control rats .
effect of arogyavardhini vati on serum lipid profiles and c - reactive protein in the rats
fenofibrate ( 65 mg / kg ) treated rats showed significant decrease in crp levels when compared with triton - treated rats ; however levels were raised when compared with normal control .
there was no significant change in the level of crp at low dose of arogyavardhini vati ( 50 mg / kg ) when compared with triton- treated rats .
however , significant decrease in the level of crp was observed at higher doses ( 100 and 200 mg / kg ) of arogyavardhini vati ( p < 0.001 ) . there was no statistical significant difference in the level of crp at maximum dose of arogyavardhini vati ( 200 mg / kg ) when compared with fenofibrate - treated rats [ table 1 ] .
there was significant decrease in liver mda and increased gsh level observed at all doses of arogyavardhini vati ( 50 , 100 , 200 mg / kg ) and fenofibrate ( 65 mg / kg ) treated rats when compared with triton - treated rats ( p < 0.001 ) . a significant increased mda and decreased gsh levels in liver of triton - treated rats ( p < 0.001 ) was observed when compared with normal control .
there was significant decrease in mda and increased gsh was observed in a dose - dependent manner [ table 2 ] .
effect of arogyavardhini vati on liver oxidative stress marker ( mda and reduced glutathione levels ) in the rats
treatment with arogyavardhini vati ( 50 , 100 , 200 mg / kg ) in triton wr-1339-induced dyslipidemic rats significantly decreased ai level in a dose - dependent manner when compared with triton - treated rats ( p < 0.001 ) .
there was no statistically significant change in the level of ai in fenofibrate ( 65 mg / kg ) treated rats and maximum dose of arogyavardhini vati ( 200 mg / kg ) treated rats when compared with normal control [ figure 1 ] .
values are expressed as mean sem , n = 6 , p < 0.001 , a when compared with normal control ; b when compared with triton - treated group , c when compared with fenofibrate - treated group
atherosclerotic cad is one of the major causes of premature death globally and it is expected to be the most important cause of mortality in india .
there are several lines of evidence with respect to the fact that hdl cholesterol is inversely related to total body cholesterol and a reduction of plasma hdl cholesterol concentration may accelerate the development of atheroscelerosis leading to ischemic heart diseases , by impairing the clearing of cholesterol from the arterial wall .
there is plethora of studies which has investigated the plants for their acute hypolipidemic activity in triton wr-1339-induced hyperlipidemic animals .
triton wr-1339 injection results increase in plasma cholesterol and triglycerides due to increase in vldl secretion by the liver accompanied by a strong reduction of vldl - c and ldl - c catabolism .
fenofibrate ( 65 mg / kg ) treated group was taken as positive control because it is effective in hypertriglyceridemia and hypercholesterolemia .
it has been well established that nutritional supplements such as herbal medicinal products , vitamin e , etc .
our present study clearly shows that arogyavardhini vati significantly lowered serum total cholesterol , triglycerides , and ldl levels , and increased hdl in a dose - dependent manner ( 50 , 100 , 200 mg / kg ) [ table 1 ] . the treatment with arogyavardhini vati also reduced the ai which is an important and sensitive indicator to determine the cardiac risk [ figure 1 ] .
there are several components of arogyavardhini vati which are known to have hypolipidemic effects , i.e. , picrorrhiza kurroa , terminalia chebula , terminalia bellerica , emblica officinalis , and guggulu . the mechanisms by which arogyavardhini vati exerted the beneficial effects is presently not clear .
ellagitannins and the ellagic acid obtained on hydrolysis of these tannins ( by lipases and/or esterases ) are inhibitors of squalene epoxidase , a rate - limiting enzyme of cholesterol biosynthesis .
inflammation is known to reduce hdl and the enhancement of hdl observed in the present study may arise from the control of inflammation by arogyavardhini vati . the serum crp level which is a marker of systemic infection was significantly reduced at the end of the treatment in our study which are also reported in literature . therefore , it is likely that a reduction in serum lipid levels observed in the present study by arogyvardhini vati may be mediated through above mechanisms .
lipid peroxidation is the most commonly used parameters for assessing oxidative damage in the human body . in this process ldl - c and other lipid containing molecules may be oxidized in the blood stream , exerting adverse effects on a variety of processes like inhibiting antithrombin iii activity , producing procoagulant activity , enhancing platelet aggregation , modulating vascular responses , and acting as mitogen .
the formation and activation of atherosclerotic lesion is a multi - faceted process involving many determinants , including oxidative modification of ldl .
oxidized ldl causes foam cell formation , leukocyte adhesion to the endothelium , cytotoxicity , and vascular endothelial dysfunction leading to impaired edno synthesis and biological activity . in the present study , arogyavardhini vati administration caused a significant reduction of liver mda and increased gsh level [ table 2 ] .
lowering of oxidative stress with concomitant lowering of cholesterol indicated that there was reduced oxidative stress after administration of arogyavardhini vati in a dose - dependent manner .
the results of present study indicate antiatherosclerotic roles of arogyavardhini vati which can indirect effect due to enhanced lipid metabolism by liver .
this study showed that the liver antioxidants induced by arogyavardhini vati may have protective effect against ldl oxidation , thereby preventing or slowing the events leading to the initiation of atherosclerosis .
the observation made from this study showed that arogyavardhini vati possesses a stronger antioxidant potential .
arogyavardhini vati may be a useful therapy for hypercholesterolemia through reducing oxidative stress ( decreasing mda and increasing gsh ) and lipid levels ( decreasing serum total cholesterol , triglyceride , ldl levels and increasing serum hdl level ) .
the results of the present animal study pave the path to conduct clinical study and arogyavarhdini vati was found to be safe and efficacious in dyslipidemia patients .
Output:
| background : hyperlipidemia is a major risk factor of coronary heart disease .
currently available hypolipidemic drugs have been associated with number of side effects .
arogyavardhini vati , an ayurvedic polyherbal formulation has been used for liver disorders .
therefore , present study was designed to evaluate the effect of arogyavardhini vati in triton wr-1339-induced hyperlipidemia in rats.objectives:anti-hyperlipidemic activity evaluation of arogyavardhini vati against triton wr-1339-induced hyperlipidemia in rats.materials and methods : overnight fasted male wistar rats ( 150 - 200 g ) were randomly divided into normal control group [ 4% dimethyl sulfoxide ( dmso ) , i.p . ] , positive control group ( triton wr-1339 in 4% dmso , 400 mg / kg , i.p . ) , standard drug treated ( fenofibrate 65 mg / kg , p.o . for 7 days after inducing hyperlipidemia ) and arogyavardhini vati treated ( 50 , 100 , 200 mg / kg , p.o . for 7 days after inducing hyperlipidemia ) .
rat doses were calculated by extrapolating the equivalent human dose ( therapeutic dose , sub - maximum , and maximum dose ) .
serum total cholesterol , triglyceride , low - density lipoprotein ( ldl ) , high - density lipoprotein hdl , liver malondialdehyde ( mda ) , and glutathione ( gsh ) levels were estimated at end of experiments.results:arogyavardhini vati significantly decreased serum cholesterol , triglyceride , ldl , and c - reactive protein ( crp ) and significantly increased serum hdl in a dose - dependent manner . decreased mda and increased gsh levels in liver were observed at all doses of arogyavardhini vati ( 50 , 100 , 200 mg / kg ) and fenofibrate - treated groups when compared with triton - treated group .
atherogenic index ( ai ) level was significantly decreased in fenofibrate and arogyavardhini vati ( 200 mg / kg ) treated rats when compared with normal control.conclusion:arogyavardhini vati , a traditionally used ayurvedic medicine may be a useful therapy for hypercholesterolemia through reducing oxidative stress ( decreasing mda and increasing gsh ) and lipid levels . |
PubmedSumm8815 | ***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: prosthetic joint infections ( pji ) are a serious complication associated with total knee replacement ( tka).1 fungal pji is a rare occurrence with few cases reported.123456 phelan et al . reported the first case of candidal pji in 1979.3
candida albicans is the most commonly isolated fungus.3 to the best of our knowledge , this is the first fungal pji reported from india , with candida tropicalis being the causative organism .
a 62 year old hypertensive non diabetic female presented with pain , swelling in the left knee and difficulty in walking in the left knee for the last 6 weeks .
a 15 cm vertical midline surgical scar healed by primary intention of the initial tka was present on anterior aspect of knee .
radiologically , there was osteolysis over the anterior femoral cortex , posterior femoral condyles and under the tibial base plate [ figure 1 ] .
complete hematological study and urine microscopy revealed no significant abnormality besides elevated erythrocyte sedimentation rate ( esr ) ( 75 mm at 1 hour ) and c - reactive protein ( crp ) ( 84 mg / l ) .
anteroposterior ( a ) and lateral radiographs ( b ) of knee joint showing osteolysis around femoral and tibial components .
tka was done 2 years ago knee joint aspiration was carried out under sterile conditions .
characteristics of the aspirate were 5 ml fluid , cloudy with low viscosity , white blood cell count was 15,000/cubic mm , with 68% polymorphonuclear leucocytes .
gram staining was negative , but 10% koh mount , done to rule out fungal infection as a standard hospital protocol , was positive suggesting a fungal infection . a decision to perform 1 stage of revision tka
was taken after consultation with the patient and her family . in consultation with infectious disease specialist
there was turbid synovial fluid , granulation tissue , implant loosening and adherent cement synovial fluid and tissue was sent for culture and sensitivity studies .
implant removal , debridement and antibiotic ( vancomycin ) plus antifungal ( amphotericin b ) impregnated cement spacer insertion was done [ figure 2 ] .
medical therapy included intravenous fluconazole 400 mg od for 6 weeks followed by oral fluconazole 400 mg bd for 12 weeks .
sabouraud dextrose agar and the rapid api 20 microtube system were used for identification of species .
peroperative clinical photographs showing first stage of revision total knee replacement , after implant ( a ) removal and cement spacer inserted ( b ) anteroposterior radiograph of the knee joint showing cement spacer patient was followed up at weekly intervals and after 20 weeks , the esr ( 23 mm at 1 hour ) and crp ( 6.3
postoperative period was uneventful and patient was discharged on oral fluconazole 400 mg bd for 10 weeks .
peroperative clinical photograph showing second stage of revision total knee replacement with final implants the surgical wound healed adequately and after physiotherapy , a painless range of motion of 10 - 90 with a stable knee was obtained .
patient maintained status quo until last followup 24 months after 2 stage of revision surgery [ figure 5 ] .
anteroposterior ( a ) and lateral ( b ) photographs of knee joint at 24 months followup showing implant in situ
fungal pji is known to occur in patients who are immunocompromised , have a underlying systemic illness or prolonged use of antibiotics.12345 despite this almost half the cases occur in patients without any identifiable risk factor.3 our patient had no identifiable risk factor .
c.albicans is the most common cause for fungal pji reported in english literature.12345678910 most of the reported cases , do not have systemic fungal disease.4 wu and hsu reported a patient with preoperative cutaneous candidiasis who developed candidal pji.10 no primary source of candidal infection was identified in our case .
there is very minimal probability of being implanted during the primary surgery ( the primary tka was over 2 years and symptoms are 6 weeks old ) .
late infections probably are hematogenous ; however , a definitive answer can not be given .
debridement with successful retention of the implants and suppressive antifungal therapy has been reported.4678 in few initial reports , surgeons performed debridement and resection arthroplasty alone , but this led to poor functional outcomes.3 delayed reimplantation offers the best chance to a successful functional outcome.123 we followed the same principle and performed a two stage revision arthroplasty .
one in vitro study on fungal biofilm has shown c.albicans producing quantitatively more biofilm than candida parapsilosis , candida glabrata and c. tropicalis .
these films have rapidly developed resistance to fluconazole.11 the optimal time to reimplantation has been debated.3 hwang et al .
have performed reimplantation at an average of 9.5 weeks.1 it has been recommended that in cases of pji with unusual or virulent organisms , the period between resection and reimplantation should be prolonged.3 after keeping patient on an extended course of antifungal therapy in consultation with infectious disease specialist , we performed a delayed reimplantation at 20 weeks .
we ensured that the esr , crp was normalized ; repeat aspiration was negative prior to reimplantation surgery .
amphotericin b is the gold standard , but is nephrotoxic and may not be useful for long term administration.310 fluconazole has demonstrated fewer side effects and can be used long term in patients .
successful treatment with fluconazole as the sole antifungal agent has been reported.367 a high bio - availability , extended half - life , absence of serious side effect and high concentration in joint fluid make fluconazole an excellent choice.10 our choice was fluconazole for the above mentioned reasons .
we followed the recommendations of infectious disease society of america and gave fluconazole in a combination of parenteral and oral formulation for a total period of 30 weeks [ table 1].123710 the cement spacer was loaded with amphotericin b , based on previous literature , for local action , but we do not have any analysis of the elution rate or the concentration it achieved in the joint . at present , there is no consensus on the type , dose or efficacy of antifungal used in cement spacers.12310 further research is required in this area . to conclude based on our experience and review of literature ,
we say that fungal pji , though rare , is a serious complication and is more difficult to manage than bacterial pji .
resection arthroplasty with antifungal therapy followed by delayed reimplantation offers the best possible result . despite this , further modalities of treatment including options during 1 stage of revision tka , the choice and total duration of antifungal therapy and time of reimplantation should be explored .
Output:
| fungal prosthetic joint infection after total knee arthroplasty ( tka ) is a rare complication .
lacunae exist in the management of this complication .
62 year old lady presented with pain and swelling in left knee and was diagnosed as candida tropicalis fungal infection after tka .
she underwent debridement , resection arthroplasty and antifungal plus antibiotic loaded cement spacer insertion , antifungal therapy with fluconazole followed by delayed revision tka and further fluconazole therapy .
total duration of fluconazole therapy was 30 weeks . at 2 year followup
, she has pain less range of motion of 10-90 and there is no evidence of recurrence of infection . |
PubmedSumm8816 | ***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: neonatal sepsis is a frequent complication of very low birth weight ( vlbw ) infants and it is an important cause of neonatal morbidity and mortality [ 1 , 2 ] .
vlbw infants develop 2.7 times more sepsis than other infants since their immune system and skin barrier are immature and they are exposed to many invasive diagnostic and therapeutic procedures .
morbidity and mortality in a neonatal intensive care unit ( nicu ) can be reduced by knowledge of the epidemiology of the microbiology , infection rate profile and antibiotic sensitivity , and by introducing practices that are based on clinical evidence [ 4 , 5 ] .
special attention must be given to infection by pseudomonas aeruginosa due to a high mortality rate .
the aim of this study is to identify the risk factors involved in the mortality caused by sepsis of a vlbw infants population with sepsis , in particular , the role of pseudomonas aeruginosa , a very aggressive pathogen .
the infants were hospitalized in the nicu of a high - risk maternity in a tertiary - level public hospital specialized in caring for highly complex patients .
secondary objectives are to determine the frequency and distribution of the pathogens that cause infection and to describe the characteristics of this population .
all vlbw infants were born at the maternity of servidores do estado hospital ( she ) , rio de janeiro , rj , brazil and admitted in the nicu of the same hospital , just after birth , between 1 april , 2001 and 30 september , 2004 meeting the following criteria : birth weight ( bw ) < 1500 g , clinical evidence of systemic infection and positive blood culture result for bacterium or yeast on one or more blood cultures obtained at any time while infants were inpatients in the nicu .
infants died of nonsepsis causes , with lethal congenital malformations and chromosomal abnormalities were excluded . this retrospective cohort study collected data from the medical records of the selected vlbw infants using an investigation protocol .
relevant informations included antenatal and intrapartum history : gestational age ( ga ) based on the date of the last menstruation , uterus fundus measurement , and ultrasonography performed until 12 weeks of ga ; time elapsed between rupture of membranes and birth ; mode of birth ; apgar score at the first , fifth , and tenth minute of life ; gender ; bw ; bw and ga relationship according to usher and mclean 's growth curves .
events related to infection episodes : incidence of sepsis , defined by the presence of clinical signs and symptoms as apnea , gastrointestinal problems , increased need for oxygen or ventilatory support , and lethargy / hypotonic , and by one or more positive blood cultures for bacterium or yeast obtained at any time during the infant 's stay at the nicu .
any organism , including coagulase - negative staphylococcus ( cons ) was considered the caused agent of sepsis and not a contaminant if the criteria of the vermont oxford network database were present : clinical signs of sepsis , positive blood culture for cons , and intravenous antibacterial therapy for at least five days after obtaining blood culture or until death , in case it occurs within five days after obtaining blood culture .
whenever cons and another pathogen were identified in the same blood culture , only the other pathogen was recorded in the database , cons was considered contaminant and this agent was discharged ; age at the time of onset of sepsis considered to be the day on which the first blood culture for the event was positive : early - onset sepsis ( eos ) defined as infection occurring before or at 72 hours of life and late - onset sepsis ( los ) , after 72 hours of life ; organisms cultured and associated with death from sepsis ; neonatal comorbidities : perinatal asphyxia defined as the presence of five - minute apgar score below six and signs of encephalopathy as lethargy / stupor , hypotonia , and abnormal reflexes ; respiratory distress syndrome ( rds ) defined as the need for oxigenotherapy , clinical features of rds , and ventilation support and abnormal thorax radiograph in the first 24 hours of life ; necrotizing enterocolitis ( nec ) classified according to the system of bell et al . ; temperature instability , defined as temperature < 36.5c or > 37.5c or a variation of > 1c in a period of 24 hours and blood changes such as neutropenia , defined by a neutrophil count < 1.5 10/l and thrombocytopenia , defined as a platelet count < 80 10/l .
therapeutic interventions : use and length of use of intravascular catheter , defined as a peripherally inserted central catheter or by a vascular dissection and arterial or venous umbilical catheter , inserted before the onset of sepsis ; use and length of use of mechanical ventilation and of total parenteral nutrition ( tpn ) ; time when enteral feeding was initiated and length of stay in the nicu .
clinical outcome : neonatal death was considered related to infection when clinical signs and symptoms of sepsis evolved to signs and symptoms of irreversible septic shock as systemic hypotension , acidemia , anuria , and hypoxia ; and/or signs and symptoms of irreversible disseminated intravascular coagulation syndrome as thrombocytopenia , major bleeding episodes as pulmonary hemorrhage , and , ultimately , progressing to death .
bivariate analysis was used to evaluate the association between potential risk factors and sepsis - related mortality . for statistical inference
, the proportions were compared with the chi - square test ( ) or with fisher 's exact test with yates correction when the expected value in any cell of a 2 2 table is < 5 .
p - value of .05 or less was considered significant . the cut - off for continuous data
the cut - off was determined for the value with the highest accuracy from the area of the roc curve , it means , to the highest area under the roc curve .
the odd ratios ( ors ) were calculated with confidence intervals of 95% ( ci95 ) for each risk factor .
a stepwise backward unconditional multivariate logistic regression was performed to control for confounding and to assess the independence of the identified risk factors .
all variables with a p - value of .05 or less on bivariate analysis were included in the initial model .
the final model included the statistically significant variables in unconditional logistic regression analyzed by p - value of the test walds .
statistical analysis was performed using the software epi info version 3.3.2 , spss version 12 , and epi data version 3.1 .
between 1 april , 2001 and 30 september , 2004 , 203 vlbw infants were admitted to the nicu of seh , rj . during their stay in the nicu , 71/203 ( 35% ) had one or more episodes of sepsis . for most vlbw infants , 61/71 ( 86% ) , sepsis onset occurred after 72 hours of life .
most of the vlbw infants , 55/71 ( 77.5% ) had one episode ; 11/71 ( 15.5% ) two ; 4/71 ( 5.6% ) three ; 1/71 ( 1.4% ) four , totalling 87 episodes .
a great number of the infected neonates , 30/71 ( 42.3% ) were bw 1000 g , classified as extreme low birth weight ( elbw ) infants .
the mean vlbw infant 's age for all sepsis events was 12.9 ( 12.1 ) days , being 9.8 ( 9.3 ) for the first and 26 ( 15.6 ) for the second episode .
the majority of infection events , either eos or los , were due to gram - positive organisms , 52/87 ( 59.8% ) .
cons was the most common pathogen of all events ( 31/87 ; 35.5% ) and among gram - positive events ( 31/52 ; 59.6% ) .
p. aeruginosa was the most common gram - negative pathogen ( 8/87 ; 9.1% ) , followed by klebsiella sp . and
acinetobacter sp . yeasts were found in 6/87 ( 6.9% ) episodes and candida albicans was always the causing pathogen .
the continuous data are presented as means and standard deviations and the categorical data are presented as percentages ( table 2 ) .
overall 21 of the 71 vlbw infants with sepsis ( 29.6% ) died , being 2/10 ( 20% ) from eos , and 19/61 ( 32.7% ) from los .
there were significant differences in death rates from sepsis , depending on the organisms isolated from the last positive culture ( table 3 ) .
episodes of sepsis with gram - negative organisms were more likely to result in death than episodes with gram - positive or fungus ( 13/29 ; 44.8% versus 7/52 ; 13.4% versus 1/6 ; 16.7% ; p < .05 ) . within this high - risk group ,
vlbw infants with p. aeruginosa sepsis were most likely to die ( 6/8 ; 75% of infants with p. aeruginosa infections died ; p < .05 ) .
elbw infants ( bw 1000 g ) were significantly more likely to die than those with bw > 1000 g ( 17/30 ; 56.7% versus 4/41 ; 9.7% ; p < .05 ) .
the mean ga , bw , and five - minute apgar score of vlbw infants who died were lower than that of those who survived ( 29.4 versus 32 weeks ; 875 versus 1130 g ; 7.4 versus 8.4 ; p < .05 each one ) .
vlbw infants submitted to intravascular catheter and mechanical ventilation were significantly more likely to die than those not submitted to these procedures ( 19/47 ; 40.4% versus 2/24 ; 8.3% ; and 19/42 ; 45.26% versus 2/29 ; 6.9% ; p
< .05 each one ) . enteral feeding onset before or at 72 hours of life and length of stay were highly significant predictors of survival ( p < .05 ) .
the bivariate analysis is shown in table 4 . the predictive model based on a stepwise
backward unconditional multivariate logistic regression for 71 vlbw infants showed that bw independently contributed most to the dependent variable death , with a cut - off point of 1000 g. bw 1000 g infants presented a sepsis - related mortality rate 9.6 times higher than bw > 1000 g infants ( p < .05 ) .
the use of mechanical ventilation presented a clinically significant risk ( sepsis - related mortality rate 6.7 times higher ) but the statistical significance was marginal ( p = .05 ) .
length of stay was statistically significant with a negative coefficient , that is , the risk of death from sepsis decreased as length of stay increased ( p < .05 ) .
in our four - year cohort , sepsis was frequent , 35% , with the highest risk of occurrence in the first two weeks of stay .
even thought was caused mainly by gram - positive organisms , represented by cons , the mortality was higher when caused by gram - negative organisms , particularly p. aeruginosa .
neonatal sepsis - related mortality rate was high , 29.6% , in most cases involving elbw infants , 56.7% , and due to gram - negative organisms , 44.8% , especially p. aeruginosa , 75% .
the number of vlbw infants studied was low , however , representative of the whole population of neonates with bw < 1500 g assisted in a nicu of a reference center for high - risk pregnant women , during the selected period .
being a retrospective study , there was a lack of comprehensive information about risk factors .
for this reason , the possible risk factors of sepsis - related mortality were reported under chart review and included characteristics of the vlbw infants population and events related to infection episodes .
this finding differs from the reports of stoll et al . and rnnestad et al .
that , in the recent years , there was a change in the profile of the pathogens causing eos in nicu , with increase of gram - negative organisms , especially escherichia coli .
the incidence of eos due to group b streptococcus ( gbs ) was low , a single episode , probably because , in most cases the evaluated vlbw infants were product of the interruption of a high - risk pregnancy by caesarian section with ruptured of amniotic membranes at birth . according to hickman et al .
, these two factors contribute to the decrease of the vertical transmission of gbs and the lowest occurrence of eos due to this agent , as in our study .
there was a predominance of gram - positive organisms in los , 48.2% , mainly cons , 27.5% .
costa et al . in portugal , khashu in canada , sarkar et al .
in the united state of america , and richards et al . in colombia reported similar findings , what demonstrates that these organisms are prevalent agents of los in different countries and continents .
p. aeruginosa was the most frequent agent of los , 9.1% , among gram - negative organisms .
in contrast to our findings , afroza and trotman and bell reported k. pneumoniae as the most usual infectious agent among gram - negative organisms in los .
the reason for the high incidence of p. aeruginosa in our population must be object of future studies .
the sepsis - related mortality rate of vlbw infants was high , 29.6% , when compared to the rates reported in the literature , 17.3% to 21% [ 5 , 6 , 17 ] .
vlbw infants with gram - negative sepsis were at the greatest risk of death , 44.8% .
p. aeruginosa was the most aggressive agent of sepsis , responsible for the highest sepsis - related mortality rate , 75% , as reported by studies of gordon and isaacs .
bw 1000 g was identified by logistic regression as the strongest independent sepsis - related mortality predictor .
elbw infants , a great vulnerable population to neonatal complications , presented the highest sepsis - related mortality rate , 56.6% .
afroza related that , among many risk factors for infection , the single most important factor is low birth weight , as we observed .
this finding suggests that efforts to reduce neonatal sepsis - related mortality must be turned especially to this population .
the use of mechanical ventilation was identified by logistic regression as a strong independent sepsis - related mortality predictor , which is in agreement with flidel - rimon et al . and stoll et al .
this may be caused by the fact that neonates who need ventilation are the sickest patients , but also may be in part related to preventable ventilator - associated infection .
enteral feeding initiated before or at 72 hours of life was a predictor of survival .
our findings suggest the practice of early onset of feeding , and of the discerning indication and maintenance of invasive procedures directed to the treatment of vlbw infants to control sepsis - related mortality in this population . in summary ,
sepsis - related mortality is very high in low birth weight infants , mainly in extreme low birth infants .
attention to the control of prematurity , knowledge of the neonatal flora and antibiotic sensitivity profile , introduction of early nutritional support with early onset enteral feeding and efforts to decrease ventilator related events may play a role in decreasing the mortality and morbidity of this very serious disease .
Output:
| the aim of this study
is to identify risk factors for sepsis - related
mortality in low birth weight
( < 1500 g ) infants .
we performed
retrospective cohort study to investigate risk
factors for sepsis - related mortality in all
neonates birth weight < 1500 g
admitted to level iii neonatal intensive care
unit , brazil , april 2001/september 2004 .
of the
203 cases , 71 ( 35% ) had sepsis . of those ,
gram - positive was identified in 52/87 blood
cultures ( 59.8% ) , the most common
coagulase - negative
staphylococcus ( 31/87 ; 35.5% ) .
gram - negative was present in 29 of the 87
positive blood cultures ( 33.3% ) , with
pseudomonas aeruginosa ( 8/87 ;
9.1% ) , the most frequent agent .
overall 21
of 71 infants with sepsis ( 29.6% ) died .
risk
factors for sepsis - related mortality were
gestational age 28 weeks , birth weight
1000 g ( 9.6 times more often
than birth weight > 1000 g ) ,
five - minute apgar 7 , gram - negative
sepsis , mechanical ventilation ( 6.7 times higher
than no use ) , and intravascular catheter .
sepsis - related mortality was due , mainly , to
pseudomonas aeruginosa ; birth
weight 1000 g and mechanical
ventilation were strong sepsis - related mortality
predictors . |
PubmedSumm8817 | ***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 term chronic periaortitis refers to a spectrum of idiopathic diseases characterized by a fibroinflammatory reaction that extends from the adventitia of the abdominal aorta and the common iliac arteries into the retroperitoneum .
this often leads to the encasement of the adjacent structure , e.g. ureters or inferior vena cava .
idiopathic retroperitoneal fibrosis , inflammatory abdominal aortic aneurysms and perianeurysmal retroperitoneal fibrosis are its various clinical presentations.1)2 ) it is most often diagnosed by a periaortic enhancement based on imaging studies , owing to the difficulty of using an aortic wall biopsy .
the patient , a 73-year - old man , was admitted with abdominal pain and general ache for 3 months .
eight years ago , a coronary angiogram at another medical center , because of chest pain , showed normal coronary arteries .
three years ago , he started to complain of an intermittent dull pain from the upper abdomen to the chest . a year ago
, he visited another medical center with acute chest pain where he was diagnosed as acute aortic dissection , debakey type i , at that time .
a follow - up chest ct showed an aggravated descending aortic hematoma and bilateral hydronephrosis . on admission day , his vital signs were stable ; blood pressure was 110/68 mm hg , heart rate 65 beats per minute , body temperature 36.5. physical examination revealed no abnormal findings .
the initial laboratory findings showed an elevated level of inflammatory markers ; erythrocyte sedimentation rate ( esr ) 100 mm / hr ( normal range 0 - 10 mm / h ) , c - reactive protein ( crp ) 4.19 mg / dl ( normal range < 0.5 mg / dl ) and ferritin 837.5 ng / ml ( normal range 30 - 400 ng / ml ) .
the serum creatinine was 1.82 mg / dl but the urinalysis did not showed overt proteinuria , probably caused by post - renal obstruction .
the immunoglobulin g ( igg ) level was borderline high , 1627 mg / dl ( normal range : 700 - 1600 mg / dl ) and the igg subtype iv accounted for approximately 4.4% , 0.73
autoantibodies , such as antinuclear antibody , antineutrophil cytoplasmic autoantibody and rheumatoid factor were negative .
complement three ( c3 ) and four ( c4 ) levels were also between normal range , 138.7/38.6 mg / dl ( normal range 90 - 180 mg / dl , 10 - 40 mg / dl ) .
the 2d - echocardiography showed normal systolic function and normal sized left ventricle without regional abnormality .
the follow - up ct scan showed aggravated abdominal aortic intramural hematoma but also bilateral ureteral obstruction related to retroperitoneal fibrosis . for bilateral hydronephrosis due to ureteral obstruction
1 ) . the serum creatinine level had not risen since , but it was also not normalized and remained around 1.8 mg / dl .
after consultation with the physician who conducted the chest surgery , we continued medical therapy for chronic abdominal aortic intramural hematoma . because of the chronic recurrent disease course and ct finding , we considered the diagnosis of chronic periaortitis with retroperitoneal fibrosis .
chronic periaortitis may present as dull , poorly localized pain , nonspecific systemic illness , raised inflammatory markers and renal impairment due to ureteric obstruction.3 - 5 ) positron emission tomography ( pet)-ct showed an increased standardized uptake values level in not only the aortic arch , descending thoracic aorta and major branch ( maximum 4.3 ) , but also the abdominal aorta ( maximum 5.2 ) and common iliac artery ( maximum 5.3 ) ( fig .
2 ) . on review of the biopsy specimen achieved from previous surgery on the ascending aorta ,
the hematoxylin - eosin stain showed a consistent infiltration of lympho - plasma cells without granuloma formation in the media of the aortic wall ( fig .
3 ) . in immunochemistry staining , positive findings were revealed at cd20 , cd3 , lambda and kappa stain . with the diagnosis of chronic aortitis with retroperitoneal fibrosis complicated to bilateral hydronephrosis , we consulted rheumatology , and high - dose steroid therapy ( 1 mg / kg prednisolone ) and azathioprine ( 50 mg t.i.d ) medication were started .
several days later , his complaints including weakness and abdominal pain improved and laboratory findings demonstrated improving results ( esr 39 mm / hr , crp 0.09 mg / dl , serum creatinine 1.37 mg / dl ) .
he was discharged and re - visited our institution 2 weeks later for follow up .
he complained of weakness and follow up laboratory findings showed extensive elevation of inflammatory markers ; esr 107 mm / hr , crp 39.28 mg / hr . on that very day , he died a sudden death .
however , subsequent studies have suggested that chronic periaortitis is a systemic immune - mediated or inflammatory process.6 ) this is a rare disease with protean manifestations but , if correctly diagnosed , can be successfully managed .
early diagnosis may be important in reducing the mortality.3)4 ) clinical features of chronic periaortitis is usually related to the mechanical effects of the retroperitoneal fibrosis on the adjacent structures , such as back or abdominal pain , ureteral colic - like pain , deep vein thrombosis , claudication , and testicular pain .
however it also presents with constitutional symptoms , such as fatigue , weight loss and anorexia , probably reflecting the systemic inflammatory nature of the disease .
laboratory investigations are useful but not diagnostic.5)7)8 ) the pathologic changes in chronic periaortitis involve both the aortic wall and the surrounding soft tissues . the inflammatory infiltrate
mainly consists of mononuclear cells , such as lymphocytes , plasma cells and macrophages and scattered eosinophils , which predominate at the media - adventitia junction and extend throughout the adventitia.6)8 ) immunoglobulin g4-related lymphoplasmacytic aortitis is characterized by the enhanced tissue migration of igg4-positive lymphocytes accompanied by an increase in serum igg4 levels although this case did not fit that description.9)10 ) diagnosis should start by excluding possible primary causes of retroperitoneal fibrosis and is made by means of imaging studies .
ct and mri are the choice modalities for not only the diagnosis but also follow - up .
iino et al.11 ) have reported a sensitivity of 83.3% , a specificity of 99.7% and an accuracy of 93.7% for the diagnosis of in flammatory abdominal aortic aneurysms using ct.3 ) pet with 18f - fluorodeoxyglucose ( fdg ) is emerging as a useful functional imaging modality for assessing disease activity . in the early stages of the disease , there is a strikingly higher periaortic uptake of fdg , which disappears after successful medical therapy.12 ) this is a rare case which was confirmed as tissue diagnosis , not only an imaging diagnosis with ct finding .
recent retrospective analysis has found that the combination of steroids and azathioprine as effective as and safer than steroids plus cyclophosphamide .
steroid , alone or in combination with surgery , is usually effective , but prospective randomized trials are required to establish the best treatment approach.3)4)13 ) suspicion of chronic periaortitis is mostly important to treatment of these patients and careful follow - up is essential because of its chronic - relapsing clinical course .
Output:
| a 73-year - old man with a history of hypertension and ascending aortic dissection was hospitalized for aggravated abdominal pain and general ache for 3 months .
follow - up ct showed aggravated abdominal aortic hematoma with aneurysm , atherosclerotic periaortitis and bilateral hydronephrosis .
an initial laboratory finding showed elevated levels of inflammatory markers and renal dysfunction .
positron emission tomography - ct showed an increased standardized uptake values level in the aortic arch , descending thoracic aorta , major branch , abdominal aorta , and common iliac artery . for bilateral hydronephrosis
, a double j catheter insertion was performed .
tissue specimens obtained from previous surgery on the aorta indicated the infiltration of lympho - plasma cells without granuloma formation in the aortic wall . after a combined therapy of high dose steroid therapy with azathioprine , the patient 's initial complaints of abdominal pain , weakness and azotemia improved .
this case was diagnosed as chronic periaortitis based on aortic inflammation at biopsy , which was complicated with retroperitoneal fibrosis and ureteric obstruction . |
PubmedSumm8818 | ***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: skeletal muscle injury may result from toxin injection , crushing , freezing , and mechanical disruption induced by forceful stretches of muscle fibers .
skeletal muscle fiber damage may also result from intense , unaccustomed , extreme ( i.e. , ultra - endurance events such as marathon running , triathlon , etc . ) and/or eccentric types of exercises that are characterized by forceful lengthening contractions during which muscle fibers are overstretched.1 according to the model of proske and allen,2 within stretched fibers , some sarcomeres may be more resilient than others resulting in greater absorption of the stretch by the weaker sarcomeres which , depending on the magnitude of the stretch , become more vulnerable as the overlap between myosin and actin filaments is minimized toward the end of the stretch . following numerous eccentric stretches , more and more of the weaker sarcomeres are gradually overstretched , and
as fiber stretching continues , the more resilient sarcomeres become overstretched . since myofilaments of these sarcomeres may not return to their original overlapping state during the relaxation phase of the muscle , a mechanical disruption of these sarcomeres develops which is eventually transmitted to neighboring areas in muscle vicinity resulting in subcellular damage , that is , a collapse of membrane surrounding the sarcoplasmic reticulum , transverse tubules , and the muscle fibers themselves .
this series of events compromises the process of excitation contraction coupling in damaged sarcomeres and results in the release of calcium ions from sarcoplasmic reticulum into the cytoplasm where they stimulate proteolytic enzymes that promote further muscle fiber degradation.1,2 during this first phase , aseptic exercise - induced muscle damage ( eimd ) leads to the onset of an inflammatory response associated with the activation of leukocytes , muscle edema , deterioration of muscle function , delayed - onset of muscle soreness ( doms ) , increased release of muscle proteins into the interstitial space , and circulation and a rise in muscle temperature.3 even after an extensive injury , skeletal muscle demonstrates an extraordinary ability for healing .
consequently , a regeneration or healing phase follows the first inflammatory phase.4 muscle regeneration is related to the activation of a set of mononucleated cells , known as satellite cells , which subsequently proliferate , differentiate , and enter the damaged myofibers to synthesize new fibers or contribute to the healing of other fibers with a less severe damage.5 this phase is characterized by a marked rise of muscle protein synthesis.4 the inflammatory and the regeneration phases are operationally interconnected , and the disturbance of the former may hamper the later.6 evidence suggests that suppression of the inflammatory phase may lead to an attenuated overcompensation or healing during the regeneration phase.7 the scope of the present article is to review the first inflammatory phase and disclose important implications for exercise training and overall athletic performance .
finally , the third part presents the changes in skeletal muscle performance during the inflammatory response and discusses important implications for sports performance .
eimd is associated with muscle soreness or discomfort and a marked decline of muscle strength during the first 1272 h postexercise depending on the magnitude of the muscle - damaging exercise , and as stated earlier , it is related to the disruption of subcellular structures.8 although this phenomenon was described as early as the first part of the 20th century,9,10 the mechanisms underlying eimd are not entirely understood . despite that isometric ( static work , length of the muscle remains unchanged ) and concentric ( length of the muscle decreases )
muscle contractions are able to elevate skeletal muscle damage markers , the vast majority of published studies support the notion that eccentric work is primarily associated with eimd.1,3,4,8 eccentric ( lengthening ) work , either in their isolated form on an isokinetic dynamometer or as a part of the stretch - shortening cycle during downhill running , is used experimentally to study eimd . in fact , eccentric eimd is thought to be the basis for the increase of skeletal muscle mass ( hypertrophy ) seen with exercise training , especially resistance exercise training , suggesting that muscle micro - trauma induced by mechanical stress of acute exercise is a prerequisite for its subsequent growth during the adaptation phase.11,12 moreover , givli12 suggested that eimd may also be utilized to develop safer and more effective training and recovery protocols based on a personalized approach .
study of eimd aids to understand the mechanisms governing muscle degeneration and regeneration , so that findings may be extrapolated to various clinical conditions that demonstrate deviations in these mechanisms such as in dystrophies , inflammaging , cancer , and so on . for example , muscular dystrophies are characterized by extensive skeletal muscle degeneration due to the lack of dystrophin , calcium toxicity , free radical generation , activation of proteolytic enzymes , degradation of muscle proteins , and finally loss of muscle function and patient s physical independence.13 understanding the molecular mechanisms linking muscle damage with inflammatory cascade and proteolysis using the eimd model to induce mechanical strain to the cytoskeleton of the muscle could help toward the development of potential treatments for the clinical symptoms associated with this disease.14,15 during the last few years , a number of pharmacological agents and/or nutritional supplements have been tested in this direction using the eimd model.1618 rheumatoid arthritis ( ra ) represents another example .
ra demonstrates an intense inflammatory response through the production of the inflammatory cytokines at the site of the disease ( i.e. , joints ) affecting distant tissues and play a significant role in skeletal muscle wasting.19 furthermore , oxidative stress is frequently reported in patients with ra since cells present in inflamed joints ( e.g. , macrophages , neutrophils , and lymphocytes ) have the ability to produce free radicals.20 therefore , finding ways to manipulate the inflammatory responses and modulate the redox response following eimd could give insights on cellular mechanisms leading to muscle cachexia and how to confront clinical conditions like ra and potentially others .
doms and strength loss during eimd were originally attributed to subcellular disruption of skeletal muscle fibers.10,12 this notion was further supported by the indirect evidence of increased concentration of muscle proteins into the circulation in response to eimd , suggesting a potential leakage of intracellular content due to damage of muscle fiber membrane.12,21,22 this theory was further supported by marked sarcomeric distortions ( e.g. , z - line streaming ) identified by electron microscopy following eimd in both human and animal studies12,23,24 or infiltration of extracellular dyes into the muscle in animal studies.16,25 damage of muscle fiber membrane also causes influx of extracellular substances ( e.g. , albumin and fibronectin).12,26,27 increased membrane permeability has been linked to the stimulation of sodium and calcium channels in response to repetitive stretching of muscle fibers by lengthening contractions.28,29 nevertheless , a large variation exists in the manifestations of the magnitude of eimd induced by eccentric exercise protocols ranging from extensive local or systemic inflammatory responses and myofiber trauma7,12,30 to less pronounced injury in humans31 probably due to large variations in muscles tested as well as exercise protocols used .
moreover , protocols using electrical stimulation on animals to simulate eccentric contractions , although useful to study molecular mechanisms underlying eimd , may not be physiologically relevant to that produced by humans.32 electron microscopy revealed that eimd is characterized by extensive fiber necrosis , z - line streaming at sarcomere level for as long as 13 days following eccentric exercise depending on the magnitude of the exercise stimulus,12,23,24,30,33 and deterioration of a significant structural ( e.g. , desmin and dystrophin ) and myofibrillar proteins ( e.g. , myosin ) , suggesting an increased rate of degradation.32,3436 necrotic parts of injured myofibers appear histochemically as inflated and orbicular.37 although others argue that eccentric exercise does not cause necrosis,38 myofiber necrosis may be accompanied by macrophage infiltration , especially at the perimysium and endomesium , through toll - like receptors indicating an abrupt mobilization of the immune system during the first hours postexercise.30,39,40 interestingly , damaged myofibers also demonstrate the aggregation of satellite cell - derived myoblasts.30,38,4143 these findings suggest that doms and strength loss are primarily related to this disruption of contractile and structural proteins located in sarcomeres .
yu et al44 suggested that these structural deformations of muscle fibers do not indicate muscle damage but rather a regeneration process suggestive of an adaptation at cellular level .
animal models seem to demonstrate a greater rate of subcellular derangement than human models.44,45 muscles of the upper limbs seem to be more susceptible to eimd probably due to their smaller muscle mass and utilization in daily activities.46,47 extracellular matrix , mainly connective tissue , is affected by eimd as well .
muscle fibers are mechanically connected with extracellular matrix through a complex organization of membrane - bound proteins ( i.e. , integrins , dystroglycans , and proteoglycans ) that enable mechanical transmission among muscle fibers and fascicles.48 histological data indicate that eimd widens parts of the perimysium and endomysium with connective tissue dissociated from muscle fibers into a more expanded interstitium.27 these findings are coupled with others showing increased and prolonged collagen turnover indicative of a remodeling of extracellular matrix in response to its damage by exercise.49,50 however , extracellular matrix contains not only collagen fibers but also endothelial and pericyte cells , immune cells , stromal cells such as fibroblasts , nerve cells , and satellite cells that all combine to produce a physiological response , that is , muscle contraction .
it is uncertain how all these cells are affected by eimd and whether their potential damage or remodeling affects skeletal muscle fiber homeostasis .
for example , intramuscular mechanical pressure during eimd is transferred through the extracellular matrix inducing an early release of growth factors from fibroblasts that result in the activation of adjacent satellite cell populations via selective intracellular signaling pathways which may promote muscle healing.51,52 vascular cells such as pericytes are also involved in eimd by activating nuclear factor - kappa b ( nf-b ) signaling which is implicated in immune cell mobilization and satellite cell proliferation.7,53,54 however , it must be mentioned that nf-b pathway mediates the upregulation of the activity of the ubiquitin proteosome system ( ups ) by proinflammatory cytokines ( i.e. , tumor necrosis factor - alpha [ tnf- ] and interleukin-6 [ il-6 ] ) thereby contributing to protein degradation of skeletal muscle proteins and overall eimd.55 it is unclear whether the activation of ups contributes or exacerbates eimd or it represents a protective mechanism that clears damaged protein molecules and as such accelerates the inflammatory cascade and the subsequent healing .
the involvement of the nf-b ups pathway in eimd constitutes a valuable experimental model to study skeletal muscle atrophy in conditions such as sepsis and cachexia induced by cancer and other clinical conditions .
therefore , it seems that extracellular matrix may be actively involved during eimd and may affect muscle fiber healing , a perspective that needs to be addressed by future investigations .
as mentioned earlier , eimd is associated with prolonged deterioration of muscle strength , doms , edema , increased temperature , and leakage of muscle proteins into the circulation.56,57 prolonged ( 114 days ) muscle strength reduction ( 10%70% ) is considered as one of the most valid markers of eimd since among all markers they exhibit the highest correlation with histological evidence of muscle disruption.8,56,58,59 recovery kinetics of muscle strength depend on genetics , the type of exercise , muscle group(s ) involved , intensity , volume , and novelty of exercise.28 strength loss is attributed to the so - called half - sarcomere nonuniformity , which states that most of finer length adjustment is accommodated by the weakest half - sarcomeres , which become weaker as muscle lengthening progresses and advances beyond the point of myofilament overlap and ultimately microtears develop.2,60 repeated stretching further increases traumatized sarcomeres , and injury of muscle fibers is exacerbated causing membrane disruption and perforation of channels stimulated by mechanical stretch.2,60 damage of junctophilins , that is , proteins connecting t - tubules with the membrane of sarcoplasmic reticulum mediating the communication between the calcium release channel and the dihydropyridine receptor , may also contribute to strength losses due to uncoupling of the excitation
contraction coupling mechanism and calcium kinetics from sarcoplasmic reticulum resulting in strength reduction.63,64 this mechanism accounts for ~75% of early ( up to 72 h ) muscle strength deterioration with injury of other force - generating and transmitting structures accounting for the remaining 25%.65 damage of junctophilin proteins results in the rise of intracellular calcium which then stimulates calcium - activated proteolytic enzymes ( i.e. , calpains ) that further degrade contractile and other muscle proteins,66 a mechanism also shown by experimentation with dystrophic mdx mice with an inherent stimulation of calcium channels.67 in fact , removal of calcium from muscle s environment or inhibition of calcium channels with pharmacological agents restores or attenuates strength decline following eccentric work in some studies with mdx mice68,69 but not in healthy muscle.70 according to warren et al,65 degradation of contractile proteins may further contribute to strength loss during prolonged ( > 72 h ) muscle injury .
although evidence implicates various other structural and contractile proteins , such as -actinin-3 , in strength loss following damaging exercise,71,72 more research is needed in order to understand the mechanical aspect of their contribution .
doms usually peaks 12 days postexercise and recovers to baseline levels after 47 days.73,74 in contrast to muscle strength loss , doms demonstrates a moderate to low correlation with histological evidence of eimd probably due to a significant variability of subjects.73 doms is attributed to muscle fiber disruption , disturbance of calcium homeostasis , and firing of iv nerves in response to various inflammatory by - products.75,76 in fact , synthesis and release of inflammatory agents ( e.g. , bradykinin , prostaglandins , histamine , and nerve growth factor ) by proinflammatory cells ( e.g. , immune cells ) postexercise may actually trigger selective pain receptors and produce soreness.77,78 available evidence suggests that nitric oxide ( no ) produced by muscle no synthase may also stimulate nociceptors of c - fibers , thereby inducing a pain sensation.76 generation of free radicals by the nicotinamide adenine dinucleotide phosphate ( nadph ) oxidase mechanism of the immune cells may also contribute to the damage of injured and noninjured muscle fibers and the onset of doms , a phenomenon also known as respiratory burst - induced secondary damage.1,8 allen et al28 suggested that skeletal muscle responses to eimd follow a continuum with the type of eccentric muscle activation , genetic variability , muscle group engaged , and overload characteristics ( intensity , volume , and degree of novelty ) being the main determinants of the type of adaptations induced .
eimd is more severe when electrical stimulation is utilized to induce eccentric contraction ( as compared to voluntary eccentric activation ) , genetic background is optimal ( high vs. low respondents ) , and intensity , volume , and novelty are of sufficient magnitude.28 when eimd is less severe , there is an increased likelihood for positive adaptations , whereas in more severe eimd , an intense disruption of muscle fibers occurs and an augmented inflammatory response develops.28 in more extreme cases , a maladaptation occurs resulting in musculoskeletal injuries ( e.g. , strains ) , fiber necrosis , insufficient regeneration , and probably development of scar tissue.4,28,70 other factors may also affect the predisposition and susceptibility to eimd .
sex may be related to variations often seen in eimd manifestations with women demonstrating strength decrements , doms , and membrane disruption of smaller magnitude79,80 probably due to a prophylactic effect of estrogens on muscle fiber membranes , calcium homeostasis , and inflammatory reaction.8183 whether doms responses are sex - dependent is less clear .
other factors that may attenuate eimd manifestations are regular exercise training and utilization of nutritional supplements ( i.e. , anti - inflammatory agents , antioxidants , and creatine supplementation).7,84,85 since athletes have a heavy schedule , with training or sometimes competing more than once a day , finding ways to maximize or accelerate the recovery process from exercise training becomes crucial for their performance .
nutritional strategies , either by using dietary supplements or foods , have been proposed in the literature to encounter this challenge .
it has been shown , for example , that protein supplementation , mainly through the ingestion of amino acids , has a positive effect in reducing muscle soreness following an exercise bout and accelerating functional recovery.86 furthermore , subjects receiving food supplements such as cherry or pomegranate juice had a faster recovery in performance following an eimd protocol.8789 in addition , creatine supplementation has been shown to attenuate eimd following an eccentric exercise protocol.90 potential mechanisms that explain the effect of creatine supplementation on eimd include a reduction in the inflammatory response and oxidative stress and regulation in the calcium homeostasis as well as promotion of proliferation and differentiation of satellite cells.91 however , not all supplements have been proven to be effective,92,93 and further research is needed to identify foods and supplements that are effective in either preventing eimd or speeding up the recovery process .
the first leukocyte subpopulation that infiltrates traumatized muscle is the neutrophils within 46 h and remains elevated during the 24 h postinjury.17,9496 macrophage infiltration into the injured muscle follows 114 days postinjury depending on the magnitude of the insult.17,95,97 the mission of the leukocyte subsets is to remove cellular debris such as damaged protein molecules by releasing reactive oxygen and nitrogen species during a process called respiratory burst,7,96,98100 proteolytic enzymes,52 and by synthesizing proinflammatory cytokines such as il-1 , il-6 , il-8 , tnf- , and monocyte chemotactic protein-1 which are also expressed by muscle cells probably within the first 24 h after exercise.97,101 at this time , eimd results in changes of the expression of leukocyte receptors as well as their activity thereby regulating their ability to infiltrate into the damaged tissue.102 these changes are paralleled by an upregulation of major adhesion molecules.22,103 proinflammatory cytokines seem to start the disintegration of cellular fragments.104 a second wave of proinflammatory cytokines ( e.g. , il-6 and transforming growth factor ) are produced by damaged skeletal muscle several days within recovery.97,105,106 other proinflammatory cytokines may be expressed and released by infiltrating immune cells such as il-4 and il-1 receptor antagonist ( il-1ra).95,106 removal of cellular debris may be a prerequisite for the subsequent regeneration of injured myofibers.107 consequently , injured muscle develops an intense chemotactic action to attract immune cells that are usually detected first in the extracellular compartment ( 13 days ) and then intracellularly ( 48 days).7,35,39,108 the greater the damage the greater the infiltration of immune cells in the muscle environment.39,108,109 recent evidence suggests that this inflammatory phase may be under redox - dependent regulation through the mediation of key intracellular signaling pathways such as that of nf-b and mapk which control cytokine synthesis and immune activation.7 the acute inflammatory response following damaging exercise elevates leukocyte numbers not only within the muscle milieu but also in the circulation , suggesting that eimd elicits a systemic inflammatory response as well .
this immune response is greater following eccentric exercise protocols ( i.e. , eccentric dynamometry , eccentric cycling , and downhill running ) than other types or modes of exercise incorporating both concentric and eccentric actions such as level running , stepping , jumping , resistance exercise training , and sport activity.95,103,104,110120 these differences are largely attributed to the characteristics of exercise ( intensity , duration , and volume ) , muscle groups involved , and types of contraction that affect stress hormones at different degrees.1,22,114,121123 these systemic immune changes are accompanied by alterations in the circulatory levels of proinflammatory cytokines such il-1 and tnf-,7,121,123,124 indicating that eimd may cause cytokine secretion by cells other than muscle ( e.g. , immune cells ) .
interestingly , after extensive eimd , il-6 , also produced by skeletal muscle , may remain elevated even after the completion of the inflammatory phase as it has been implicated in the activation of satellite cell during the regeneration phase7,125,126 and release of anti - inflammatory molecules such as cortisol , il-1ra , and il-10.127 collectively , these results suggest that eimd induced both local and systemic inflammatory responses as depicted by changes in immune cells and cytokines . on the other hand
, several investigations suggest that during this initial proinflammatory phase , a number of anti - inflammatory molecules such as il-10 , il-12 , il-1ra , soluble tnf- receptors , and granulocyte - colony stimulating factor are secreted.7,110,124,128 systemic levels or muscle expression of leukemia inhibitory factor ( lif ) , interferon ( ifn)- , and cytokines 2 , 5 , 12 , 13 , 15 , and 17 seem to remain unaffected by eimd .
whether all types of exercises trigger such a response is questionable since the greatest elevations of these anti - inflammatory cytokines have been seen following extreme types of exercise such as marathon running with il-1 , tnf- , and il-6 rise preceding that of tnf- receptors and il-1ra.129 although some investigators suggested that these anti - inflammatory cytokines may be released by mobilized immune cells,130 the tissues secreting these molecules are unknown .
anti - inflammatory cytokines seem to suppress inflammation by hindering expression and activation of pro - inflammatory cytokines and generation of immune cells.131133 several studies have shown a correlation between the systemic levels of proinflammatory cytokines and ck activity and myoglobin levels ( eimd markers ) in the circulation postexercise.134136 although this observation is important , it does not explain the exact role of cytokines in eimd - induced inflammatory response . furthermore , the origin of these cytokines remains obscure despite findings suggesting muscle and immune cells as their potential source of release .
paulsen et al8 believe that in vitro studies do not consider the complex interaction between various tissues and humoral agents during and after exercise .
consequently , under in vivo conditions , cytokine production and release may occur from specific cell types exposed to specific local inhibitory or stimulating molecules.8 although human studies are valuable , tissue sampling may be problematic since muscle homogenates or immune cell extracts may include various cell types that are difficult to distinguish , and they all may contribute to cytokine production.8 cytokine levels in the circulation are merely product of their appearance and disappearance kinetics in that compartment and explain very little with regard to the tissue of their origin .
most of these molecules are produced by damaged myofibers , and they exist only at the local environment and as such their measurement in the blood is not possible.137 serial sampling of muscle biopsies or inhibition of specific cytokines may be more useful in elucidating their role in eimd - induced inflammation.8 animal studies showed that cytokine depletion or deficiency may attenuate recovery , suggesting that these molecules are important for muscle healing.138,139 this is mainly attributed to the inadequate mobilization of neutrophils and macrophages to the site of injury and/or an attenuated myogenic response.140142 interestingly , antioxidant supplementation attenuated the elevation of proinflammatory cytokines in days 13 postexercise and resulted in reduced recovery of muscle strength during the regeneration phase , suggesting that cytokines may be implicated in the recovery process.7
eimd and its associated inflammatory response is of paramount importance for athletes performance for two basic reasons : 1 ) the rate of deterioration and recovery of performance and discomfort ( doms ) after an athletic activity is largely dependent on the magnitude of eimd - induced inflammatory response and 2 ) it affects the frequency of training stimuli , that is , the time needed for optimal recovery in between practices , official events , and/or an event and a practice .
a > 20% decline of the force - generating capacity of muscles exhibits a close association with the magnitude of muscle damage and its associated inflammatory response.56,143145 smaller reduction of muscle strength is usually not accompanied by histological evidence of eimd.8 paulsen et al8 suggested that strenuous isolated eccentric activity produces a greater degree of eimd than the so - called eccentrically biased activities such as downhill running or intense - level running .
evidence indicates that the magnitude of force , the degree of lengthening , velocity of movement , and overall volume of eccentric load are probably the most important factors dictating the rate of muscle injury in response to exercise.146156 in fact , it has been shown that eimd induced by a football match is associated with the number of explosive types of movement that incorporate a strong eccentric component.57,157 in cases of mild performance decline , defined by paulsen et al8 as a drop of strength by < 20% , creatine kinase activity ( ck ) in blood remains < 1,000 u / l , inflammation is limited , and recovery is usually fast ( within 1248 h ) independent of type of exercise.39,59,74,95,96,112 , in the case of moderate performance decline , defined by paulsen et al8 as a drop of strength by < 20%50% , myofiber necrosis may be observed ( mostly in high - respondents),39 ck exceeds 1,000 u / l , the inflammatory response is more intense with leukocyte infiltration into the injured muscle , and degradation of structural and contractile proteins may be evident and recovery is usually completed within a week.22,35,39,158,159 in the case of severe performance decline , defined by paulsen et al8 as a drop of strength by > 50% , necrosis is usually observed in parts of the myofibers , ck may exceed 10,000 u / l , soreness is quite high , muscle swelling is evident , the inflammatory response is intense and characterized by a marked accumulation of immune cells into the traumatized tissue , and recovery usually takes 13 weeks or even longer if strength loss is > 70%.24,30,39,108,109,160166 in severe eimd , increased proteolysis and muscle disruption is observed , even during early recovery , due to disturbances in calcium homeostasis.145,167 in these three scenarios , athletes may need to use different recovery strategies in order to be able to train or compete as soon as possible .
recovery treatments may be classified in four major categories : 1 ) pharmacological ( e.g. , inflammatory agents , nf-b inhibitors , estrogen therapy , phosphodiesterase inhibitors , ace inhibitors ) , 2 ) nutritional approaches and supplements ( e.g. , antiantioxidants , herbal remedies , alcohol ingestion , -3-fatty acids , -hydroxy--methylbutyrate , protease supplementation , nucleotide supplementation , tea consumption , beetroot , caffeine , creatine , enzyme supplementation , and carbohydrate and/or protein supplementation ) , 3 ) rehabilitation and physical therapy methods ( e.g. , cryotherapy , heat - related treatments , compressive loading techniques , trekking poles , ultrasound and electrical current modalities , massage , hyperoxia or hypoxia , laser therapy , spa therapy , mechanomyographical feedback , vibration therapy , acupuncture , and homeopathy ) , and 4 ) exercise - related treatments ( e.g. , stretching and low - intensity exercise ) , and numerous studies and reviews have examined their effectiveness in reducing eimd and accelerating recovery.168171 of those , nonsteroidal anti - inflammatory agents ( depending on dosage and time of ingestion ) , protein supplementation , -hydroxy--methylbutyrate supplementation , massage ( depending on the time of administration and technique used ) , antioxidant supplementation , and exercise - based treatments have been shown to exert positive action.168171 these recovery approaches aim to reduce swelling , improve blood flow , pain sensation , immune cell recruitment , and/or improve healing by activating satellite cells and anabolic factors as well as improving tendon healing .
one has to remember that athletes are interested not only in the attenuation of the eimd - related inflammatory response but also and more importantly in effective and timely performance recovery .
certain concerns have been raised regarding the use of anti - inflammatory agents based on reports suggesting that these products not only disrupt the inflammatory response but also hinder the adaptive response to training.7,172 however , the periods during which anti - inflammatory agents are used need to be discerned .
there are training periods during which athletes need to compete and train with very high frequency ( e.g. , in - season training ) , and cessation would be beneficial .
in contrast , there are periods during which athletes train aiming for long - term adaptations , and anti - inflammatory agents may disrupt both eimd and training adaptations . in the latter case , athletes should rethink about using such recovery approaches .
however , more research is needed in order to determine whether anti - inflammatory agents interfere with training adaptations .
now it is also well - understood that athletes may be low- , moderate- , and high - respondents to eimd , a fact that also explains the substantial interindividual variability in the responses seen following various types of exercise protocols used to induce muscle micro - injury.73,108,155,163,168,173175 this phenomenon may be attributed to a number of factors such as age,154,176,177 preconditioning,178180 gender,80,166 genetics,181,182 physical conditioning level,57,183185 and joint range of motion.186 therefore , sport practitioners should determine whether their athletes are low- , moderate- , or high - respondents , be advised to establish individual normative values for each one , and avoid absolute comparisons among athletes or generalizations .
it must also be mentioned that preconditioning , a phenomenon also known as repeated bout effect , may protect athletes from eimd , that is , after a first session of damaging exercise , skeletal muscle tissue adapts and is less vulnerable to injury in subsequent sessions of the same type of exercise.153,180,187 in fact , it has been shown that repetition of a damaging exercise results in less eimd , inflammation , oxidative stress , leukocyte infiltration , and strength loss.5,111,159,187,188
exercise - induced inflammation is caused by eimd which is mainly associated with eccentric type of contractions that lengthen the muscles . under conditions of repetitive lengthening contractions , weaker sarcomeres
are compromised initiating micro - tearing of myofibers that spreads out to the cellular membrane and other subsarcolemal structures as well as to extracellular matrix and connective tissue .
calcium efflux from disrupted sarcoplasmic reticulum and stretch - dependent channels activate proteolytic enzymes that contribute to muscle damage by degrading structural and contractile proteins .
although the exact mechanisms are largely unknown , eimd triggers an inflammatory response characterized by the accumulation and infiltration of neutrophils and macrophages into the damaged tissue .
the activation and mobilization of these immune cells are mediated by cytokines released by injured muscle and other cells and may be under redox regulation .
immune cells remove cellular debris and protein fragments to allow for the subsequent muscle regeneration and healing . during
the inflammatory phase , muscle strength declines and doms develops at a rate dictated by the magnitude of the stretching stimulus . during this phase
, athletic performance is compromised for hours to days depending on the magnitude of muscle damage as well as a number of other factors .
there is a large interindividual variability of the responses to eimd , and this has to be acknowledged by sport practitioners .
although a good number of studies have investigated eimd and inflammation , the exact mechanisms responsible for the onset of doms remain obscure .
research needs to unravel the neural pathways triggering the sensation of muscle soreness , the molecular mechanisms associated with immune cell activation , and the mechanisms regulating the transition from the inflammatory phase to the healing phase . so far , there are no clear guidelines regarding recovery strategies following eimd mainly due to inconsistencies in protocols , time of administrations , dosages , exercise protocols , and type of techniques used among studies
. future research should provide clear evidence regarding optimal treatments for effective and timely recovery of both eimd and performance following various types of exercise training modes and methods as well as competition .
new genetic and molecular methodologies will allow scientists to answer critical questions regarding the pathways regulating muscle damage and healing .
Output:
| the study of exercise - induced muscle damage ( eimd ) is of paramount importance not only because it affects athletic performance but also because it is an excellent model to study the mechanisms governing muscle cachexia under various clinical conditions .
although , a large number of studies have investigated eimd and its associated inflammatory response , several aspects of skeletal muscles responses remain unclear . in the first section of this article ,
the mechanisms of eimd are reviewed in an attempt to follow the events that result in functional and structural alterations of skeletal muscle . in the second section , the inflammatory response associated with eimd
is presented with emphasis in leukocyte accumulation through mechanisms that are largely coordinated by pro- and anti - inflammatory cytokines released either by injured muscle itself or other cells .
the practical applications of eimd and the subsequent inflammatory response are discussed with respect to athletic performance .
specifically , the mechanisms leading to performance deterioration and development of muscle soreness are discussed .
emphasis is given to the factors affecting individual responses to eimd and the resulting interindividual variability to this phenomenon . |
PubmedSumm8819 | ***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: percutaneous nephrolithotomy ( pnl ) is a common treatment option for patients with renal stones .
these emerge during initial puncture and lead to injuries in the surrounding organs ( e.g. , colon , pleural cavity , lung , spleen , liver , and duodenum ) ( 1 ) .
though very rare , they may lead to morbidity in the form of septicemia , peritonitis , abscess formation , and nephrocolic or colocutaneous fistula . hence , knowing the position of the retrorenal colon to prevent surgical complications during pnl and other surgical modalities is a priority . in the present manuscript
, we studied the number of retrorenal colon presence in the ct images taken before pnl applications .
the medical records of 804 patients who underwent pnl in our clinic from 2006 to 2012 were reviewed retrospectively .
patients ct images taken before pnl were studied for the position of both the ascending and descending colon in relation to the right and left kidneys respectively .
patients without ct images and patients with severe musculoskeletal defects , abdominal masses , previous surgery , renal abnormalities ( large renal cysts , ectopic kidney , and horseshoe kidney ) and ascites were excluded from the study .
all ct images taken in supine position were evaluated by the same radiologist for retrorenal colon presence .
ct images were as previously identified ( 2 ) ; to the horizontal plane a parallel line was drawn through the posterior edge of each kidney ( posterior renal line ) at three renal levels : upper pole , middle pole and lower pole .
the number of cases with partial colon extension posterior to the posterior renal line was determined .
these were further separated to see if any part of the colon extended directly behind the lower pole ( figures 1 - 4 ) , middle pole and upper pole of the kidney .
figures 1 - 4 - anatomical variations of colon related to the kidney : colon extended directly behind the lower pole .
of the 394 patients included in the present study , 178 were female and 216 were male with a mean age of 42.2 years .
27 patients ( 6.9% ) had retrorenal colon with 18 ( 4.6% ) on the left and 4 ( 1.0% ) on the right side .
the other 5 ( 1.3% ) patients had bilateral retrorenal colons ( table-1 ) . in comparison to kidney location ,
table 1distribution of retrorenal colon according to kidney level.levelleftrightbilateraltotalupper0000middle0000lower184527total184527
during the studied period , colonic perforation was observed in only 2 cases ( 0.3% ) that did not had ct scans taken before pnl intervention .
pnl was first described in 1976 and has become in the last 30 years almost the standard treatment modality for renal stones ( 3 ) . despite the high success rates , it is still an invasive procedure associated with significant morbidity that involves life - threatening complications .
pnl outcome depends heavily on planning and successful execution of initial kidney access as it may carry an increased risk of damage to surrounding organs . in order to gain access to the desired renal calyx with minimal complications it is necessary to evaluate renal anatomy and the surrounding organs .
intravenous urography ( ivu ) has historically been the main preoperative imaging technique for pnl .
the spread and increasing presence of multiphase ct scanners has made it the main imaging preference in many centers .
ivu however still remains valuable for the preoperative planning and evaluation of kidney stones due to its ability to demonstrate fine details in the collecting system anatomy of the kidney . but a poorly performed ivu may have limit valuable information required before pnl application . therefore , dynamic ct has recently become the gold standard in urolithiasis diagnosis and evaluation ( 4 ) .
ct used for the diagnosis of renal stones , also delineates the extent , orientation , and location of the stones within the kidney and thus enable the most suitable pnl tract selection .
moreover , by showing the relationship of the kidney and stone to the surrounding structures enables to minimize the risks of injury to the spleen , liver , or to an unsuspected retrorenal colon .
pre and post pnl related complications rate up to 83% , including extravasation , transfusion , and fever ; yet , major complications such as septicemia and colonic or pleural injury are rare ( 5 ) .
colonic perforation , a rare complication of pnl , is reported in less than 1% of cases ( 6 ) . during pnl ,
the age of the patient , existence of horse shoe kidney , previous kidney surgery , left kidney inferior location access , lateral posterior axillary line access , hypermobile kidney , and the existence of retrorenal colon are among the factors that predispose to colon perforation ( 5 , 7 ) .
a retrorenal colon is more frequently found on the left side and is most likely to be situated near the inferior kidney pole ( 8) . retrorenal colon is found in approximatively 0.6% of the general population according to the hadar - gadot and sherman et al .
, ct images showed that the left colon was posterior in 16.1% of cases , and the right colon was posterior in 9% of cases at the level of the lower pole ( 11 ) .
total ratio of retrorenal colon was 1.7% , with 1.2% on the left side , 0.3% on the right side and 0.2% bilateral in the atar et al .
hopper et al . reported in their study based on 500 abdomen ct scans that the overall frequency of retrorenal colon was 1.9% if the images were taken in supine position .
when 90 patients were studied in the prone position , retrorenal colon was found in 10% ( 12 ) . in the present study , retrorenal colon in pnl patients
was found in 27 cases , ( 6.9% ) of which 18 ( 4.6% ) were on the left side , 4 ( 1.0% ) on the right side , and 5 ( 1.3% ) bilateral .
all ct scans in the present study were performed in supine position . however , in the literature the prevalence of retrorenal colon varies according to the patients position .
al . study , analyzing a series of 500 supine and 90 prone abdominal ct scans , determined the colon positioned posterior to the kidney in 1.9% and 10% of cases , respectively .
they found that there is a high risk of colon perforation during pnl in the prone position ( 13 ) .
if supine and prone positioned patient images are to be compared , the prone position seems to be associated with a significantly shorter nephrostomy tract length and a greater number of potential puncture sites .
a shorter tract length may ease percutaneous access and nephroscope mobility within the collecting system and thus improve stone - free rate and decrease hematuria risk .
a greater range of potential access angles may result in decreased risk of visceral injury ( 14 ) . in the croes pnl study group
1079 pnl applications were conducted in prone and 232 in supine positions without revealing a difference in complication rates ( 15 ) .
pnl was applied a short time ago mainly in endourology clinics ; yet , pnl related complications were generally documented by authors and departments whose main interest is pnl .
however , nowadays pnl has become a routine practice in all urology clinics and the reported complications may differ from the actual ones . in the present study , the retrorenal colon rate of 6.9% of patients who underwent pnl shows actually how close the urologists are to intervene to a retrorenal colon perforation .
unfortunately , in the two retrorenal colon perforation cases , no ct images were taken before pnl intervention and thus our ability to evaluate colon perforation risk proactively was nullified . on the other hand
, no colon perforations occurred in any of the cases who had ct images obtained before pnl intervention . in order to prevent colon perforation during pnl ,
alternative imaging techniques are available . however , a precise and reliable standardization of imaging techniques seems currently not possible .
thus , ultrasound or ct guided puncture to the kidney calyx , in cases with previously reported anatomic variations without inflicting harm to other organs , might be used .
moreover , 3d ct can provide excellent representation of kidney anatomy and be used while planning a pnl intervention ; however , it does not show the relationship between the calices and different organs , such as the colon in particular and kidney motion ( 16 ) .
retrorenal colon is more frequently found on the left side and on the lower pole of the kidney .
therefore , when accessing the lower pole of the kidney , especially on the left side , the risk of colonic injuries should be considered during pnl .
Output:
| objective the aim of this study was to investigate retrorenal colon incidence in percutaneous nephrolithotomy ( pnl ) interventions made in our clinic.materials and methods clinical data of 804 pnl patients , accumulated over a 7 year period ( 2006 - 2012 ) , was surveyed .
the patient files were reviewed retrospectively , and only those who had abdominal computed tomography ( ct ) images before pnl intervention were included in the study . in the ct images , the position of both the ascending and descending colon in relation to the right and left kidneys were evaluated.results according to our hospital reports , 394 patients with ct images were included in the present study 27 patients ( 6.9% ) had retrorenal colon , of which 18 ( 4.6% ) were on the left side , 4 ( 1.0% ) on the right side and 5 ( 1.3% ) had bilateral retrorenal colons .
colonic perforation complication was seen only in two patients and the colonic perforation rate was 0.3% .
these two cases had no ct images.conclusions pnl , in the process of becoming the standard treatment modality , is a safe and reliable technique for renal stone treatment .
colonic injury should be taken into consideration during pnl interventions of the lower pole of the kidney ( especially on the left side ) due to the location of retrorenal colon . |
PubmedSumm8820 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
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Input: the treatment of metastatic melanoma has been revolutionized in the last three years , with the fda registration of yervoy , a monoclonal antibody blocking lymphocyte regulatory receptor cytotoxic t lymphocyte - associated antigen 4 ( ctla-4 ) , and shortly afterward , the entry to the clinic of zelboraf , a small molecule inhibitor of mutated b - raf . from being an incurable disease ,
stage iv melanoma has become an illness in which prolonged and even complete responses can be envisioned .
however , while the prospects have improved for stage iv disease , for patients with american joint committee on cancer ( ajcc ) stage iii disease no new treatment options have been developed and validated since the approval of interferon ( ifn ) almost two decades ago [ 17 ] .
a pegylated formulation did not offer improved tolerability and treatment was discontinued due to toxicity .
both the eortc trials and the ecog pooled analysis showed that ajcc stage iii patients with macroscopic lymph node involvement derived the smallest survival benefit , if any , from ifn. in this situation , melanoma vaccines could have been an alternative to ifn , since they could induce a tumor - specific immune response to inhibit micrometastases at a stage when the suppressive effects of an advanced tumor are not yet an obstacle . in the few controlled clinical trials reported to date , vaccinated patients did not experience a survival benefit .
this fact , together with the paucity of objective responses to active immunization in stage iv melanoma patients using different vaccination strategies , rendered a general impression of the futility of cancer vaccines [ 11 , 12 ] . the resurgence of interest in cancer vaccination was the result of several clinical trials demonstrating that a component of active immunization could improve clinical outcome of immunotherapy protocols .
examples include the addition of a peptide vaccine to the administration of high dose interleukin-2 ( il-2 ) and the use of a gmcsf - secreting tumor vaccine in combination with ctla-4 blockade for metastatic prostate cancer .
these trials led to the increasing understanding that cancer immunotherapy is a multifaceted strategy and that a single treatment modality would not suffice . noting that individuals exhibit heterogeneity of tumor antigens , the use of autologous tumor as a basis for vaccination can provide antigen authenticity .
the unique expression profile of normal and mutated proteins in the patient 's tumor cells is presented in conjunction with their own major histocompatibility complex ( mhc ) molecules , and this combination is necessary to induce antigen - specific reactive lymphocytes .
the coadministration of bacillus calmette - gurin ( bcg ) , a widely used immunological adjuvant , with the autologous vaccine , has previously been shown to enhance response to autologous vaccination protocols [ 17 , 18 ] . in this paper
we report our experience with an autologous melanoma vaccine as an adjuvant therapy for melanoma patients in the advanced categories of ajcc stage iii disease : macroscopic lymph node involvement and resectable in - transit metastases .
we demonstrate that clinical immune response ( delayed type hypersensitivity , dth ) is linked to improved survival .
furthermore , using this vaccination protocol , molecular analysis of the melanoma showed that cancer testis antigens ( ctas ) , which are generally considered targets of immune response , are predictive of survival .
interestingly , patients who had previously received the melanoma cell vaccine had improved overall survival when treated with ipilimumab immunotherapy for metastatic disease .
this prospective phase ii , single - institution , single - arm study included patients with operable ajcc stages iiib and c melanoma .
since we did not have pathological data on ulceration of the primary melanoma for all patients , ajcc stage iiib was defined for any t ( tumor ) with pathological n1b , n2b , and n2c .
the aim of the study was to document overall and disease - free survival ( primary outcome ) and to correlate skin reactivity to the autologous tumor of patients that were treated with the autologous melanoma cell vaccine with survival ( secondary outcome ) . to participate , patients had to undergo complete removal of their metastatic disease and have a normal ct scan within 30 days prior to vaccination .
additional inclusion criteria included an age of 18 years or older , normal liver and renal function tests , baseline lactate dehydrogenase ( ldh ) value below the laboratory upper limit of normal , and ability to provide informed consent .
fertile patients were requested to use adequate anticonceptive measures throughout the study period . screening procedures included baseline blood analyses ( hematological , chemical ) and computed tomography ( ct ) and/or magnetic resonance imaging ( mri ) of the entire body , including the brain , every 4 months in the first 2 years and then every 6 months for 10 years .
the study was not sponsored and was conducted following approval by the institutional ethics committee ; written informed consent was obtained from all patients .
seventy - five patients from this group were included in an immune monitoring study reported earlier .
for the preparation of the autologous vaccine , melanoma cell lines were established from resected metastases .
briefly , cells were extracted mechanically from fresh and sterile tumor specimens , frozen , and stored in liquid nitrogen in a medium containing 2.5% human albumin and 20% dmso until needed . to assure melanocytic progeny , the expressions of s100 , mart-1 , and gp100 were determined by immunostaining using polyclonal rabbit anti - s100 , monoclonal a-103 , and hmb-45 abs , respectively ( dako ) .
positive staining of more than 50% of cells with at least one of these antibodies was required .
mhc class i - related chain a ( mica ) expression was determined by flow cytometry of melanoma cell lines using anti - human mica - apc ( allophycocyanin ) , r&d systems , minneapolis , mn , usa . cell lines were routinely tested for mycoplasma contamination by ez - pcr ( biological laboratories , beth haemek , israel ) , according to the manufacturer 's instructions .
tumor cultures that were found contaminated were incubated in the presence of 10 mg / ml ciproxin 200 ( bayer ) for two weeks , with change of medium every three days .
the cells were retested after treatment and were used only after being found mycoplasma - free .
melanoma cell lines were expanded to the required number necessary for preparation of at least 8 vaccine doses of 1025 10 cells each and cryopreserved at 70c . on the day of treatment ,
one dose of cells was thawed , washed , and irradiated to a dose of 230 gy . at this stage , cells were still viable .
conjugation of melanoma cells with dnp was performed as described , leading to death of the cells ( as determined by trypan blue exclusion ) .
bcg ( statens serum institut , denmark ) was added to the vaccine prior to injection , diluted to 1 : 50 for the first three vaccine doses and up to 1 : 500 for the following doses , to avoid overreactivity at the injection site .
bcg was reported to trigger dendritic cell maturation and to aid in diverting the cd4 t cell response towards a th1 phenotype .
briefly , patients were sensitized to dnp , to enhance the response to the vaccine , by applying 0.1 ml of 2% dnp dissolved in acetone - corn oil ( sigma ) topically to the inner aspect of the arm ten days prior to injection of the first vaccine .
cyclophosphamide , 300 mg / m per dose , was given 4 days preceding the first and second vaccines .
this practice was based on the observation that cyclophosphamide prior to vaccination can reduce the proportion of t regulatory cells and enhance tumor - specific immune response [ 2225 ] .
generally , vaccines were injected in 3 adjacent sites on the upper arm or thigh , avoiding limbs with dissected lymphatic basins .
patients were evaluated periodically every 3 months and had a total body ct scan performed every 6 months , or as required according to their symptoms .
evaluation of dth to autologous melanoma cells was performed on the vaccine days 5 and 8 , by intradermal injection of 13 10 irradiated ( 170 gy ) autologous melanoma cells .
erythema diameter of 5 mm and less was arbitrarily defined as negative ; 510 mm weak ; 1015
thirty - five melanoma cell lines that were retrieved from 35 vaccinated patients were selected for gene expression analysis based on retrospective survival data of the donors .
gene expression profiling was performed using an assay based on a collection of cellular genomic signatures that produced a pattern - matching tool and formulation - based deduction of a wider expression profile .
one thousand transcripts were identified , from which the remainder of the transcriptome could be computationally inferred .
these 1,000 landmark transcripts were measured on luminex beads , as part of the connectivity map ( c - map ) project ( unpublished , r. narayan , broad institute of harvard university and mit , cambridge , ma ) .
cultures underwent a median of 4 passages ( range 213 ) and mrna was extracted from melanoma cell microcultures harvested at 90% to 100% confluence , produced in a synchronous way , under identical conditions of growth , in four replicates .
initial analysis was conducted with a bioconductor- ( r- ) based test ( ssat ) , which applies a cox - regression analysis followed by a second test based on rank statistics . the analysis determines the best cut - off value that separates patients into those with favorable versus worse survival time .
rna was normalized to gapdh - rna content using abi 7500 sds software , v1.2.2 ( applied biosystems inc .
positive and negative controls , as well as samples with no dna , were included in every qrt - pcr experiment .
pcr reactions were performed using abi qrt - pcr thermocycler ( 7500 real time pcr system , applied biosystems inc . , foster city , ca ) .
the qrt - pcr program was run for 45 cycles , following an initial incubation at 95c , 10 min .
each cycle consisted of 95c 15 sec and 60c 1 min .
b - raf genotype was determined using cobas 4800 ( roche ) . during the autologous vaccine study period ,
ipilimumab ( yervoy , bms ) was administered in our institution to patients with metastatic melanoma in the framework of bms studies ca184 - 004 , 024 , and 025 . since its fda approval as a standard second - line treatment
patients from the autologous vaccine study which later developed nonresectable metastatic disease were among a larger group recruited for these protocols .
the comparison of survival curves between groups was carried out using the kaplan - meier survival analysis with the log rank test .
all tests applied were two - tailed , and a p value of 5% or less was considered statistically significant .
a total of 126 patients ( 55% male ; median age , 59 years ) with postoperative ajcc stages iiib and c ( 45% stage iiib ; 55% stage iiic ) were enrolled . for patient characteristics
twenty - four patients ( 19% ) presented with enlarged lymph nodes ( lns ) at the time of diagnosis of the primary melanoma ; 11 ( 9% ) had unknown primary lesion ; 22 ( 17% ) had metastases in transit .
nineteen patients ( 15% ) had noninvolved sentinel ln but developed macroscopic disease later , in the same lymphatic basin .
forty - two patients ( 33% ) had not undergone a sentinel ln biopsy and developed macroscopic ln involvement .
the mean number of involved lymph nodes was 2.4 , ranging from 0 ( satellites ) to 17 .
fifty - six patients ( 44% ) had undergone radiotherapy in addition to the surgical procedure , which was added when more than three nodes were involved or in cases of extracapsular invasion by melanoma cells .
no grade 3 - 4 adverse events ( ctcae v4 ) were encountered among the 126 vaccinated patients . in all patients , an erythematous nodule developed at the vaccination site and resolved in the course of 36 months leaving a depressed scar .
the os and disease - free survival ( dfs ) of participating patients were measured from the day of the first vaccine until the current analysis was performed .
a total of 126 patients were included , with a median follow - up of 44.5 months ( range 8189 months ) .
os survival data was available for all 126 patients and dfs data was available for 107 patients . os and dfs were analyzed for dth < 15 mm ( weak / positive dth ) versus dth > 15 mm ( strong positive dth ) .
overall , for the whole cohort , the 5-year os was 54% and dfs was 34% .
there was no difference between os of stage iiib and iiic patients ( p = 0.182 ) .
of 119 patients with recorded dth response , 48 patients ( 40% ) attained strong positive dth ( dth > 15 mm ) , whereas 71 ( 60% ) had a weak dth response ( < 15 mm ) .
the patients with strong dth response had a 5-year os of 75% and dfs of 47% .
in contrast , patients with weak dth had a significantly lower 5-year os of 44% ( p < 0.0001 ) and dfs of 26% ( p = 0.27 ) .
using the kaplan - meier analysis and the log rank test , the single parameter that most strongly correlated with os and dfs in a univariate analysis was the dth response ( figure 1 ) . in table 3 , os and dfs are compared between patients attaining dth responses of 10 and 15 mm and patients who did not develop such response . for patients who attained strong positive dth ( > 15 mm ) , the 5-year overall survival hazard ratio ( hr ) was 0.24 ( 95% ci 0.10.53 ; p < 0.001 ) .
the hr for 5-year disease recurrence was 0.4 ( 95% ci 0.10.83 , p = 0.015 pearson 's chi square test ) , but in a longer follow - up , the protection from recurrence decreased to a hr of 0.63 ( 95% ci 0.31.32 ; p = 0.2 ) .
age , gender , and depth of invasion of the primary melanoma had no impact on survival . in a survival analysis done for
dth cut - off of 10 mm , a similar trend was noted with a smaller p value ( 0.003 ) for improved 5-year os in patients attaining a dth response of > 10 mm ( 64% ) versus 32% in patients with dth < 10 mm .
thus , the acquisition of powerful skin reactivity against nonmodified autologous melanoma cells , which reflects the development of specific cell mediated immunity , correlates favorably with survival , supporting previous results by us and by others , for example , [ 16 , 18 , 26 ] . for
56 patients in whom more than 3 involved lymph nodes were removed , radiation therapy was added to the resected lymphatic basin .
even though the patients requiring this added treatment belonged to a grave prognostic group , radiotherapy may enhance the immune response of the patients .
five - year os of these patients was 58% compared to 33% of those who received radiotherapy and had a weak dth response ( p = 0.024 ) .
the c - map project was based on a collection of cellular genomic signatures to drugs , disease states , and cancer , in order to produce a pattern - matching tool and a formulation - based deduction of a wider expression profile .
one thousand transcripts were identified from which the remainder of the transcriptome could be computationally inferred .
these 1,000 landmark transcripts were measured on luminex beads ( unpublished , r. narayan , broad institute of harvard university and mit , cambridge , ma ) .
thirty - five tumor samples , representing distinct subclasses of poor and good responders , were selected for c - map analysis : ( 1 ) eighteen poor responding patients with a median os of 19 months ( range 834 ) , all of whom failed to develop strong skin reactivity to their autologous tumor , and ( 2 ) seventeen good responding patients with median os of 105 months ( range 46194 ) , 12 of whom also developed strong skin reactivity ( dth data missing for one ) .
figure 2 shows the hierarchical clustering of 50 genes expressed on patients ' melanoma cells , which yield a significantly improved or worsened hr for survival .
cancer testis antigens ctag2 ( ny - eso-2 ) , magea1 , ssx1 , and ssx4 clustered together in the hierarchical diagram ( depicted in a circle in figure 2 ) .
high expression of each of these cta genes was associated with a reduced risk of death .
as cta genes are coexpressed , we performed a principal component analysis ( pca ) of the genes to stratify the patients , using the princomp function in r. we found the first principal component ( pc1 ) to explain more than 80% of the variance when expression values from the 35 samples corresponding to all 51 probe sets from cta genes in the c - map array were used ( figure 3(a ) ) . to validate the predictive data extracted from c - map , we used qpcr results obtained from 21 melanoma line samples for mage - a1 , ssx1 , ssx4 , and ny - eso-1 ( ctag1b ) .
similar to the in silico data , a pca analysis based on these four genes was able to explain 75% of the variance . in both analyses , stratifying the patients into low / intermediate and high expression based on pc1 values , we show worse outcome for low cta expressors ( below quartile 1 ) compared to high expressors ( above quartile 4 ) , p = 0.02 ( figure 3 ) .
a similar analysis performed using an unrelated melanoma cohort ( gse19234 ) , which never had an autologous vaccine , did not reveal an association between cta gene expression and survival ( not shown ) , suggesting that cta gene expression is not a prognostic factor by itself but becomes one in the context of autologous vaccination .
mica ( mhc class i related chain a ) , another gene which correlated with a reduced risk of death and for which there is an antibody for flow cytometry , was used to validate the expression data ( figure 4 ) .
out of 11 samples analyzed , 10 yielded mica protein expression ( by flow cytometry ) concordant with the gene expression value . in 8 samples
the data was predictive of patient 's current status , whether alive , no evidence of disease ( ned ) , or died of disease ( dod ) .
b - raf status was determined for 32 patients of the 35 that were analyzed for gene expression .
the median survival for patients with v600e mutation was 50 months compared with 45 months for the wild type ( wt ) group ( p = 0.9 ) .
since most patients in the series who had recurrent disease died before 2012 , none of them were treated with b - raf inhibitors when they developed metastases , and consequently differences in survival could not be attributed to better treatment options .
four out of 11 patients with v600e mutations had strong dth response ( 36% ) , compared with seven out of 21 ( 33.3% ) in the wt group ( p = 0.86 ) .
thirty - five patients who received melanoma cell vaccine and developed nonresectable metastatic disease were referred to ipilimumab treatment in bms studies ca 184 - 004 , 024 , and 025 and later as a standard second - line treatment .
these patients were compared with a nonselected concurrent group of other 35 patients , who never received the vaccine ( table 2 ) .
the majority , 62 patients ( 89% ) , received ipilimumab at a dose of 3 mg / kg .
response evaluation criteria in solid tumors ( recist ) were used to define response to treatment .
complete response was achieved in six patients ( 8.6% ) , partial response in 14 ( 20% ) , and stable disease in 7 ( 10% ) .
multivariate analysis revealed that the single parameter that correlated with an improved os time was previous treatment with melanoma cell vaccine . in the group of 35 vaccinated patients , median os was 31 months with a 3-year survival of 46% , compared with a median os of 9 months and 3-year survival of only 19% in the nonvaccinated patients , ( p = 0.007 , pearson 's chi square test ) .
the results from this retrospective cohort of patients suggest that response rate and survival are improved when ipilimumab treatment succeeds autologous melanoma vaccine .
in this phase ii study we administered a vaccine composed of the autologous tumor given to melanoma patients as a postoperative adjuvant for ajcc stage iii disease following resection of macro metastases .
the study was single - armed , as it was initiated prior to the registration of ifn as standard of care for the adjuvant treatment of melanoma stages iib and iii . in an initial cohort , which included patients of worse prognoses ( stages iiib , iiic , and iv ) we observed an unexpected good survival rate with this vaccine . in view of the reduced toxicity of the vaccination regimen , we did not offer patients a high dose interferon arm after its registration .
thus , we opted to continue with the protocol in its single - arm design , to record survival rates in adjuvant stage iiib and c patients . eventually , these patients were the less likely ones to derive benefit from adjuvant ifn therapy , since treatment with the standard of care ifn-2b or peg - ifn did not yield any survival advantage for them .
the projected 5-year os for these patients was estimated at 40% and the dfs at 30% , as shown in the kaplan - meier curves generated in a meta - analysis from eortc trials 18952 and 18992 of patients with ajcc stage iii - n2 . in our group of patients with the same stage disease , the 5-year os reached 54% , with a median os of 88 months and a 5-year dfs of 34% ; these were achieved with no major adverse effects . in another series ,
the nordic study , the best median survival , 72 months , was derived from intermediate - high doses of ifn-2b for one year .
these results , worse than those we observed with the autologous vaccine , were generated in a group of patients in which 35% had earlier stage disease ( iiia ) .
notably , in our study population , patients with a strong positive skin reaction to their unmodified melanoma had much better prognosis , with a 5-year os of 75% and dfs of 44% .
the link between immune parameters that attest to the development of antitumor response and improved survival has been previously observed [ 17 , 3036 ] .
dth is a crude measurement , but an easy test to apply on all patients .
several vaccine clinical trials included a dth test as part of their clinical evaluation and reported a positive correlation between dth response and longer survival [ 37 , 38 ] .
biopsies taken from skin injection sites revealed vaccine - induced antigen - specific t cells [ 39 , 40 ] .
we previously demonstrated effective antimelanoma cd4 t cell activity associated with improved survival in a cohort included in the present study .
thus , a positive dth reaction could be indicative of the emergence of antimelanoma immunity , and the improved survival of patients attaining strong dth would attest to the vaccine 's protective effects .
since autologous tumor tissue is often not available for vaccine preparation , defined antigens , consisting of short or long peptides , are used as a substitution [ 4143 ] .
the enthusiasm for the use of defined antigens decreased when successful generation of antigen - specific t cells failed to protect against tumor progression [ 11 , 44 ] .
loss of mhc and impaired peptide presentation by the melanoma were among the reasons for vaccine failure , but another limitation is that many tumor - progeny antigens are essentially self - antigens that evoke weak responses . unlike wildtype proteins , mutations have the potential to generate neoantigens which are better targets .
the significance of mutation - derived neoantigens was illustrated when adoptively transferred tumor - infiltrating lymphocytes that destroyed melanoma in patients were surveyed and found to target mutated epitopes .
furthermore , recent data has clearly demonstrated that these mutations are , in large part , the functional targets of immune checkpoint blockade .
but until the hurdles of preparing a totally individualized vaccine are overcome , the best source of mutated antigens , as we have previously shown , is still the autologous tumor and , ideally , those tumors that express both mhc class i and class ii . another important component of melanoma cell vaccines , as reflected by our data , are a class of antigens known as cancer testis antigens .
ctas are products of several multigene families , many of which map to chromosome x , that have arisen through chromosomal duplications and were initially identified through immunologic assays . when associated with disease outcome ,
ctas sometimes confer worse prognosis , but when protective immune responses are recorded , ctas are dominant targets .
for example , rising antibody responses to cta ny - eso-1 ( ctag1b ) were recorded following shrinkage of melanoma in a patient with abscopal tumor response , and among patients treated with ipilimumab , seropositivity to ny - eso-1 with associated cd8 t cell response correlated with 77% clinical benefit . using a luminex - based method to generate a gene expression array and qpcr validation , we showed increased expression of magea1 , ctag1 , ctag2 , ssx1 , and ssx4 in patients with improved survival .
we suggest that these patients ' prolonged survival is attributed to the melanoma immunogenicity potentiated by the ctas and augmented by the vaccination procedure .
lastly , our data implies that patients who had been immunized against the autologous tumor prior to receiving ipilimumab survived longer than patients who did not receive an autologous melanoma vaccine .
ctla-4 receptor blockade prevents inhibition of activated effector lymphocytes and selective increase in the ratio between t effectors and regulatory t cells within the tumor . in patients with preexisting immune response
, the removal of inhibitory signals boosts antitumor activity , leading to the hypothesis that prior vaccination might induce in a subset of patients a population of specific antitumor cytotoxic t cells and a potent immune response following immune checkpoint blockade . in this respect , it was encouraging to note that in a cohort of vaccinated patients that had received ipilimumab , the 3-year survival was 46% , compared with 19% for the nonvaccinated patients
in this noncontrolled phase ii study we have shown that adjuvant treatment with autologous melanoma vaccine yields overall and disease - free survival rates that are not inferior to those obtained with interferon alpha . in a subgroup of patients who attained a strong positive skin response to unmodified autologous tumor ,
lastly , improved survival time following ipilimumab treatment was observed for patients who had previously been vaccinated .
thus , we suggest that autologous melanoma vaccine induces protective immunity and may offer leverage for other immunotherapies .
Output:
| background .
there is not yet an agreed adjuvant treatment for melanoma patients with american joint committee on cancer stages iii b and c. we report administration of an autologous melanoma vaccine to prevent disease recurrence .
patients and methods .
126 patients received eight doses of irradiated autologous melanoma cells conjugated to dinitrophenyl and mixed with bcg .
delayed type hypersensitivity ( dth ) response to unmodified melanoma cells was determined on the vaccine days 5 and 8 .
gene expression analysis was performed on 35 tumors from patients with good or poor survival .
results .
median overall survival was 88 months with a 5-year survival of 54% .
patients attaining a strong dth response had a significantly better ( p = 0.0001 ) 5-year overall survival of 75% compared with 44% in patients without a strong response .
gene expression array linked a 50-gene signature to prognosis , including a cluster of four cancer testis antigens : ctag2 ( ny - eso-2 ) , magea1 , ssx1 , and ssx4 .
thirty - five patients , who received an autologous vaccine , followed by ipilimumab for progressive disease , had a significantly improved 3-year survival of 46% compared with 19% in nonvaccinated patients treated with ipilimumab alone ( p = 0.007 ) .
conclusion .
improved survival in patients attaining a strong dth and increased response rate with subsequent ipilimumab suggests that the autologous vaccine confers protective immunity . |
PubmedSumm8821 | ***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 centers for disease control and prevention ( cdc ; atlanta , ga , usa ) has been performing passive surveillance for c. gattii in the united states since 2009 .
isolates were collected as part of routine surveillance for c. gattii or submitted to the fungal reference laboratory at the cdc for identification .
we identified all isolates to the species level as described ( 8) and used the consensus protocol for multilocus sequence typing ( mlst ) ( 9 ) .
in the course of this surveillance , several isolates were received from states in the southeast ; genotypic analysis revealed that these isolates consisted of 2 molecular types , vgi and vgiii ( 8) .
of > 400 isolates received from throughout the united states , 42 were molecular type vgi .
mlst analysis of vgi isolates showed a cluster of isolates with a single mlst sequence type originating in the southeastern states ( figure 1 ) .
five isolates from georgia and 1 each from florida , tennessee , and michigan were indistinguishable by mlst ( sequence type 162 ) .
a second isolate from georgia differed from this group by 1 single - nucleotide polymorphism ( snp ) in the intergenic spacer gene locus .
maximum - parsimony tree of multilocus sequence typing analysis of vgi isolates of cryptococcus gattii from the southeastern united states . in the predominant clade ,
1 isolate was from michigan ; all remaining isolates were from the southeastern united states .
nearest neighbor isolates were included for comparison , and an environmental vgi isolate from australia was used as an outgroup .
scale bar indicates 1 single - nucleotide polymorphism . because the population of vgi isolates from the southeastern states ( vgi - se )
was only recently identified , it might be a newly emerging population similar to the independent emergences of vgiia and vgiic in the pnw ( 68 ) . to further characterize this cluster , we used whole - genome sequence typing ( wgst ) of isolates from this cluster , other closely related isolates , and unrelated control isolates ( table 1 ; figure 2 ) .
, san diego , ca , usa ) , used gatk unified genotyper version 2.4 ( broad institute , cambridge , ma , usa ) for snp detection , and constructed maximum - parsimony snp trees using paup * ( sinauer associates , inc . , sunderland , ma , usa ) , as previously described ( 6 ) .
maximum - parsimony tree of whole - genome sequence data of isolates of cryptococcus gattii from the southeastern united states .
nearest neighbor isolates were included for comparison , and an environmental vgi isolate from australia was used as an outgroup .
although the overall topology of the tree we generated remained almost identical to that seen by mlst , we were able to separate each of the isolates within the cluster using wgst ( figure 2 ) .
a total of 41,024 snps were within the vgi - se cluster , which had an average branch length of 4,558 snp differences between any 2 isolates .
the isolate from georgia that differed in mlst by 1 snp was placed well within the cluster by wgst . outside the cluster , the nearest neighbor , an isolate collected from a resident of oregon with a history of living near the southeastern united states in texas ( table 1 ) , differed by > 29,000 snps .
the other cluster of vgi isolates was separated from vgi - se by 49,992 snps .
previously , whole - genome sequencing was performed on isolates of c. gattii molecular type vgii exclusively from the pnw .
results showed that the vgii isolates consisted of 3 different highly clonal and recently emerged populations with only 107 , 132 , and 137 snps identified within the vgiia , vgiib , and vgiic populations , respectively ( 10 ) ( table 2 ) .
the average branch length between any 2 isolates was < 18 snps for the vgiia and vgiic populations and only slightly higher for the vgiib population . on the basis of snp diversity ,
the vgi - se subtype is substantially older than the clonal vgii populations in the pnw and has likely been in the united states for a much longer time . *
these isolates , accessed from the same national reference laboratory , were submitted without clinical history ; therefore , we can not discern whether they represent the diversity of 2 isolates from 1 patient over time or whether they are part of a local clonal population .
all of the patients for whom disease manifestation was known had meningitis ( table 1 ) .
this finding differs notably from c. gattii vgii patients in the pnw , among whom a substantial proportion ( 59% ) had a primary pulmonary infection ( 8) . the average age of the patients with isolates in the vgi - se cluster was 46 ( range 1870 ) years . for most patients ,
the source of infection was unknown , although 2 of the patients had been exposed to rotting wooden structures ( 1 demolished a wooden structure , 1 power - washed old houses ) .
our data indicate that the clonal diversity of the c. gattii vgi - se clade in the southeastern united states is an order of magnitude greater than that seen in isolates from the pnw .
hypothesized that the emergence in the pnw began in the mid-1990s in british columbia , canada , and spread to the united states in the early 2000s ( 12 ) .
comparison of the average number of snps detected among the 3 vgii clonal groups in the pnw with the average number of snps detected between the vgi - se isolates indicates that the vgi - se isolates have been in place substantially longer .
the limitation to this conclusion is that we do not know the rate of mutation for the vgi or vgii molecular types ; however , there is no reason to believe that they would be substantially different .
there may also be higher rate of recombination within the vgi - se clade related to opposite - sex or same - gender sexual recombination .
the isolates from this clade for which the mating type is known are all , but that does not preclude the possibility that some mating type a isolates exist in the environment in the southeastern united states .
the first identified isolate of c. gattii in the united states was reported from west virginia in 1924 ( 11 ) , although the isolate was not recognized as c. gattii vgi until decades later ( 12 ) .
two other historical reports of c. gattii isolates from the southeastern united states exist : the first , from 1968 , describes clinical and environmental isolates from savannah , georgia ; the other , from 1982 , describes isolates from alabama , tennessee , and louisiana from patients with no travel history to a c. gattii endemic region ( 13,14 ) .
although both of these reports use the previous name for c. gattii , c. neoformans serotypes b and c , their results clearly indicate that c. gattii has existed in the southeastern united states for > 40 years , as opposed to the recent emergence in the pnw during the past 2 decades .
a more recent report describes a c. gattii vgi isolate from an hiv - positive patient in north carolina ( 15 ) ; those authors surmised that the isolate was related to travel to san francisco , but that assumption may have to be revised . no current molecular clock for c. gattii indicates the time required to generate the level of diversity seen in the vgi isolates
however , our findings lend credence to the hypothesis that c. gattii has circulated in the southeastern united states long enough to be considered endemic .
Output:
| cryptococcus gattii is a recognized pathogenic fungus along the pacific coast of the united states from california to washington . here
we report that c. gattii may also be endemic to the southeastern united states and has probably been present there longer than in the pacific northwest . |
PubmedSumm8822 | ***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 models with heterogeneities in the mechanical properties show large - scale patterns of stress maxima and minima when they are compressed .
1 . the nature of the patterns in stress and how the patterns are impacted by elastic heterogeneity
2 , which shows the equivalent von mises stress for four of the models . in all models illustrated here
although this degree of variation in elastic properties is unrealistic , i use this model as an extreme end - member . in fig . 2d
the young s moduli of the grains varies from 100 to 120 gpa , which is similar to the degree of variation seen in high - symmetry minerals like beta quartz or halite .
the other models have variations in elastic properties that are intermediate ( table 1 ) .
although the patterns occur on a scale much larger than the grain - scale , they do not reflect the pattern of grain boundaries because individual grains contain significant stress gradients . in fig .
2d the pattern can be described as isolated islands of low equivalent stress , but in fig .
the change in patterning from the most heterogeneous model to the least is in the spacing of the streams and the intensity of the stress concentration in the
streams. the vertically oriented patterns originate from variations in the magnitude and direction of the maximum compressive stress ( 3 ) . a subordinate horizontal pattern ( best seen in fig .
figure 3 shows a portion of a model with the full stress tensor plotted . with the exception of the softest grains ,
the orientation of the maximum compressive stress can deviate substantially away from the macroscopic compression direction and the stress state can even become tensile .
these variations are produced by the difference in elastic properties of neighboring grains even before plastic flow in the weakest grains initiates .
the patterns in stress are established in the first displacement increment and change only in numerical value until the first yielding occurs . as yielding initiates
, the patterning in 3 deteriorates , while the patterning in 1 intensifies ( fig .
4 ) . all of the models produce strain localization in the form of shear bands ( fig .
5 ) , and the spacing of the shear bands is coupled to the stress patterning ; denser patterning produces more closely spaced shear bands concentrating smaller degrees of stain .
therefore , the location of shear bands is dictated by the spatial distribution of locations where yielding first occurs ( fig .
the degree to which shear bands grow and intensify or not as a function of global strain depends on the level of work hardening included in the plasticity model .
all models with heterogeneities in the mechanical properties show large - scale patterns of stress maxima and minima when they are compressed .
1 . the nature of the patterns in stress and how the patterns are impacted by elastic heterogeneity
2 , which shows the equivalent von mises stress for four of the models . in all models illustrated here
although this degree of variation in elastic properties is unrealistic , i use this model as an extreme end - member . in fig . 2d
the young s moduli of the grains varies from 100 to 120 gpa , which is similar to the degree of variation seen in high - symmetry minerals like beta quartz or halite .
the other models have variations in elastic properties that are intermediate ( table 1 ) .
although the patterns occur on a scale much larger than the grain - scale , they do not reflect the pattern of grain boundaries because individual grains contain significant stress gradients . in fig .
2d the pattern can be described as isolated islands of low equivalent stress , but in fig .
the change in patterning from the most heterogeneous model to the least is in the spacing of the streams and the intensity of the stress concentration in the
streams. the vertically oriented patterns originate from variations in the magnitude and direction of the maximum compressive stress ( 3 ) . a subordinate horizontal pattern ( best seen in fig .
figure 3 shows a portion of a model with the full stress tensor plotted . with the exception of the softest grains ,
the orientation of the maximum compressive stress can deviate substantially away from the macroscopic compression direction and the stress state can even become tensile .
these variations are produced by the difference in elastic properties of neighboring grains even before plastic flow in the weakest grains initiates .
the patterns in stress are established in the first displacement increment and change only in numerical value until the first yielding occurs . as yielding initiates
, the patterning in 3 deteriorates , while the patterning in 1 intensifies ( fig .
4 ) . all of the models produce strain localization in the form of shear bands ( fig .
5 ) , and the spacing of the shear bands is coupled to the stress patterning ; denser patterning produces more closely spaced shear bands concentrating smaller degrees of stain .
therefore , the location of shear bands is dictated by the spatial distribution of locations where yielding first occurs ( fig .
the degree to which shear bands grow and intensify or not as a function of global strain depends on the level of work hardening included in the plasticity model .
the fem models presented here make predictions about the heterogeneity and spatial distribution of elastic and plastic strain in polycrystalline materials that are consistent with experimental observations as well as results from other numerical studies .
many microstructural studies of plastically deformed polycrystals observe intragranular heterogeneity of plastic strain ranging from those conducted on highly anisotropic materials like olivine and ice67 to metals , which generally have more isotropic single - crystal rheological properties2891011 .
the degree of strain heterogeneity is thought to be a function of the anisotropy of the material17 .
the development of shear - strain localization at very low degrees of strain has been observed in a number of materials781112 .
the development of tensile elastic strain during compression has been observed in ice7 and zirconium11 .
large variations in stress states within single grains and plastic features that span many grains have been observed in three - dimensional ( 3d ) finite element models of polycrystalline fcc metals1 .
however , consistent with what is observed in synchrotron and neutron diffraction studies of deforming materials , elastically stiffer grains on average strain less than more compliant grains ( see , for example , the study by turner and tome13 , or diffraction data within the study by burnley and zhang14 ) ( fig .
. referred to as force chains , the patterns are produced by stress percolation20 and consist of semi - linear subsets of particles arranged parallel to compression that bear the applied load through the so - called
granular materials are most obviously distinct from fully dense polycrystalline materials in that the constituent grains have limited or no cohesion . both shear tractions and tensile forces
there are extreme variations in the mechanical properties of the constituent structural components ( grain boundaries and grain interiors ) , whereas in fully dense polycrystalline materials variations between structural components , which may or may not include rheologically distinct grain boundaries21 , are comparatively muted . thus , granular materials and fully dense polycrystalline materials fall on a continuum of variation in component properties .
the value in making this connection is that it suggests new ways of thinking about deformation of polycrystalline materials .
for example , force chains are understood to be the underlying mechanism of shear localization in granular materials ( see discussion in the study by tordesilla and muthuswamy22 and references therein ) .
therefore , examining the role of stress patterning in shear localization in polycrystalline materials may prove fruitful .
the magnitude of stress concentrations in the stress patterns and the regularity with which they occur may well yield to statistical descriptions , as they do in granular materials23 and should lead to a better understanding of phenomena that are tied to stress concentrations , such as the development of stylolites , slatey cleavage and compositional banding in rocks2425 , as well as help explain how these rhythmic features initially arise from unpatterened rocks such as shale and granite .
the recognition of stress patterning will have a number of important implications for experimental characterization and modeling of rheological properties . in experimental studies ,
experimental samples whose size allows only a portion of the stress pattern to be captured , may present difficulties for obtaining reproducible results ; a phenomena that would be most noticeable in high - pressure studies where sample sizes are restricted . changing the grain size or overall size of experimental samples
can be cumbersome , but numerically it should be comparatively painless to predict the appropriate rve by increasing the size of the grain ensemble being modeled until the tails of the stress distribution are fully described .
another important implication of stress patterning is that it provides a framework for modeling aggregate behavior over multiple - length scales based on single - crystal properties .
robust predictive models of the mechanical behavior of rocks are needed for understanding the mechanical behavior of the interior of the earth and other planets because extrapolations in both length scale and strain rate will always be required26 .
the need for reliable predictive rheological models is not confined to the geosciences but extends to engineering and materials science problems that present a variety of challenges for direct observation ; for example , shock loading of nuclear weapon components or detonation of plastic - bonded explosives .
these extrapolations can be made with more confidence if they are generated by models that are based on the physics of deformation : capturing the behavior of the crystal lattice as well as the short- and long - range interaction between grains within the polycrystal .
plastic and viscoplastic self - consistent models describe single - crystal plasticity but assume that a single set of average boundary conditions apply to each grain .
these models could be modified such that the boundary conditions applied to each grain are allowed to vary over a range suitable to the elastic and plastic heterogeneity of the structural components of the material .
perhaps the most important impact that the recognition of stress patterning can have is if it , as a simple and intuitive paradigm , can replace the default assumption of a reuss state ( isostate ) of stress in the minds of those who work on stress - related phenomena .
although it has been long recognized that the reuss state of stress is an oversimplification , the assumption still pervades our thinking on everything from the attenuation of seismic waves to the development of paleopiezometers . by providing a means of leaving the reuss stress state assumption behind ,
the recognition of patterning in stress should lead to new insights in a number of disciplines .
each grain was modeled as a hexagon containing 48 six - noded triangular elements ( fig .
1 ) ; this type of element uses a parabolic interpolation function along each edge .
the nodes on the boundaries of each grain are shared with the elements along the edge of the neighboring grain , thus grain boundaries are demarcated only by a change in elastic and plastic properties . as there can be no offset along a grain boundary in the model ,
the model consists of 2,574 hexagonal grains that have been assigned randomly into 25 subsets .
the constitutive equation used for linear elastic solids is : where ij is the stress tensor , ij is the kronecker delta , ij is the strain tensor , is the lame constant , and g is the shear modulus .
can be expressed as : and g can be expressed as : where v is the poisson s ratio and e is the young s modulus .
plastic behavior initiates when the equivalent von mises stress ( vm ) , which is calculated as follows : equals the specified yield strength .
post - yielding behavior was either perfectly plastic or included a work - hardening slope .
the young s modulus and poisson s ratio assigned to each grain set for the models presented in the illustrations are given in table 1 .
for all materials shown in the figures , the yield strength was set to 1/100th of the young s modulus and no work hardening was included .
nodes along the bottom edge were not allowed to move in y ( the vertical axis ) .
nodes along the left edge were not allowed to move in x ( the horizontal axis ) .
depending on the goal of the experiment , either a constant edge load was placed on the top edge of the model or a constant displacement was applied to each node on the top of the model .
each grain was modeled as a hexagon containing 48 six - noded triangular elements ( fig .
1 ) ; this type of element uses a parabolic interpolation function along each edge .
the nodes on the boundaries of each grain are shared with the elements along the edge of the neighboring grain , thus grain boundaries are demarcated only by a change in elastic and plastic properties . as there can be no offset along a grain boundary in the model ,
the model consists of 2,574 hexagonal grains that have been assigned randomly into 25 subsets .
the constitutive equation used for linear elastic solids is : where ij is the stress tensor , ij is the kronecker delta , ij is the strain tensor , is the lame constant , and g is the shear modulus .
can be expressed as : and g can be expressed as : where v is the poisson s ratio and e is the young s modulus .
plastic behavior initiates when the equivalent von mises stress ( vm ) , which is calculated as follows : equals the specified yield strength .
post - yielding behavior was either perfectly plastic or included a work - hardening slope .
the young s modulus and poisson s ratio assigned to each grain set for the models presented in the illustrations are given in table 1 .
for all materials shown in the figures , the yield strength was set to 1/100th of the young s modulus and no work hardening was included .
nodes along the bottom edge were not allowed to move in y ( the vertical axis ) .
nodes along the left edge were not allowed to move in x ( the horizontal axis ) .
depending on the goal of the experiment , either a constant edge load was placed on the top edge of the model or a constant displacement was applied to each node on the top of the model .
how to cite this article : burnley , p. c. the importance of stress percolation patterns in rocks and other polycrystalline materials .
Output:
| a new framework for thinking about the deformation behavior of rocks and other heterogeneous polycrystalline materials is proposed , based on understanding the patterns of stress transmission through these materials . here , using finite element models ,
i show that stress percolates through polycrystalline materials that have heterogeneous elastic and plastic properties of the same order as those found in rocks .
the pattern of stress percolation is related to the degree of heterogeneity in and statistical distribution of the elastic and plastic properties of the constituent grains in the aggregate .
the development of these stress patterns leads directly to shear localization , and their existence provides insight into the formation of rhythmic features such as compositional banding and foliation in rocks that are reacting or dissolving while being deformed .
in addition , this framework provides a foundation for understanding and predicting the macroscopic rheology of polycrystalline materials based on single - crystal elastic and plastic mechanical properties . |
PubmedSumm8823 | ***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: thirty crowns were produced to fit a model of a prepared central incisor ( tooth no .
a deep chamfer finish line was used because this is recommended by most manufacturers of dental ceramics .
the model was made as a natural tooth preparation with rounded edges and a finish line that curved apically on the buccal and palatal surfaces .
ten crowns were made with alumina cores , 10 with zirconia cores , and 10 with glass - ceramic cores ( table 1 ) .
the cores of alumina and zirconia were made to a uniform thickness of 0.6 mm .
the glass - ceramic cores were built up to an anatomic form that requires only a thin layer of veneering ceramic ( fig .
the cores were veneered with veneering ceramics that were suited for the core materials according to the manufacturers ' recommendations .
the crowns were luted with zinc phosphate cement ( de trey zink ; dentsply detrey , konstanz , germany ) to 30 identical epoxy models of the preparation .
excess cement was removed and after a 5-min setting time the crowns were placed in distilled water at 37c for at least 24 h. the crowns were subsequently loaded at the incisal edge with a flat , steel cylinder of 30 mm in diameter cushioned with a 2-mm - thick rubber disc of hardness 90 shore a ( epdm 90 ) to avoid contact damage ( fig .
the load was applied in a universal materials testing system at 0.5 mm min until fracture occurred ( lloyd instruments , leicester , uk ) .
details of the materials used in the trial specimens as received from the dental technician before veneering .
note that the glass - ceramic core has thicker walls than both the alumina and zirconia cores .
axial load is applied on the incisal edge at 1 mm min ( red arrow ) , but cushioned to avoid contact damage .
the load causes the epoxy model to compress vertically and expand horizontally ( blue arrow ) , which causes tension at the cervical margin of the crown .
the area of expected concentration of tension is marked with a red arrow at the top of the curvature .
the fracture analysis results were compared with the video recordings to verify the crack start and crack propagation .
the fracture features were compared with a reference group of 25 crowns ( from 21 incisors and four premolars ) fractured in clinical use and obtained from norwegian dentists .
non - parametric statistics were used for the comparison between groups ( ibm spss statistical software , armonk , ny , usa ) .
there were statistically significant differences among the groups ( kruskall wallis test p < 0.001 , fig .
the fracture loads of the zirconia - based crowns were statistically significantly higher than were those of the other two materials ( mann whitney u - test p < 0.001 ) .
there was no statistically significant difference between the alumina and glass - ceramic crowns ( mann whitney u - test p = 0.25 ) .
the fracture modes achieved with the test methods resembled the fracture patterns observed in clinical failures of the retrieved reference crowns ( fig .
the median values are indicated as horizontal lines in the box , and the bars represent the maximum and minimum values .
the boxes indicate size and location of the magnified images surrounding the central image . dotted arrow indicate crack propagation , black arrow indicate fracture origin and white arrow indicate fracture end .
typical fracture modes in the different material categories for the test crowns and the crowns in the reference group .
all primary core fractures were initiated in the cervical area in the approximal region , as observed in the clinical reference group .
one crown with a zirconia core delaminated completely between the core and the buccal veneering ceramic ( adhesive fracture ) .
a similar fracture was observed in one of the clinical reference crowns with zirconia although this was a cohesive fracture within the veneer .
all the other zirconia crowns exhibited partial delamination of the veneering ceramic in addition to the core fractures .
minor secondary chipping of the veneering ceramic was observed in all crowns ( cohesive fractures ) .
twenty - three of the 30 test crowns exhibited secondary fractures in the core material .
these were mainly caused by bifurcations of the main fracture ( 16 specimens ) and new cracks starting at the opposite side of the crown margin compared with the start of the primary fracture ( seven specimens ) .
the provoked in - vitro fracture modes closely matched the in - vivo fracture modes observed in retrieved reference crowns , indicating that the test method is well suited for simulating clinical stress in all - ceramic crowns .
vertical tension in the cervical crown margin seems to have initiated fractures from the cervical margin in the approximal area .
the tension is difficult to measure but seems to be created by clinically relevant axial loads .
the finding that zirconia was stronger than the other two materials is in accordance with previous findings and assumptions ( 1518 ) .
however , the mean fracture load was lower than in previous studies of crown - shaped specimens ( 3,1924 ) .
the fractures were initiated in the cervical margin as a result of tension created by the expanding abutment , as observed in a previous study that used the same method ( 13 ) .
the cervical margin is the thinnest area of the crown and the area most susceptible to machining damage ( 25 ) .
the occlusal surface is usually the thickest area of the crown ; furthermore , the occlusal surface is supported by the occlusal area of the tooth . in previous in - vitro trials
the fractures have been initiated from occlusal contact damage ( 5 ) or from cone cracks under the occlusal surface ( 10,26 ) . with a rigid abutment material ,
therefore , higher loads are required to obtain fractures . however , few clinical core
veneer crowns have had the same fracture mode as presented in these in - vitro tests .
clinically fractured crowns may have many different fracture modes depending on the material , design , and load .
however , it is more complicated to retrieve such fractures without damaging the remaining crown .
bulk fractures or chipping have been shown to start from contact damage on the occlusal surface in monolayer crowns without high - strength cores ( 26 ) .
furthermore , fractures starting from the inner surface of the core in the occlusal area as a result of radial cracks have been presented both in clinical failures ( 10,26,27 ) and in laboratory failures ( 28 ) . the focus of this study was to simulate the fracture modes observed in the retrieved clinical fractures we received and thus the aim was to avoid the other types of fracture modes . to fully comprehend the behavior of all - ceramic crowns
so far , it seems that chipping is more predominant than core failures , especially for zirconia crowns ( 4,29 ) .
nevertheless , zirconia core failures do occur in spite of the high strength , and it would be of interest to find out why .
the finding , in the present study , that all core fractures started in the approximal area indicates that this is the weakest point of the crowns or the area that is most exposed to tension .
this may be explained by the differences in mechanical properties between dentin and dental ceramics .
ceramics are stiff and brittle and deform very little before fracture during loading ( 30,31 ) .
a high occlusal load will compress the dentin , resulting in an increase in the diameter of the tooth cervically ( bulging ) , which in turn will cause tension at the crown margins ( hoop forces ) ( fig .
2 ) . a previous study revealed that an expansion of 0.1% was sufficient to cause a fracture of alumina crowns for molars ( 13 ) .
palatal expansion of the cervical crown margin for the present specimens , but it is reasonable to assume that an expansion of approximately 7 m has occurred .
the crown margins are usually not even or leveled , creating stress foci in the areas that curve toward the occlusal surface ( e.g. approximal ) .
this curve is often located where the crown height is lowest , which gives a shorter axial wall .
the combination of the curvature and the shorter axial wall in this area is probably the reason that most fractures start here .
finite element analyses have found increased concentration of stress in the cervical margin with increased difference in axial wall height in the bucco
distal walls ( 34 ) . however , the observed fractures in the test specimen and the reference crowns do not follow the shortest path across to the other side .
the zirconia crowns displayed delamination of the veneer during fracture , whereas the other two crown types only had minor chipping within the veneering ceramics .
these findings are in accordance with clinical findings where chipping is reported more frequently for zirconia - based restorations than for other all - ceramic restorations ( 31,3537 )
. moreover , event though adhesive fractures were found in all zirconia crowns , these occurred at a higher load than the fracture load in the other groups .
the crown with total delamination differed significantly from all other test crowns , but was similar to an in - vivo crown that had been removed as a result of fracture of veneering ceramic only .
clinical failure and would require replacement owing to the large impact on function and esthetics .
chipping damage is more frequently observed in clinical trials and has been successfully simulated in vitro previously .
all these findings indicate that the results are clinically relevant and can be used for clinical decision making .
furthermore , they indicate that the test method is well suited for comparing load at fracture and fracture modes of different all - ceramic crowns .
the glass - ceramic crowns achieved similar fracture - strength values as the alumina - based crowns , even though glass - ceramic is a weaker material , as measured in flexural strength tests of bar - shaped specimens ( 15 ) .
this may be explained by the differences in the geometry of the cores at the crown margin ( fig .
the alumina cores had a uniform thickness of 0.6 mm with a thin edge at the crown margin to allow room for veneering ceramic all the way down to the margin , allowing the opaque , uniform color of the alumina to be covered .
the glass - ceramic cores are more translucent than alumina and can be made in many different tooth colors .
it is not necessary to have veneering material all the way to the margin on these crowns in order to achieve optimal esthetics .
these cores were built up to an anatomic form and with a thicker crown edge than on the alumina and zirconia copings .
the glass - ceramic cores were covered with thinner layers of veneer and glaze than the alumina and zirconia coping to achieve an anatomically correct crown . when evaluating the fracture strength in this trial
it must be taken into consideration that the glass - ceramic crowns can probably achieve better strength values clinically when adhesive luting agents are used ( 38 ) .
the information from the manufacturers indicates that both conventional and adhesive luting agents can be used .
several in - vitro studies have been performed to assess the importance of the geometry of the finish line , but the results of the different trials are ambiguous .
some trials find that the deeper the chamfer , the stronger the crown ; others find no significant difference ( 7,3941 ) .
as most of these trials have loaded the crowns in such a way that the fractures start occlusally or on the incisal edge , it is not surprising that the effect of the finish - line design is limited .
one study , using a method similar to that of the present study , found that the geometry of the finish line is of great importance to both fracture initiation and fracture strength for dome - shaped glass structures ( 11 ) .
further studies , using clinically relevant test methods , must be performed to verify the effect of finish - line geometry for dental ceramic crowns in order to recommend changes in the design of the restoration or the preparation .
the newly developed test method is well suited for assessing the clinically relevant fracture load of different all - ceramic crown materials .
all the tested crowns fractured at loads that indicate suitability for clinical use in anterior crowns .
the authors declare that no conflicts of interest exist for any of the products or equipment mentioned in the paper .
Output:
| comparison of fracture strength and fracture modes of different all - ceramic crown systems is not straightforward .
established methods for reliable testing of all - ceramic crowns are not currently available . published in - vitro tests rarely simulate clinical failure modes and are therefore unsuited to distinguish between the materials .
the in - vivo trials usually lack assessment of failure modes .
fractographic analyses show that clinical crowns usually fail from cracks initiating in the cervical margins , whereas in - vitro specimens fail from contact damage at the occlusal loading point .
the aim of this study was to compare three all - ceramic systems using a clinically relevant test method that is able to simulate clinical failure modes .
ten incisor crowns of three types of all - ceramic systems were exposed to soft loading until fracture .
the initiation and propagation of cracks in these crowns were compared with those of a reference group of crowns that failed during clinical use .
all crowns fractured in a manner similar to fracture of the clinical reference crowns .
the zirconia crowns fractured at statistically significantly higher loads than alumina and glass - ceramic crowns .
fracture initiation was in the core material , cervically in the approximal areas . |
PubmedSumm8824 | ***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:
| genomic and metagenomic
investigations have recently led to the
delineation of a novel class of natural products called ribosomally
synthesized and post - translationally modified peptides ( ripps ) .
ripps
are ubiquitous among living organisms and include pharmaceutically
relevant compounds such as antibiotics and toxins .
a prominent example
is polytheonamide a , which exhibits numerous post - translational modifications ,
some of which were unknown in ribosomal peptides until recently . among
these post - translational modifications ,
c - methylations have been proposed
to be catalyzed by two putative radical s - adenosylmethionine
( rsam ) enzymes , poyb and poyc . here
we report the in vitro activity of poyc , the first b12-dependent rsam enzyme
catalyzing peptide c-methylation .
we show that poyc
catalyzes the formation of s - adenosylhomocysteine
and 5-deoxyadenosine and the transfer of a methyl group to l - valine residue .
in addition , we demonstrate for the first
time that b12-rsam enzymes have a tightly bound mecbl cofactor
that during catalysis transfers a methyl group originating from s - adenosyl - l - methionine .
collectively , our results
shed new light on polytheonamide biosynthesis and the large and emerging
family of b12-rsam enzymes . |
PubmedSumm8825 | ***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 are various analgesic options like systemic opioids , neuraxial blocks , non steroidal anti inflammatory drugs ( nsaids ) , local infiltration , and so on ; however , in renal transplant patients systemic opioids are used with caution because of altered pharmacodynamics and opioid - related side effects .
hence , we decided to explore an alternative technique for postoperative analgesia in the form of continuous transversus abdominis plane ( tap ) block .
it is more suitable for operations where parietal pain is a major cause of pain .
renal transplant recipients are ideally suited to gain maximum benefit from tap blocks as the incision involves the lower abdomen which is usually covered by this block without any intraperitoneal extension eliminating the visceral pain component .
results of various trials suggest that the effect of single shot tap block lasts for variable duration of time hence , we decided to insert catheter in tap plane under direct vision to increase the duration of analgesia .
after obtaining approval by the hospital ethical committee and written informed consent , 43 american society of anesthesiologists risk iii patients scheduled for open iliac fossa renal transplantation were enrolled in a prospective , randomized , double - blind , controlled study .
patients allergic to local anesthetics drugs , opioid addicts , hepatic disease and psychiatric disorders were excluded from our study .
patients were randomly allocated to group s ( study group ) and group c ( control group ) by sealed envelope method .
the patients , observer , and staff providing postoperative care were blinded to group assigned .
pulse , electrocardiogram , noninvasive blood pressure , peripheral oxygen saturation ( spo2 ) , end - tidal co2 ( etco2 ) , central venous pressure were monitored throughout the procedure and urine output was measured after clamp release .
a multiorifice epidural catheter was placed above the approximated transversus abdominis , through an epidural needle .
about 5 - 6 cm of catheter was positioned between the ta and internal oblique muscles ( ioms ) .
[ figures 1 and 2 ] after closure of wound , before reversal 1 mg / kg of 0.25% bupivacaine for group s or normal saline for group c was given as a bolus .
this was followed by an infusion of 0.125% bupivaciane at 0.25 mg / kg / h for group s and an infusion of normal saline for group c in postoperative room by the infusion pump .
insertion of epidural needle in transversus abdominis plane placement of epidural catheter visual analogue score ( vas ) at rest and movement was noted at the interval of 2,4,6,12 and 24 h. postoperatively . when vas score was more than 3 , inj .
time for the first request of rescue analgesic and total pentazocine consumption in 24 h. was noted .
sedation scores were assigned by the investigator using a sedation scale ( awake and alert= 0 , asleep but easily aroused = 2 , deep sleep = 3 ) .
antiemetics , that is , inj ondansetron 8 mg were given to any patient who complained of nausea or vomiting and to all patients who received pentazocine .
the primary outcome measure in this study was 24 h opioid ( pentazocine ) consumption .
secondary outcome measures included time to first request for analgesic , vas score , and side effects associated with pentazocine consumption like nausea and sedation score .
the sample size was calculated on the basis of 24 h pentazocine consumption for the patients undergoing open renal transplantation .
we conducted a pilot study which showed 24 h pentazocine consumption of 39 13.4 mg in control group versus 18 16.4 mg in study group .
based on this pilot study , we calculated 16 patients per group would be required to get a power of 95% and error of 0.05 .
statistical analysis was performed using statistical package of social sciences , that is , spss version 12 .
data are expressed as mean standard deviation for continuous variables and number ( % ) for categorical variables .
fisher 's exact test and chi - square analysis was used for comparing categorical data .
statistical analysis was performed using statistical package of social sciences , that is , spss version 12 .
data are expressed as mean standard deviation for continuous variables and number ( % ) for categorical variables .
fisher 's exact test and chi - square analysis was used for comparing categorical data .
the catheter was blocked in one patient in each group and there was accidental removal of catheter in one patient of group s. so they were excluded from the study .
there was no significant difference in demographic profile as well as duration of anesthesia and surgery between the two groups [ table 1 ] .
vas pain scores were significantly high in group c compared to group s at rest and on movement [ figures 3 and 4 and tables 4 and 5 ] . patients in group s had significantly longer time for first analgesia ( tfa ) request than those in group c. total consumption of pentazocine was higher in group c ( 56.42 12.46 mg ) as compared with group s ( 9.75 13.95 mg ) .
total number of patients requiring rescue analgesia in group s was only 9 as compared with group c where all patients required rescue analgesia [ table 2 ] .
graph depicting visual analogue score score at rest graph depicting visual analogue score score on movement postoperative analgesic requirement in 24 h postoperative sedation score visual analogue score at rest visual analogue score scores on movement postoperative sedation score was higher in group c [ table 3 ] .
there were no signs of systemic toxicity of local anesthetic in any of our patients .
preexisting pain , anxiety , fear of graft rejection , and emotional stress increase the risk of significant postoperative pain in renal transplant patients . main principle of tap block is to deposit local anesthetic in plane between iom and transversus abdominis muscle to block the sensorimotor innervations of the anterior abdominal wall which is supplied by anterior rami of the spinal segmental t7-t11
. it can be single shot or continuous via catheter to prolong its analgesic effect .
we kept epidural catheter in tap plane by open technique for 24 h as there is significant decline in the use of analgesics in renal transplant recipients from the 2 day after surgery and usually they are switched over to oral analgesics .
vas scores were significantly higher in group c compared with group s both at rest and on movement all throughout 24 h. in study by mukhtar and khattakm pain scores up to 12 h were similar to our study ; however , there was no difference in pain at 24 h in two groups probably because they gave a single shot block in their study .
the first dose of rescue analgesia was required after about 270 347.96 min and total consumption of pentazocine ( opioid ) in 24 h was higher in group c. in a study by jankovic et al . , where they gave continuous tap block in seven patients for renal transplant .
there was 80% reduction in morphine requirement during the first 24 h. our result regarding opioid consumption in first 24 h is not similar to the result shown by wong et al . , where unilateral tap block was given prior to general anesthesia in renal transplant patients . in their study ,
median fentanyl consumption was lower at 2 , 4 , and 6 postoperatively in tap block group but did not reach statistical significance .
no significant postoperative nausea vomiting ( ponv ) was observed in both the groups as prophylactic ondansetron was given .
sedation score was higher in control group which is similar to study done by mukhtar et al .
there was minimal chance of hematoma as catheter was placed under direct vision minimizing chances of inadvertent vascular injury .
these patients are more prone to infection as they are immunocompromised . to prevent tap catheter - related infection ,
the catheter was removed after 24 h and patients were switched over to oral analgesics as it is an extraperitoneal surgery .
we preferred open technique as tap plane in renal transplant is accessed without any major dissection .
it is not a blind technique with minimal probability of injury to surrounding structures or inadvertent intravascular injection .
open technique allows anatomically accurate placement of the tap catheter and prolongs the analgesic effect of the tap block . from this study
, it seems that tap block holds considerable promise for patients undergoing renal transplant ; however , further large well - controlled studies are required in terms of its safety , optimal dose , and volume of local anesthetic before it can be implemented in routine clinical practice .
the transversus abdominis plane catheter technique for postoperative control after renal transplant has proved to be of equal efficacy in relieving the postoperative pain after renal transplant .
Output:
| background and aims : transversus abdominis plane ( tap ) block is suitable for operations where parietal pain is a major cause of pain .
renal transplant recipients are ideally suited to gain maximum benefit from tap block as the incision classically involves the lower abdomen .
this study was conducted to evaluate the analgesic efficacy of continuous tap block in transplant recipients.material and methods : in a prospective double - blind study , 40 chronic renal failure patients undergoing open renal transplant were randomly divided into two groups . at the end of surgery during closure , a multiorifice epidural catheter was placed in tap plane .
study group ( group s ) received inj bupivacaine bolus 1 mg / kg ( 0.25% ) followed by infusion 0.25 mg / kg ( 0.125% ) through the catheter , whereas control group ( group c ) received normal saline through the catheter .
inj pentazocine ( 0.3 mg / kg ) was given as rescue analgesic at visual analogue score ( vas ) > 3 in any group at rest or on movement .
the analgesic efficacy was judged by vas , time of first rescue analgesic , and total analgesic consumption in 24 h.results:patients in group s had significant lower vas scores , longer time to first rescue analgesic ( 270 347.96 vs. 42.85 32.27 min ) and lower pentazocine consumption ( 9.75 13.95 vs. 56.42 12.46 mg ) in 24 h. there was significant sedation in group c.conclusion:the tap catheter technique for postoperative pain control after renal transplant has proved to be effective in relieving the postoperative pain after renal transplant with less pentazocine requirement and less sedation . |
PubmedSumm8826 | ***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: throughout the world , the proportion of older people in the general population has increased in recent years . in addition to other general health issues
there is a high level of tooth loss , dental caries , periodontal disease , xerostomia and cancer [ 1 , 2 ] .
there are several studies on the dental status of institutionalized older people throughout the world .
for example , studies have been reported from the united states , australia [ 4 , 5 ] , canada , india , italy [ 8 , 9 ] , greece , croatia , the fiji islands , hong kong and singapore , indicating that the dental status of institutionalized older people is generally poor , with a high decayed , missing , or filled teeth ( dmft ) index . in brazil ,
the demographic transition has been particularly accelerated , which has been associated with a higher demand for long care facilities for older people . despite this , data on institutionalized older people from brazil are scarce .
some reports from south brazil suggest that the oral health of institutionalized older people is poor [ 15 , 17 ] .
data on the dental status of institutionalized older people from the northeast of the country , which has different socioeconomic and cultural characteristics from the south and is considered the poorest region of the country , are virtually nonexistent .
in particular , there is no data on the factors that contribute to poor oral health status in these special populations and the state of oral hygiene practices . to assist in filling this gap ,
a cross - sectional study was performed assessing oral status and hygiene practices of residents in a nursing home in fortaleza , a capital city in northeast brazil .
this cross - sectional study was performed in the institution lar torres de melo , a nursing home in fortaleza , capital of cear state in northeast brazil .
lar torres de melo is the largest institution for older people in the state and typically would have about 220 residents .
all individuals residing in the institution and who matched the who definition for older people were eligible for the study .
of the 220 residents , 167 ( 75.9% ) met this inclusion criterion of 65 years of age .
the study consisted of a clinical oral examination ; a structured interview using a pretested questionnaire to assess oral hygiene practices , such as frequency of oral hygiene , type of hygiene , and visits to dentists ; the analysis of the patients ' records to obtain data on age , marital status , time in the institution , general literacy level ( years of schooling ) , and retirement status .
professional carers were interviewed in some cases , particularly when the older people were not in the physical or mental condition to answer questions . the clinical oral examination consisted of assessment of the dmft using brazilian standard procedures , which were similar to who standards . to reduce interobserver bias ,
detailed clinical data , including periodontal diseases and the use and need of prosthesis of the study population , are published elsewhere .
data were double entered into a database using the epi info software package ( version 6.04d , centers for disease control and prevention , atlanta , usa ) and checked for entry errors .
after bivariate analysis using t test and kruksal wallis test , appropriate multiple linear regression , using the dmft as the dependent variable , was performed .
all variables with a significance level of p < .25 were included in the regression analysis .
regression analysis was done with stata software ( version 8 ; stata corporation , college station , tex , usa ) .
the study was approved by the ethical review board of the federal university of cear , brazil . informed written consent
one hundred and sixty individuals were included in the study ( 95.8% of the target population ) .
the mean age was 76.6 years ( standard deviation = 8.6 years ) , with a maximum age of 100 years .
the mean time of living in the institution was 8.2 years ( range : 1 month50 years ) .
ninety - three ( 58.1% ) were edentulous , and the mean number of teeth missing was 28.4 .
the mean dmft of all study participants was 29.7 ( sd = 4.4 ; edentulous participants were allocated a dmft of 32 ) .
the mean dmft for the 67 dentate individuals was 26.6 ( sd = 5.3 ) ; 16 ( 23.9% ) of these presented a dmft of 32 .
of all participants , 109 ( 68.1% ) had a dmft of 32 , which meant that they did not have a single healthy tooth .
almost 90% practiced oral hygiene , and more than three - quarters of these did not need the help of a professional carer .
a minority had visited a dentist in the preceding three months , most commonly for dental extraction .
only 58 participants perceived a need for treatment ; however , clinical examination revealed the need for at least some dental treatment in all 160 cases . in the bivariate analysis ,
only sex , age , and general literacy level were significantly associated with the dmft ( table 3 ) .
however , this variable was confounded by age ( i.e. , the mean age of females was higher than that of males ) . in the multiple regression analysis , age (
= 0.11 ; p = .005 ) , general literacy level ( = 0.79 for each additional year of schooling ; p = .003 ) , and practice of any type of oral hygiene ( = 2.5 ; p = .02 ) were independently significantly associated with the dmft .
however , only 13% of the variance of the dmft could be accounted for by these three independent variables ( r = 0.13 ) .
a lower dmft was observed among individuals who performed their own oral hygiene and used a toothbrush .
however , these and other variables regarding oral hygiene habits ( such as practicing any type of oral hygiene , frequency of oral hygiene , cleaning the tongue , and regular tooth brushing after meals ) did not show any significant association with the dmft .
our study shows that the experience of dental caries ( as represented by the dmft index ) in institutionalized older people in northeast brazil is extremely high .
the data also found that there were insufficient oral hygiene practices in this special population .
similar to most studies on institutionalized older people throughout the world [ 314 ] , a high proportion of the population was edentulous .
the oral health status in the general older people population has been addressed increasingly in the past years , but the oral health of institutionalized older people and underprivileged populations continues to be a neglected issue [ 1 , 2023 ] .
the dmft varies considerably not only between different socioeconomic groups , but also between different countries and cultures , and it is consistently higher in institutionalized people than among community - dwelling populations [ 415 , 17 , 24 ] .
for example , in hong kong , the mean dmft index was 21.4 in institutionalized as compared to 17.7 in noninstitutionalized older people .
a small number of other studies from southern brazil indicate that the oral health status of institutionalized as well as noninstitutionalized older people was also very poor [ 15 , 17 , 25 ] . in southern brazil ,
the dmft in institutionalized was as high as 30.8 , which was similar to our study population from the northeast ( dmft = 29.7 ) .
a representative national survey made in 2002/2003 on oral health conditions in the brazilian population revealed a mean dmft of 27.8 in community - dwelling older people .
oral hygiene practices in the study population were inadequate , and this group of older people had poor access to dental health care . in all residents , a need for treatment by a dentist was detected by the clinical assessment , but only 44% had perceived that need . in brazil , residents in these institutions tended to have very poor socioeconomic conditions , and the findings of the present study indicate that dental health care for the poorest and oldest in society needs more attention .
initially , these issues were discussed with the director of the institution , and a dentist now regularly performs preventive and curative oral health care activities .
an integrated approach is needed , and oral health education should include all stakeholders . additionally , it is necessary to implement curative and rehabilitation measures in these populations to reduce the need for future dental treatment . due to the cross - sectional design
, causal and temporal relationships between independent variables and dmft could not be clearly established .
in addition , a possible limitation of the study was that it was conducted in a single institution , although this was the largest nursing home in the state of cear . in conclusion
, this study shows that the dental status of institutionalized older people in the state of cear is very poor .
there is a lack of perceived need for dental services and of adequate oral self - care .
dental health education is also needed focusing on the special needs of this neglected and socioeconomically deprived population to improve their quality of life .
Output:
| in this study we describe the dental status and oral hygiene practices in institutionalized older people and identify factors associated with poor dental status .
a cross - sectional study was performed in a nursing home in fortaleza , the capital of cear state ( northeast brazil ) .
the number of decayed , missing , and filled teeth ( dmft ) was assessed in the residents of the nursing home ( n = 167 ; mean age = 76.6 years ) .
the mean dmft value was 29.7 ; the mean number of missing teeth was 28.4 .
ninety - three ( 58.1% ) were edentulous .
almost 90% practiced oral hygiene , but only about half used a toothbrush .
only 8% had visited a dentist in the preceding three months .
most of the variables regarding oral hygiene habits ( such as the use of toothbrush , frequency of oral hygiene per day , regular tooth brushing after meals ) did not show any significant association with the dmft . in multivariate regression analysis , age , general literacy level , and practice of oral hygiene
were independently associated with the dmft ( r2 = 0.13 ) . institutionalized
older people in northeast brazil have poor dental status , and oral hygiene practices are insufficient .
dental health education is needed focusing on the special needs of this neglected and socioeconomically deprived population to improve their quality of life . |
PubmedSumm8827 | ***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 loss of gait ability after stroke becomes a lifetime disability in addition to social
activity limitations .
furthermore , the
gait assessment must be reliable and valid to assess the gait disorder and treatment effects
and establish a future treatment plan .
however , few gait assessment tools have been
described to date that can be used to comprehensively assess gait ability2 .
gait assessment tools currently range from
those that use biomechanical and kinematic analyses3 to those with a simple clinical design that can be easily and
swiftly applied4 . however , skillful
clinicians and repeated tests are required to ease the difficulty of this technological
application , save time , and collect accurate data2 .
in addition , impractical issues arise from day - to - day clinical
applications due to the difficulty obtaining results and interpreting the data1 . timed up - and - go tests and walking velocity tests ( 512 m ) , which are the most common
methods used in clinical research , are basic tests that reflect an individual s gait
ability5 .
hence , they can be used as
assessment standards since they have the advantage of providing diverse therapeutic
interventions by grasping the functional gait performance of patients with data that are
affordable to obtain and easy to manage and interpret6 .
gait speed can be a useful assessment tool for estimating
functional independence and treatment effects .
stroke patients have different gait speeds
since they become stressed about their present functional status ( physical and
psychological ) , while the assessment distance may also differ ( 512 m)7 , 8 .
moreover , since
speed is measured at a certain point in time , its universal application may be limited .
the inter - rater reliability ( icc ) of the mfac in patients with hip fractures is 0.96 , with
a construct validity of r=0.81 on the elderly mobility scale ( ems)9 , while the inter - rater reliability for acute stroke patients
has a consistency ratio of 93% and a weighted kappa of 0.9710 .
nonetheless , the inter - rater reliability of the mfac for acute
stroke patients has not yet been reported , and there is an unclear correlation between gait
speed and functional mobility performance .
in addition , the unmodified fac is still being
used in korean clinical research , and the clinical application cases of mfac have not yet
been reported in this country .
therefore , the present study aimed to investigate the
validity of the correlations between inter- and intra - rater reliability ( icc , kappa ,
standard error of the mean [ sem ] , and minimum detectable change [ mdc ] ) through which the
psychological characteristics of the mfac can be reflected as well as the modified rivermead
mobility index ( mrmi ) .
the present study was conducted from september 2014 to may 2015 on 76 chronic stroke
patients ( diagnosed more than 6 months earlier ) who were hospitalized at hospital m for
treatment .
all of the patients understood the purpose of the study and provided written
informed consent prior to participating as required by the ethical standards of the
declaration of helsinki .
the subjects were selected if they scored more than 23 points on
the mini - mental state examination - korean version ( mmse - k ) , which is designed to test
cognitive function , and if they did not have neurological problems in the lower limbs
( determined by the ability to safely walk on a flat surface for 10 m , regardless of the use
of a cane or other aids ) and orthopedic problems in either leg . based on the aforementioned
criteria ,
76 chronic stroke patients were initially selected , but during the course of the
study , 6 dropped out and 4 quit the study after hospital discharge or with deteriorating
health . ultimately , the data of 66 patients were obtained .
the mfac , using a 7-point likert scale , was used to make distinctions between the patients
gait abilities .
the test and re - test reliability of the mfac among stroke patients has been
reported , with a consistency ratio of 93% and a weighted kappa coefficient of 0.9710 .
a gait speed test with a distance of 5 m
was performed , during which the research subjects psychological burden and stress can be
minimized11 .
the test and re - test reliability of this assessment tool is
reportedly high with an icc of 0.880.9712 .
the inter - rater reliability of mrmi for stroke patients had an icc of 0.9813 . in this study
, the shapiro - wilk test was performed using spss ( version 18.0 for windows 7 )
to test variable normality , while a frequency analysis was used to analyze the research
subjects general characteristics .
the percent of total agreement and the kappa coefficient
were calculated to show the consistency ratio of mfac between the raters , while inter- and
intra - rater reliability were measured using the intra - class coefficients
( icc2,1 ) . the absolute reliability ( without measurement error )
in addition , the stable / maximum gait speeds regarding the mfac and mrmi
performance scores were compared using the mann - whitney u test and the post - hoc
kruskal - wallis test .
the validity testing of the mfac was done with a univariate linear
regression analysis , which analyzes the causal relationship between the spearman correlation
coefficient and the stable / maximum gait speed regarding functional gait ability and mrmi .
the research subjects were 38 males ( 57.6% ) and 28 females ( 42.4% ) with an average age of
59.82 years . among these subjects ,
42 had cerebral infarction ( 63.6% ) and 24 had cerebral
hemorrhage ( 36.4% ) , while 29 had right - sided paralysis ( 43.9% ) and 37 had left - sided
paralysis ( 56.1% ) .
the average duration of illness was 13.27 months since onset , and the
patients had an average mmse - k score of 25.82 points .
twenty - four patients were able to walk
independently ( 36.4% ) , while 25 walked with one - legged walking sticks ( 37.9% ) , 15 walked
with 4-legged walking sticks ( 22.7% ) , and 2 patients used walkers ( 3.0% ) .
the average mfac
was 5.39 points , and the stable and maximum gait speeds were 60 m / s and 73 m / s ,
respectively .
the inter - rater reliability of mfac had an icc of 0.982 ( 0.9710.989 ) , kappa coefficient of
0.923 , consistency ratio of 94% , sem of 0.174 , and mdc of 0.482 , while the intra - rater
reliability had an icc of 0.991 ( 0.9860.995 ) , kappa coefficient of 0.961 , consistency ratio
of 96% , sem of 0.124 , and mdc of 0.343 , indicating high reliability .
there was a statistically significant difference between the mfac and the stable / maximum
gait speeds ( x=54.49 and 54.70 , respectively ; p<0.001 ) , and a significant
difference from mrmi was found ( x=53.76 ; p<0.001 ) .
in addition , mfac validity
had high correlations with the stable / maximum gait speeds ( r=0.880.90 ) and mrmi
( r=0.90 ) .
the mfac affected 81% and 77% of the stable and maximum gait speeds , respectively , while
affecting 82% of the mrmi .
the present study s findings corroborate the high inter- and intra - rater reliability of the
mfac .
such findings are in line with those of previous studies in which the inter - rater
reliability of mfac of patients with hip fractures had an icc of 0.969 , while the inter - rater reliability of the mfac for acute
stroke patients had a consistency ratio of 93% and a weighted kappa coefficient of 0.9710 .
the inter- and intra - rater reliability of
the present study was very high , with an icc>0.98 , kappa coefficient > 0.92 , and a
consistency ratio > 94% , all of which were measured by therapists who had worked in the
field for at least 10 years .
however , for this study , therapists with < 5 years
experience in rehabilitation treatment for stroke patients , or even unskilled therapists ,
would not have had problems performing video observations and individual assessments .
moreover , the mfac has clear standards ; however , in this study , not a single subject scored
1 or 2 points on the mfac . regarding assessment tools for clinical research , sem and mdc represent absolute
reliability to reflect psychological features for assessing treatment effects and
determining effect size , and they offer very useful information for clinicians and
therapists14 .
the sem and mdc of the
mfac , which had not been explored before , were first introduced in the present study . in
this study ,
the sem of the mfac was 0.17 , less than 10% of the average mfac score , while the
mdc of the mfac was 0.48 , less than 10% of the maximum mfac score , both of which fall within
the acceptable range15 .
the mdc
represents the smallest expected value of the individual treatment effect and is a very
important indicator for clinicians predicting a patient s achievable recovery level after
treatment15 . in the present study
, a difference was noted between the stable / maximum gait speed and mrmi
with regard to the mfac groups .
the 66 research subjects were divided into five groups based
on the mfac ( 37 points ) , and their stable / maximum gait speeds and mrmi were measured .
they
were all reported to be different . as the mfac increased from 3 points ( stable / maximum gait
speeds of 0.16 m / s and 0.25 m / s , respectively )
to 5 points ( 0.50 m / s and 0.58 m / s ,
respectively ) , the average gait speed increased with the mrmi performance score ,
representing functional mobility .
what is unique is that there was a difference even between
the stable and maximum gait speeds of 6 points on the mfac ( 0.76 m / s and 0.89 m / s ,
respectively ) and of 7 points ( 0.88 m / s and 1.12 m / s , respectively ) among the independent
ambulatory group . among the gait phase classifications that are most commonly used in clinical research , such
as that of perry ,
a gait speed > 0.4 m / s is used for indoor walking , while 0.40.8 m / s is
the gait speed of limited outdoor walking and > 0.8 m / s is used for outdoor walking16 .
in addition , the cut - off value of the
gait speed for outdoor walking is 0.661.14 m / s17 ,
18 .
however , the recent definition of
outdoor walking includes a cut - off value and distances of > 0.73 m / s and > 332 m ,
respectively , and includes being able to go up and down stairs and turn corners
independently19 , 20 . according to this definition
, the research subjects in the present
study were classified into the outdoor walking group , while the subjects whose minimum mfac
score was 6 points were expected to be assigned to the outdoor walking if their gait speed
was 0.76 m / s .
the improvement in the functional gait performance of these research subjects ( mfac of 37
points ) increased along with increased mrmi , which reflected the stable / maximum gait speeds
and functional mobility .
in general , healthy people can adjust their gait performance at
different gait speeds . however , most patients with neurological diseases respond slowly to
their surroundings because of limited outdoor walking and perform physical activities very
passively2 . therefore , improvements in
the functional gait performance of stroke patients with gait disability are well - reflected
in their gait speed and physical activity performance .
the mfac used in the present study can be a gait assessment tool for clinical research
since its validity is proven , inter- and intra - rater reliability are high , and it is
relevant to gait speed and functional mobility .
in addition , it is a sophisticated method
that can reflect the clinical improvement of a patient s gait ability , and it can be easily
used to enhance gait speeds and clinical research designs .
however , the present study has
limitations ; its findings can not be generalized because the assessments are limited to a
certain period in time , while an assessment to estimate the cut - off distance for outdoor
walking was not performed .
future studies should include assessments to estimate the
cut - offs for mfac , distance , and other factors for outdoor walking .
Output:
| [ purpose ] this study aimed to examine the inter- and intra - rater reliability and validity
of the modified functional ambulation category ( mfac ) scale .
[ subjects and methods ] the
participants were 66 stroke patients with hemiparalysis .
the inter- and intra - rater
validity of the mfac was calculated using the spearman correlation coefficient .
a score
comparison of the stable or maximum gait speed with regard to mfac and modified rivermead
mobility index ( mrmi ) performances was performed as a univariate linear regression
analysis to determine how the kruskal - wallis test affects the mrmi and stable / maximum gait
speed with regard to mfac .
[ results ] the inter - rater reliability of the mfac ( intraclass
coefficient [ icc ] ) was 0.982 ( 0.9710.989 ) , with a kappa coefficient of 0.923 and a
consistency ratio of 94% .
in contrast , the intra - rater reliability of the mfac ( icc ) was
0.991 ( 0.9860.995 ) , with a kappa coefficient of 0.961 and a consistency ratio of 96% ,
showing higher reliability . moreover , there was a significant difference in stable / maximum
gait speed between the mfac and the mrmi .
[ conclusion ] since the mfac has sufficient
inter- and intra - reliability and high validity , it can be used as an assessment tool that
reflects the gait performance and mobility of stroke patients . |
PubmedSumm8828 | ***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: though paraneoplastic pemphigus ( pnp ) and myasthenia gravis are rare , but can be associated with castleman 's disease .
its association with various autoimmune diseases is well known and hence presentation can vary . this case report is an attempt to create awareness among us not to neglect a common symptom like oral ulcers which are resistant to treatment .
a 25-year - old lady with no significant medical history including allergic diseases such as bronchial asthma was admitted to a tertiary care hospital of south india because of recalcitrant erosive lesions on her oral mucosa and lip that had begun 3 months earlier .
the patient was treated for steven johnson syndrome in a private hospital with steroids prior to the admission . on admission
, there were extensive erosions in the oral mucosa and tongue with thick hemorrhagic crusts on the lip [ figure 1 ] and erosive lesions over labia majora .
histological examination of a biopsy taken from a violaceous , indurated lesion of the lower lip showed a band - like infiltrate of lymphocytes and histiocytes throughout the papillary dermis , hydropic degeneration of basal keratinocytes , and necrotic keratinocytes within the hypertrophic epidermis .
skin biopsy was suggestive of interface dermatitis suggestive of pemphigus vulgaris [ figure 2 ] .
biopsy from un - involved buccal mucosa for direct immunofluorescence was negative for antibodies . during hospital
workup for respiratory weakness with limb weakness with preserved deep tendon reflexes was done with neostigmine test .
positive response to the test was suggestive of myasthenia gravis ; hence , pyridostigmine and steroids were started with which she was off ventilator in next 48 hours
. ultrasound abdomen and subsequently computed tomography ( ct ) imaging of the abdomen done revealed a solid tumor of 8.5 4 5.5 cm of size in right paraspinal area near the hilum of right kidney [ figure 3 ] .
mild hyperinflation without infiltrates was visible on chest radiographs , but conventional ct of the chest showed no remarkable abnormalities .
she underwent surgery for the retroperitoneal tumor and highly vascular tumor of 8 6 5 cm was removed without any intraoperative and post - operative complications .
histopathology revealed castleman 's disease of hyaline vascular variety [ figures 4 - 6 ] .
skin lesions improved at the end of 2 weeks post - operatively [ figure 7 ] and she was discharged with an advise to tapper her steroids and to continue pyridostigmine for myasthenia gravis . crusted and exfoliating dark brown velvety lesions on the oral cavity skin biopsy showing interface dermatitis suggestive of pemphigus vulgaris cect abdomen showing paraspinal mass lesion of 8.5 4 5.5 cm gross specimen showing cut surface of lymph node with pale brown homogenous appearance with intact capsule microphotograph showing pale follicle with concentric onion peel - like lymphocytes and a follicle traversed by a hyalinized vessel microphotograph showing pale follicle with concentric onion peel - like lymphocytes and a follicle traversed by a hyalinized vessel post - operative picture showing marked resolution of the lesions
three histopathological variants are hyaline vascular variant , plasma cell variant , and mixed variants .
thoracic site is most common constituting 70% cases ; among them around 80% is in mediastinum .
other common associations are hiv , kaposi sarcoma , non - hodgkin lymphoma , and polyneuropathy , organomegaly , endocrinopathy , monoclonal gammopathy , and skin changes syndrome .
paraneoplastic pemphigus ( pnp ) , an autoimmune syndrome that was first described by anhalt et al .
in 1990 , are mostly associated with lymphoproliferative neoplasms , i.e. , non - hodgkin 's lymphoma , chronic lymphocytic leukemia , castleman 's disease and , less commonly , thymoma and retroperitoneal sarcomas .
presence of intractable stomatitis and anti - plakin protein autoantibodies is a constant feature ; however , there have been reports of antibody negative pnp in literature .
progression of disease and death occurs frequently despite treatment of the associated neoplasm and regardless of therapeutic intervention for the autoimmune disease . even after complete resection of castleman 's disease
any recurrence of oral lesions or rise in antibody levels would signal recurrence or new lesions of castleman 's disease .
a study of 28 patients presenting with stomatitis with lichenoid skin lesions who later on were found to have castleman 's disease on follow - up showed fatality among 22 patients over a period of 2 years secondary to respiratory failure .
post - mortem revealed evidence of progressive bronchiolitis obliterans in those cases indicating progressive autoimmune damage to the lung .
treatment with anti - il-6 has been shown to improve platelet counts among patients with autoimmune thrombocytopenia with castleman 's disease ; however , there has been no study among patients with pnp . in our patient ,
diagnosis of myasthenia was made on the basis of neostigmine test where 0.04 mg / kg is given intramuscularly or 0.02 mg / kg intravenously ( one time only ) observing for clinical improvement of weakness .
our patient had a rare combination of pnp with extrathoracic castleman 's disease with myasthenia gravis .
castleman 's disease being hyaline vascular variety presenting with systemic manifestation is also a rare presentation . on follow - up ,
she developed progressive hypoxia and succumbed to ventricular arrhythmia at the end of 1 year .
castleman 's disease , though described as benign entity , its varied presentation with myasthenia , pnp , and progressive lung damage resulting in bronchiolitis obliterans secondary to autoimmune injury makes it lethal .
unicentric hyaline vascular variety with systemic manifestations behaves similar to multicentric and hence is associated with bad prognosis as in our case .
any non - healing oral ulcers with or without skin lesions should alert the treating physician for extensive workup and to intervene at the right time .
presentation of unicentric hyaline vascular variant castleman 's disease with systemic manifestations like paraneoplastic pemphigus ( pnp ) and myasthenia is uncommon .
Output:
| castleman 's disease is a rare autoimmune disorder with varied clinical presentations .
castleman 's commonly involves mediastinum and hence it is thoracic in most of the reported cases .
paraneoplastic pemphigus ( pnp ) and myasthenia gravis can be associated with multicentric castleman 's disease .
its association with hiv , kaposi sarcoma , and lymphoma is also well known .
we report a rare combination of unicentric , extrathoracic castleman 's disease with pnp and myasthenia gravis . |
PubmedSumm8829 | ***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 benefits of a tracheostomy are generally accepted reduced risk of laryngeal injury , weaning from intermittent positive pressure ventilation ( ippv ) , less sedation , improved patient comfort , communication and oral hygiene and , although risks exist , they are thankfully rare .
early tracheostomy may improve survival , although its impact remains controversial ( a controversy hopefully to be answered by the tracman study ) .
the impact on morbidity / mortality is difficult to assess as patient factors and events in the intensive care unit ( icu ) lead to bias so called ' confounding in indication ' but by using a propensity score , clec'h and colleagues assessed the effect of a tracheostomy on mortality , allowing for bias . in this prospective observational cohort study ,
of the 2,186 patients who received ippv , 177 received tracheostomy ( the majority surgical rather than percutaneous technique ) and , after controlling for bias and confounding variables , tracheostomies were not associated with improved icu survival .
there was no difference if the tracheostomy was placed before or after 7 days , although the median time for tracheostomy was 20 days ( double the uk equivalent ) .
in fact , tracheostomies appeared to be associated with increased post icu mortality , especially in patients discharged with the tracheostomy remaining in situ .
dr l'her states in an editorial that the patients were matched for the probabilities of getting a tracheostomy but it was possible that there were further factors that have not been controlled for for example , numerous adverse events on the icu , and so on .
the increase in post icu mortality in patients with a tracheostomy may reflect patients who were doing badly for a number of reasons and in whom the tracheostomy was left in place .
it was , therefore , not surprising that mortality was worse in this group . given the variation in opinions on the use of tracheostomies , nathens and colleagues investigated the extent of variations in tracheostomy rates in trauma centres and what institutional or patient factors caused them .
the investigators found that tracheostomy rates varied widely ( mean rate of 19.6 per 100 admissions ; range 0 to 59 ) and the variation persisted after stratification by age , mechanism of injury and severity .
the variability in tracheostomy rates appeared to be driven by chance , physician preference and local culture opposed to medical indications , although it could reflect the preference of timing ( timing was not recorded ) , where patients undergoing a late tracheostomy had the opportunity to recover before the procedure .
dr scales mentions in an editorial that despite some data that may have helped clarify the variation being unavailable and there being no data on outcomes , the decision to perform a tracheostomy appears opinion based . when literature to support a procedure is lacking , we look to expert opinion but what if this is contradictory ? one of the perceived benefits of a tracheostomy is a reduction in sedation requirements . in a retrospective analysis , dr veelo and
using a sedation protocol and a sedation intensive care score ( sedic ) patients were weaned from sedation .
of these , 62.4% required morphine before tracheostomy while 32.5% required morphine post - tracheostomy .
there were no differences in prescribed sedatives in the two days before and after tracheostomy .
the authors conclude that sedation requirements were already in steep decline prior to tracheostomy and , although they commented that this was contrary to belief that tracheostomies reduce sedation requirements , it may just reflect the withdrawal of sedation as extubation is attempted .
this does emphasize the importance of strict adherence to protocols or guidelines that aim to reduce sedation requirements in the icu .
in new york , drs solh and jaafar looked at 455 critically ill patients who underwent a surgical trachesotomy and compared the incidence and severity of complications between 89 morbidly obese patients ( body mass index ( bmi ) 40 ) and the remaining control group ( bmi < 40 ) .
complications were seen in 25% of morbidly obese patients ( mortality 2% ) compared to 14% in the control group ( mortality 0.6% ) .
the commonest serious complication was tracheostomy tube obstruction in obese patients and bleeding in the control group .
bmi , age and charlson index ( predictive index of mortality from co - morbid conditions ) were found to be significant risks in univariate analysis , while only bmi was independently associated with increased risk of tracheostomy - related complications .
interestingly , obesity was not associated with a worse outcome in a prospective observational cohort study evaluating the effects of bmi on 12 month survival in critically ill patients .
mortality did , however , increase with low albumin , advanced age and comorbid disease and the authors postulate that reasons for their contrary findings centre around different end points or bias perhaps medical problems associated with obesity rather than obesity per se are risk factors .
they suggest a high bmi may provide a nutritional reserve in times of stress but admit that although bmi is widely used , it does not distinguish between fat and muscle a waist to hip ratio may be a more accurate measure .
dr chalela and colleagues report the superior results of magnetic resonance imaging ( mri ) over computerised tomography ( ct ) for detection of acute stroke . in this single centre , prospective blind comparison of non - contrast ct and mri ,
mri detected acute stroke ( ischaemic or haemorrhagic ) and chronic haemorrhage more frequently than ct .
mri had a sensitivity of 83% while ct scored 16% for detection of acute ischaemic stroke .
the diagnostic accuracy of mri was the same for scans within the first 3 hours from onset of symptoms as it was for later scans , which is relevant for thrombolysis .
however donnan and dewey point out that 11% of patients were unable to undergo mri and the practicalities of intubated patients need to be considered .
alteplase ( tpa ) has been granted a license for use in the us and canada for ischaemic stroke .
administration within a 3 hour window from symptom onset has previously been shown to be safe and effective treated patients being at least 30% more likely to have little or no disability . prior to gaining a license in europe a large safety study was required , and thus the safe implementation of thrombolysis in stroke monitoring study ( sit - most ) was carried out . in this prospective open monitored observational study , primary outcomes were symptomatic intracerebral haemorrhage and death within three months .
data from sit - most suggest there was a noticeable reduction in 3 month mortality ( mortality 11.3% ) and this reduction was seen in both inexperienced and experienced centres .
although this may be the gold standard of acute stroke care , it will require significant expansion of current services .
patients were given thrombolysis on average 68 minutes after coming through the door and to match this would require substantial effort and investment
dr candelise and colleagues investigated whether acute admission ( < 48 hours ) to a stroke unit affected outcome of patients compared to conventional ward care in an observational follow up study of 11,572 acute stroke patients from 260 hospitals .
of these , 4,936 went to a stroke unit while 6,636 went to a conventional ward .
compared with conventional ward based care , the stroke units were associated with reduced mortality and disability these benefits persisted across all age ranges and clinical characteristics ( except unconsciousness ) , adding to the overall impression that stroke units are of benefit and no patient should be discriminated against .
there remain many unanswered questions with regards to tracheostomies , notably optimum timing and who benefits ?
a surgical tracheostomy is associated with a higher mortality in morbidly obese patients but this patient group may actually do better in the icu .
acute stroke patients should be offered an mri and subsequent thrombolysis where appropriate and continuation of care should be in stroke units and , although this represents ' best ' treatment , is this the best use of resources and efforts ?
bmi = body mass index ; ct = computerised tomography ; icu = intensive care unit ; ippv = intermittent positive pressure ventilation ; mri = magnetic resonance imaging ; sit - most = safe implementation of thrombolysis in stroke monitoring study .
Output:
| three studies explore the case for tracheostomies in the intensive care unit ( icu ) .
tracheostomies appear to have no effect on icu survival , according to a prospective observational cohort study that used a propensity score . in obese patients ,
surgical tracheostomies were associated with an increased risk of complications , although these patients appeared to have a lower mortality in the icu .
a third study failed to show that tracheostomies reduced sedation requirements .
mri appears to be the investigation of choice for the diagnosis of acute stroke and thrombolysis is a safe and effective treatment for acute ischaemic strokes .
virtually all patients with a stroke may benefit from ongoing care in a stroke unit . |
PubmedSumm8830 | ***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: uic 10339 was obtained from a sample
collected from raven lake in northern wisconsin in august 2010 and
cultured in z media .
the lyophilized cells were extracted with ch2cl2 and meoh ( 1:1 ) and dried in vacuo .
this extract showed antiproliferative activity against the human
colon cancer cell line ht-29 and was subjected to a bioassay - guided
fractionation scheme using diaion vacuum liquid chromatography .
the
fraction eluting with 60% isopropyl alcohol ( ipa ) displayed antiproliferative
activity .
lc / ms and h nmr dereplication indicated the
presence of two potentially new peptides with molecular weights of
1184 and 1446 da .
subsequent reversed - phase hplc separations yielded
trichormamides a ( 1 ) and b ( 2 ) .
trichormamide
a ( 1 ) was obtained as a white , amorphous
powder .
the molecular formula of 1 was deduced as c58h93n11o15 based on hresims
analysis ( m / z 1184.6978 [ m + h ] ) .
the h nmr
spectra of 1 in cd3oh with suppression at
4.9 ppm exhibited sharper peaks , but the resonances close to 4.9 ppm
were also suppressed .
therefore , h nmr , cosy , and tocsy
experiments were conducted in both cd3od ( without signal
suppression , but nh signals absent ) and cd3oh ( suppressed
at 4.9 ppm , but nh signals present ) , respectively , to obtain both
nh signals and clear signals close to 4.9 ppm ( supporting information s4s12 ) .
the values of chemical
shifts were reported using 1d and 2d nmr spectra obtained in cd3oh .
the h nmr spectrum of 1 exhibited
a signal pattern characteristic of a lipopeptide , including exchangeable
amide signals ( h 6.78.9 ) , signals typical
of -protons ( h 4.15.0 ) , aliphatic
methylene signals ( h 1.11.4 ) , and several
doublet and triplet methyl signals ( h 0.71.0 ) .
the two downfield doublets ( h 7.25 , j = 8.7 hz ; h 6.71 , j = 8.7 ) were
attributed to a para - substituted phenyl moiety .
analysis
of cosy and tocsy correlations of 1 revealed the presence
of 11 amino acid residues , including 10 standard -amino acid
residues : three serines ( ser1 , ser2 , ser3 ) , two prolines ( pro1 , pro2 ) ,
two isoleucines ( ile1 , ile2 ) , tyrosine ( tyr ) , leucine ( leu ) , and glycine
( gly ) .
sequential cosy correlations between nh ( h 7.44 ) , methine h-3 ( h 4.36 ) , and methylene h2 - 2 ( h 1.59 ; 2.06 ) , as well as cosy correlations
between methine h-3 ( h 4.36 ) and methylene h2 - 4 ( h 1.50 ; 1.58 ) , suggested the presence
of a -amino acid residue .
sequential cosy correlations from
h2 - 4 ( h 1.50 ; 1.58 ) to the region of
highly overlapped methylene signals ( h2 - 59 , h 1.281.33 ) , which corresponded to five carbons in
the hsqc spectrum ( c 32.9 , 30.3 , 30.2 , 27.2 , and
23.6 ) , and finally to the methyl triplet h-10 ( h 0.86 ) identified this -amino acid residue as -aminodecanoic
acid ( ada ) .
assignment of the amino acid sequence was carried
out by a combination
of hmbc , roesy , and esims / ms analysis ( figure 1 ) .
hmbc correlations from ile2-nh ( h 8.84 ) to ile1
c-1 ( c 174.1 ) , from ile1-nh ( h 6.95 ) to leu c-1 ( c 173.6 ) , from leu - nh ( h 7.71 ) to tyr c-1 ( c 175.1 ) , from tyr - nh
( h 7.30 ) to ser3 c-1 ( c 173.0 ) ,
and from ser3-nh ( h 7.57 ) to pro1 c-1 ( c 172.2 ) suggested a partial sequence of ile2-ile1-leu - tyr - ser3-pro1 .
hmbc correlation from pro1 h2 - 5 ( h 3.60 ;
3.88 ) to ser2 c-1 ( c 174.3 ) extended this sequence
to ile2-ile1-leu - tyr - ser3-pro1-ser2 . similarly , the hmbc correlations
from ser1-nh ( h 6.79 ) to ada c-1 ( c 172.2 ) , from ada - nh ( h 7.44 ) to gly c-1 ( c 170.4 ) , and from gly - nh ( h 8.75 ) to pro2
c-1 ( c 176.1 ) established the partial sequence of
ser1-ada - gly - pro2 . this partial sequence was confirmed by roesy correlations
between ser1-nh ( h 6.79 ) and ada h2 - 2
( h 1.59 ; 2.06 ) and between ada - nh ( h 7.44 ) and gly h2 - 2 ( h 3.42 ; 3.97 ) .
a roesy correlation between ser2-nh ( h 7.88 ) and
ser1 h2 - 3 ( h 4.00 ; 4.27 ) linked the two
partial sequences together into ile2-ile1-leu - tyr - ser3-pro1-ser2-ser1-ada - gly - pro2 .
the 18 degrees of unsaturation and the molecular formula suggested
that 1 was a cyclic peptide .
the chemical shifts of ile2
c-1 ( c 173.8 ) , c-2 ( c 52.1 ) and
pro2 c-2 ( c 64.5 ) , c-5 ( c 49.5 ) ,
h2 - 5 ( h 4.07 ; 4.13 ) suggested the presence
of an amide moiety at ile2 c-1 and pro2 n. therefore , the cyclic undecapeptide ring was closed between ile2
and pro2 .
mass fragmentation analysis using a quadrupole - time - of - flight
( qtof ) tandem mass spectrometer confirmed the sequence of amino acid
residues determined by nmr analysis . the parent ion [ m + h ] 1184.6 was fragmented using a 40 ev collision energy .
as expected ,
protonation and breakage of the proline amide bond is a highly favored
process , and the macro ring of 1 opened between ile2
and pro2 , forming a linear acylium ion .
the acylium ion was continuously fragmented to generate fragment
ions as illustrated in figure 2 .
the esims / ms
fragments were in complete agreement with the structure determined
by nmr studies , and the planar structure of 1 was determined
as cyclo[ile2-ile1-leu - tyr - ser3-pro1-ser2-ser1-ada - gly - pro2 ] .
key 2d nmr
correlations of trichormamide a ( 1 ) and
trichormamide b ( 2 ) .
the absolute configurations of
the amino acids were determined
using acid hydrolysis followed by the advanced marfey s method
( supporting information s14 ) .
the chromatographic comparison between marfey s derivatives
of the hydrolysate of 1 and appropriate amino acid standards
assigned the l configurations for ser1/2/3 and pro1/2 and
the d configuration for tyr .
the absolute configuration of
ada was determined as 3r by comparison of the elution
order of hydrolysate ada l- and d - fdla derivatives
with those reported in the literature .
the stereoisomers of leucine and isoleucine standards were analyzed
by marfey s method , and retention times were compared with
marfey s derivatives of hydrolysate of 1 . as
leucine
and isoleucine isomers have identical molecular weight and very similar
retention behavior in hplc , a rigorous co - injection scheme was utilized
to assign leu as d and ile1/2 as l ( 2s , 3s ) ( supporting information
s14 ) .
the final structure of 1 was determined
as cyclo[l - ile l - ile d - leu d - tyr l - ser l - pro
trichormamide b ( 2 ) was obtained
as a white , amorphous
powder .
the molecular formula was determined as c69h115n13o20 ( m / z 1446.8508 [ m + h ] ) by hresims analysis .
the h nmr spectrum of 2 in dmso - d6 ( table 2 )
also exhibited signals characteristic of a lipopeptide .
signal doubling
was observed for some of the signals in both the h nmr
and deptq spectra , indicating the presence of two conformers of 2 in solution ( integration ratio 2:1 in dmso - d6 , according to integration of the phenyl protons from
tyrosine ) .
this phenomenon has been reported for cyclic peptides with
one or more n - methylated amino acid residues .
an elevated - temperature nmr experiment was attempted to generate
one average set of signals . however , the coalescence temperature of 2 was higher than the highest operating temperature permitted
by a cryogenically cooled probe ( t = 328 k ) , and
no signal coalescence was observed .
nevertheless , the elevated - temperature
nmr experiment showed improved peak shapes and better resolved coupling
patterns as compared to the room - temperature experiments .
thus , the
structure elucidation of 2 was performed using the signals
from the major conformer at elevated temperature ( t = 328 k ) . combined analysis of the cosy and
tocsy spectra identified
the structures of seven standard amino acids : isoleucine ( ile ) , glutamine
( glu ) , serine ( ser ) , proline ( pro ) , tyrosine ( tyr ) , and two threonines
( thr1 and thr2 ) ( figure 1 and table 2 ) .
an n - methylated isoleucine ( nmeile )
was deduced by tocsy and the hmbc correlation observed from n - me ( h 3.00 ) to nmeile c-2 ( c 59.8 ) .
the presence of homoserine ( hse ) was evident by sequential
cosy correlations from nh ( h 8.01 ) to hse h2 - 4 ( h 3.42 ; 3.50 ) .
the downfield chemical
shifts of the hse c-4 methine ( c 57.3 ) and h2 - 4 ( h 3.42 ; 3.50 ) indicated the attachment
of a hydroxy group to c-4 . a broad hydroxy signal ( h 5.05 ) with a cosy correlation to a downfield methine ( h 3.52 ) , as well as sequential cosy correlations between nh
( h 8.16)/h-2 ( h 4.39)/h-3 ( h 3.52)/h-4 ( h 1.61)/h3 - 5 ( h 0.93 ) , combined with hmbc correlations from 4-me ( h 0.81 ) and h3 - 5 ( h 0.93 ) to both
c-3 ( c 76.3 ) and c-4 ( c 30.5 ) ,
indicated the presence of a 3-hydroxyleucine ( 3-ohleu1 ) .
an additional
3-hydroxyleucine ( 3-ohleu2 ) was identified using a similar approach
( table 2 ) .
the presence of a -aminodecanoic
acid was suggested from cosy , tocsy , and hsqc correlations as described
for trichormamide a ( 1 ) .
carbon chemical
shifts were assigned
from the deptq spectrum recorded at 226 mhz .
carbon chemical
shifts were assigned
from the deptq spectrum recorded at 226 mhz .
the sequence of the 12 amino acid
residues was established by analysis
of the hmbc and roesy spectra ( figure 1 and
table 2 ) .
hmbc correlations from 3-ohleu1-nh
( h 8.01 ) to ile c-1 ( c 170.8 ) ,
from ile - nh ( h 8.16 ) to ada c-1 ( c 171.2 ) , from ada - nh ( h 7.52 ) and ada h-3 ( h 4.08 ) to thr2 c-1 ( c 169.6 ) , from thr2-nh
( h 7.60 ) to tyr c-1 ( c 170.8 ) ,
and from tyr - nh ( h 7.97 ) to pro c-1 ( c 171.5 ) indicated a partial sequence of 3-ohleu1-ile - ada - thr2-tyr - pro .
roesy correlations between 3-ohleu1-nh ( h 8.01 )
and ile h-2 ( h 4.19 ) , between ile - nh ( h 8.16 ) and ada h2 - 2 ( h 2.31 ;
2.49 ) , between ada - nh ( h 7.52 ) and thr2 h-2 ( h 4.05 ) , between thr2-nh ( h 7.60 ) and tyr
h-2 ( h 4.45 ) , and between tyr - nh ( h 7.97 ) and pro h-2 ( h 4.33 ) confirmed this partial
sequence .
similarly , a partial sequence of ser - nmeile - gln-3-ohleu2-hse
was established by the hmbc correlations from ser - nh ( h 7.83 ) to nmeile c-1 ( c 169.8 ) , from nmeile
n - me ( h 3.00 ) to gln c-1 ( c 172.3 ) ,
from gln - nh ( h 7.93 ) to 3-ohleu2 c-1 ( c 171.3 ) , and from 3-ohleu2-nh ( h 7.76 ) to
hse c-1 ( c 171.3 ) . this partial sequence was also
confirmed by the roesy correlations between ser - nh ( h 7.83 ) and nmeile h-2 ( h 4.73 ) , between gln - nh
( h 7.93 ) and 3-ohleu2 h-2 ( h 4.32 ) ,
and between 3-ohleu2-nh ( h 7.76 ) to hse h-2 ( h 4.35 ) . the roesy correlations between thr1-nh ( h 7.51 ) and ser h-2 ( h 4.33 ) and between
thr1-nh ( h 7.51 ) and ser h2 - 3 ( h 3.60 ) further expanded this partial sequence to thr1-ser - nmeile - gln-3-ohleu2-hse .
an hmbc correlation from hse - nh ( h 7.95 ) to 3-ohleu1
c-1 ( c 172.3 ) , together with a roesy correlation
between hse - nh ( h 7.95 ) and 3-ohleu1 h-2 ( h 4.39 ) , connected those two partial sequences together into
thr1-ser - nmeile - gln-3-ohleu2-hse-3-ohleu1-ile - ada - thr2-tyr - pro .
the
molecular formula and degree of unsaturation indicated the cyclic
nature of 2 .
the chemical shifts of thr1 c-1 ( c 168.7 ) and c-2 ( c 55.6 ) suggested the presence
of an amide moiety at thr1 c-1 . similarly ,
the chemical shifts of pro c-2 ( c 59.5 ) , c-5 ( c 47.0 ) , and h2 - 5 ( h 3.61 ; 3.67 )
also indicated that pro n was part of an amide bond . therefore , the cyclic dodecapeptide ring was closed between
thr1 and pro .
protonation on
the amide nitrogen at pro generated amide bond cleavage to form a
linear acylium ion , which produced series of fragments ( figure 3 ) .
these observed fragments were consistent with
the amino acid sequence determined by nmr analysis , and the planar
structure of 2 was assigned as cyclo[thr1-ser - nmeile - gln-3-ohleu2-hse-3-ohleu1-ile - ada - thr2-tyr - pro ] .
acid hydrolysis of trichormamide b ( 2 ) followed by
marfey s derivatization with l- and d - fdla
and lc / ms analysis assigned the l configurations for gln ,
pro , ile ( 2s , 3s ) , thr1/2 ( 2s , 3r ) , and the nonproteinogenic amino
acid hse , d configurations for tyr and ser , and 3r configuration for ada .
the four stereoisomers of nmeile
were synthesized according to the literature . on the basis of these standards , the absolute configuration of nmeile
was determined to be l ( 2s , 3s ) .
the 2s , 3r and 2s , 3s isomers of 3-hydroxyleucine were synthesized
following bonnard s procedure and
were derivatized with l- and d - fdla respectively .
because enantiomers exhibit identical retention behavior under nonchiral
hplc conditions , the ( 2s,3r)-d - fdla derivative shows the same retention time as ( 2r,3s)-l - fdla , and the ( 2s,3s)-d - fdla derivative shows
the same retention time as ( 2r,3r)-l - fdla ( detailed explanations can be found in supporting information s26 ) . by comparing the
above four retention times with retention times of 3-ohleu1 and 3-ohleu2 l - fdla derivatives , both 3-ohleu1 and 3-ohleu2 were assigned
as 2r , 3s .
the complete structure
of 2 was determined as cyclo[l - thr d - ser l - nmeile l - gln(2r,3s)-3-ohleu l - hse(2r,3s)-3-ohleu l - ile(3r)-ada l - thr d - tyr l - pro ] .
trichormamide a ( 1 ) is a cyclic undecapeptide
characterized
by the presence of -aminodecanoic acid and two d - amino
acid residues ( d - tyr and d - leu ) .
trichormamide a
( 1 ) is a lipid - containing compound and displays amphiphilic
character with half of the amino acid sequence being hydrophobic ( ada - gly - pro2-ile2-ile1-leu )
and the other half of the sequence hydrophilic ( tyr - ser3-pro1-ser2-ser1 ) .
the amphiphilic nature of lipopeptides has been found to be strongly
correlated with their plasma membrane interactive potential .
trichormamide a ( 1 ) is structurally related to hormothamnin
a , lobocyclamide a , and laxaphycin a with conserved amino acid residues
of leu , ile1 , ile2 , and gly .
the amino acid residues homoserine ,
4-hydroxyproline , ,-didehydro--aminobutyric acid ,
and -aminooctanoic acid in the east portion of the three related
compounds were replaced by structurally related residues of ser , pro ,
ser , and ada in trichormamide a ( 1 ) ( supporting information s27 ) .
trichormamide b ( 2 ) is a cyclic dodecapeptide characterized by the presence of a -amino
acid residue ( -aminodecanoic acid ) , two d - amino acid
residues ( d - tyr and d - ser ) , and four nonstandard
amino acid residues ( 3-ohleu1 , hse , 3-ohleu2 , nmeile ) .
trichormamide
b ( 2 ) is also an amphiphilic molecule containing a hydrophobic
ada residue and seven hydroxy groups .
trichormamide b ( 2 ) is structurally related to the cyclic dodecapeptides lobocyclamides
b and c , laxaphycins b , b2 , and b3 , and lyngbyacyclamides a and b. a comparison of 2 to these structures revealed that
the presence and location of 3-ohleu1 , gln , nmeile , thr1 , and thr2
are conserved in all these peptides , indicating these amino acid residues
may be crucial for the biological functions of these molecules .
trichormamides a ( 1 ) and b ( 2 ) were evaluated
for their antiproliferative activities against the human melanoma
cell line mda - mb-435 and the human colon cancer cell line ht-29 .
trichormamide
b ( 2 ) displayed significant cytotoxic activity against
mda - mb-435 and ht-29 cell lines with ic50 values of 0.8
and 1.5 m , respectively .
trichormamide a ( 1 ) was
less active than 2 and showed ic50 values
of 9.9 and 16.9 m against mda - mb-435 and ht-29 , respectively .
compounds structurally related to 1 and 2 were reported to have 23-fold increased synergistic activities
in antimicrobial and cytotoxicity assays . however , the
limited supply of 1 stopped us from obtaining statistically
significant data in synergistic assays . in summary
, we have
obtained two new cyclic lipopeptides , trichormamides
a ( 1 ) and b ( 2 ) , each containing the -amino
acid residue -aminodecanoic acid , from the cultured freshwater
cyanobacterium trichormus sp .
their planar
structures were determined by analysis of the hresims , ms / ms , and
1d and 2d nmr experiments .
the stereoconfigurations of the amino acid
residues were assigned by the advanced marfey s method using
synthesized amino acid standards .
trichormamide b ( 2 ) was found to be more active against
mda - mb-435 and ht-29 human cancer cell lines than trichormamide a
( 1 ) , with ic50 values of 0.8 and 1.5 m ,
respectively .
optical rotations were
measured on a perkinelmer 241 polarimeter at 22 c in meoh .
1d
and 2d nmr spectra including h nmr , cosy , tocsy , hsqc ,
hmbc , and roesy were obtained on a bruker avance drx 600 mhz spectrometer .
a bruker avii 900 mhz nmr spectrometer was used to acquire the deptq
spectra .
h and c nmr chemical shifts were
referenced to the dmso - d6 ( h 2.50 and c 39.51 , respectively ) and cd3od / cd3oh ( h 3.31 and c 49.0 , respectively ) residual solvent signals .
the hmbc spectrum was recorded with an
average jch of 8 hz , and the
hsqc spectrum was recorded with an average jch of 145 hz .
high - resolution esi mass spectra and lc - ms
data were obtained using a shimadzu hplc - it - tof spectrometer .
the
hplc experiments were performed using an agilent 1100 series instrument
equipped with a diode array detector , and a waters instrument equipped
with a waters 600 pump and a waters 2487 detector .
uic 10339 was isolated from a sample collected at raven lake , wisconsin ,
in 2010 ( n 4558.7 , w 8951.5 ) .
the
unialgal ( not axenic ) strain uic 10339 was obtained through micropipette
isolation techniques .
the strain was
cultured in 8 2 l of z medium in 2.8 l fernbach flasks with
sterile air aeration .
cultures were illuminated
with fluorescent lamps at 1.03 klx with an 18/6 h light / dark cycle .
the biomass of uic 10339 was harvested after 8 weeks of growth by
centrifugation and freeze - dried .
morphological
observation was performed using a zeiss axiostar plus light microscope
equipped with a canon powershot a620 camera .
the following characters
were utilized for identification : structure of colony , morphology
of thallus , size , shape , and motility of trichomes , shape of vegetative
cells , presence or absence of mucilage or sheath , presence and arrangement
of heterocytes , presence and relative size of akinetes , and morphology
of the end cell ( supporting information s1 , s2 ) .
the morphological characterization and initial taxonomical designation
of uic 10339 were made according to the system by komrek et
al .
prior to dna extraction ,
8 ml of a static culture of trichormus sp .
uic 10339
was combined with 1.5 ml of lysozyme buffer and 0.5
ml of 20 mg / ml lysozyme stock solution and incubated at 35 c
for 1 h. after incubation , the cell mass was centrifuged and transferred
to a 2 ml microcentrifuge tube . a wizard genomic dna purification
kit ( promega )
a partial sequence
of the 16s rdna gene was pcr - amplified using the cyanobacteria - specific
primers 106f and 1509r . for a total volume
of 25 l ,
the reaction mixture contained dna ( 1 l , approximately
300 ng ) , gotaq reaction buffer ( 5 l , 5 ) , dntp mix ( 0.5
l , 10 mm ) , upstream and downstream primer ( 1 l each ,
10 m ) , gotaq dna polymerase ( 0.25 l , 2.5 u/l ) ,
and h2o ( 16.25 l ) .
the reaction was performed in
a bio - rad c1000 thermal cycler with the following reaction program :
initial denaturation for 30 s at 98 c , 35 amplification cycles
of 10 s at 98 c , 30 s at 53 c , 30 s at 72 c , and
a final extension for 10 min at 72 c .
pcr products were purified
using a minelute pcr purification kit ( qiagen ) and sequenced using
the cyanobacteria - specific primers 106f , 359f , and 1509r .
the resulting 16s rdna gene sequence was deposited
in the ncbi genbank under the accession no .
lyophilized biomass ( 6.14
g ) from eight 2 l cultures of uic 10339 was extracted with 1:1 ch2cl2/meoh three times and concentrated in
vacuo to yield 650.9 mg of extract , which was fractionated
using diaion hp-20ss resin with an h2o / ipa step gradient
( 1:0 , 4:1 , 3:2 , 2:3 , 3:7 , 1:4 , 1:9 , 0:1 v / v ) to yield eight fractions .
the fraction eluting with h2o / ipa ( 2:3 v / v ) ( 58.8 mg ) displayed
significant antiproliferative activity against the human melanoma
cell line mda - mb-435 with 100% growth inhibition at a concentration
of 25 g / ml .
lc - ms combined with h nmr dereplication
of this fraction revealed the presence of new lipopeptides .
the fraction
was subjected to semipreparative reversed - phase hplc ( varian c8 semipreparative column , 10 250 mm , 3 ml / min ) with
a linear gradient from 80% to 100% meoh with h2o over 20
min , and the subfraction eluting from 9 to 10 min was collected and
dried in vacuo .
h nmr and ms flow injection
analysis revealed that this subfraction consisted of two compounds .
the subfraction was subjected to semipreparative reversed - phase hplc
( varian c18 semipreparative column , 10 250 mm , 3
ml / min ) using isocratic 50% aqueous ch3cn .
trichormamide
a ( 1 , 0.8 mg , 0.01% of dry weight ) was eluted at 8 min ,
and trichormamide b ( 2 , 3.7 mg , 0.06% of dry weight )
was eluted at 5 min .
white , amorphous
powder ; [ ]d22 + 20 ( c 0.06 , meoh ) ; uv ( meoh ) max ( log ) 240 ( 3.07 ) , 278 ( 2.95 ) nm ; ir ( neat ) max 3312 ( br ) , 2984 , 2942 , 2831 , 1449 cm ; h and c nmr see table 1 ; hr - esi - tof - ms ( + ) m / z 1184.6978
[ m + h ] ( calcd for c58h94n11o15 , 1184.6931 ) .
white , amorphous
powder ; [ ]d22 25.9 ( c 0.32 , meoh ) ; uv ( meoh )
max ( log ) 240 ( 3.16 ) , 278 ( 2.97 ) nm ; ir
( neat ) max 3317 ( br ) , 2943 , 2831 , 1449 , 1414
, 1114
cm ; h and c nmr see table 2 ; hr - esi - tof - ms
( + ) m / z 1446.8508 [ m + h ] ( calcd for c69h116n13o20 , 1446.8460 ) .
the amino
group of l - ile was boc - protected using a previously published
protocol .
the methylation of nboc - l - ile was carried out using malkov s
method .
the boc - protected nmeile was
subjected to acid hydrolysis using the general peptide hydrolysis
scheme as described below , to yield l - n - methylisoleucine
( 73.11 mg ) , which was analyzed by the advanced marfey s method .
although citric acid from the workup was observed as a minor impurity
in the h nmr spectrum of l - n - methylisoleucine , it did not interfere with the advanced marfey s
analysis .
d - n - methylisoleucine , l - allo - n - methylisoleucine , and d - allo - n - methylisoleucine
were synthesized using the same protocol with d - ile , l - allo - ile , and d - allo - ile as starting compounds .
all were analyzed using the advanced
marfey s method as described for the peptide hydrolysate .
l - n - methylisoleucine : [ ]d22 + 17.6 ( c 0.39 , meoh ) ; h nmr data ( dmso - d6 , 400 mhz ) 3.84 ( 1h , d , j =
3.0 hz ) , 2.59 ( 3h , s ) , 1.95 ( 1h , m ) , 1.50 ( 1h , m ) , 1.32 ( 1h , m ) , 0.91
( 3h , d , j = 8.5 hz ) , 0.90 ( 3h , t , j = 7.1 hz ) ; deptq data ( dmso - d6 , 400
mhz ) 169.5 , 64.6 , 35.3 , 32.5 , 26.4 , 14.5 , 12.0 . nmr spectra
of d - ile , l - allo - ile , and d - allo - ile can be found in supporting
information s24 .
we obtained 148.0 mg of major
precursor ( r)-1-((2s,5r)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)-2-methylpropan-1-ol
and 54.5 mg of minor precursor ( s)-1-((2s,5r)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)-2-methylpropan-1-ol .
the hydroxyleucine precursors were hydrolyzed following the general
peptide acid hydrolysis process as described below .
the major precursor
gave a mixture of ( 2s,3r)-3-hydroxyleucine
and d - valine , and the minor precursor gave a mixture of ( 2s,3s)-3-hydroxyleucine and d - valine .
these two mixtures were derivatized with l - fdla and d - fdla , respectively , and the resulting four derivatization mixtures
were analyzed using the general lc - ms method as described for peptide
hydrolysate analysis .
h nmr data of major precursor ( cdcl3 , 300 mhz ) : 4.08 ( 1h , dd , j = 3.2
hz , 2.9 hz ) , 3.98 ( 1h , dd , j = 3.6 hz , 3.4 hz ) , 3.71
( 3h , s ) , 3.67 ( 3h , s ) , 3.61 ( 1h , br ) , 2.24 ( 1h , m ) , 1.99 , ( 1h , m ) ,
1.69
( 1h , br ) , 1.03 ( 3h , d , j = 6.9 hz ) , 1.02 ( 3h ,
d , j = 6.9 hz ) , 0.97 ( 3h , d , j =
6.9 hz ) , 0.70 ( 3h , d , j = 6.9 hz ) .
h
nmr data of minor precursor ( cdcl3 , 300 mhz ) : 4.17
( 1h , dd , j = 4.3 hz , 4.0 hz ) , 3.98 ( 1h , dd , j = 3.7 hz , 3.6 hz ) , 3.71 ( 3h , s ) , 3.70 ( 3h , s ) , 3.65 ( 1h ,
br ) , 2.27 ( 1h , m ) , 1.82 , ( 1h , m ) , 1.68 ( 1h , br ) , 1.04 ( 3h , d , j = 6.9 hz ) , 0.90 ( 3h , d , j = 6.9 hz ) ,
0.89 ( 3h , d , j = 6.9 hz ) , 0.69 ( 3h , d , j = 6.9 hz ) . approximately 0.3 mg of 1 and 2 was hydrolyzed with 1 ml of 6
n hcl for
20 h at 110 c
in separate teflon - sealed ace pressure tubes .
the cooled hydrolysate
mixtures were evaporated to dryness , and traces of hcl were removed
from the reaction mixtures by repeated evaporation .
each acid hydrolysate ( approximately
0.3 mg ) was separated into two equal portions for derivatization with
either l - fdla or d - fdla .
each portion was dissolved
in 110 l of acetone and 50 l of h2o , followed
by mixing with 20 l of 1 n nahco3 .
finally , 20 l
of l - fdla or d - fdla ( 10 mg / ml in acetone ) was added ,
and the mixtures were heated to 40 c for 1 h. the reaction mixtures
were then cooled to room temperature , and 20 l of 1 n hcl was
added to quench the reaction .
the cooled reaction mixtures were evaporated
to dryness and redissolved in 300 l of ch3cn .
lc - ms
analysis was carried out using a reversed - phase column ( phenomenex
kinetex c18 , 250 4.6 mm , 5 m , 1.0 ml / min )
with a linear gradient from 25% to 65% aqueous ch3cn containing
0.1% formic acid over 50 min .
the selective ion chromatograms of l - fdla and d - fdla derivatives of each amino acid were
compared for the assignment of amino acid configurations .
detailed
reports of retention times of each amino acid can be found in supporting information s14 and s23 .
cytotoxicity assays against
the mda - mb-435 and ht-29 cancer cell lines were conducted according
to established protocols .
Output:
| two new cyclic lipopeptides , trichormamides
a ( 1 )
and b ( 2 ) , were isolated from the cultured freshwater
cyanobacterium trichormus sp .
uic 10339 .
the strain
was obtained from a sample collected in raven lake in northern wisconsin .
the planar structures of trichormamides a ( 1 ) and b ( 2 ) were determined using a combination of spectroscopic analyses
including hresims and 1d and 2d nmr experiments .
the absolute configurations
of the amino acid residues were assigned by the advanced marfey s
method after acid hydrolysis .
trichormamide a ( 1 ) is
a cyclic undecapeptide containing two d - amino acid residues
( d - tyr and d - leu ) and one -amino acid residue
( -aminodecanoic acid ) .
trichormamide b ( 2 ) is
a cyclic dodecapeptide characterized by the presence of four nonstandard
-amino acid residues ( homoserine , n - methylisoleucine ,
and two 3-hydroxyleucines ) and one -amino acid residue ( -aminodecanoic
acid ) .
trichormamide b ( 2 ) was cytotoxic against mda - mb-435
and ht-29 cancer cell lines with ic50 values of 0.8 and
1.5 m , respectively . |
PubmedSumm8831 | ***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: future releases of tcsnp will integrate new t. cruzi sequences as they become available . many of these are expected to come from a resequencing effort that is underway in our lab .
planned updates to the website functionality include the development of a standardized api and web services through which other databases can consume the information provided by tcsnp and the development of functionality to design primers by interfacing with primer3 ( 19 ) , while using the snp information in this process .
the tcsnp database is composed of a web application written in perl , running against a postgresql database .
the database schema is based on the genomics unified schema ( gus , http://gusdb.org ) with local customizations .
the web application has been developed using a model - view - controller architectural pattern , where the work of each layer is performed by a specialized perl component [ all components are available from cpan ( 20 ) ] .
access to the database from perl ( i.e. the model ) is done through a hybrid combination of ( i ) an abstraction of the database schema using perl 's dbix::class package and ( ii ) custom sql queries executed using perl 's database access interface ( dbi ) .
the controller component managing user 's requests and dispatching calls to other components is perl 's catalyst ( 21 ) .
a number of custom controller modules were developed , which contain the business logic of the tcsnp application . finally , the viewer component is perl 's template toolkit , which uses custom templates to render web pages using information provided by the controller .
the database runs on dedicated freebsd servers , with the catalyst web application running under the apache web server .
the reference genome sequence of the cl brener strain of t. cruzi was obtained from genbank using the umbrella accession number aahk00000000 ( july , 2005 ) . other t. cruzi sequences ( mrnas and ests )
were also obtained from genbank using custom entrez queries ( may , 2007 ) . before loading into the database
this was necessary because of the variations in how different authors write the names of strains in genbank submissions and publications .
cl brener strain appears in different genbank sequences as cl brener , cl - brener , clbrener , cl - brenner , cl brenner , cl brenner , or cl brener ( note the different capitalization , use of middle dash , spaces and the writing of the strain name using a single or a double n ) . because the database allows users to perform searches using strain names , it was important to reduce redundancy where possible .
in some cases , however , it was important to keep the distinction between similar strain names , for example to discriminate between cloned stocks and their parental uncloned strains .
as an example , we have kept caniii and caniii cl1 ( cl1 stands for clone 1 ) , and sc43 and sc43 cl1 as different
redundancy is still present , however , and further curation of strain names can be done .
we also encourage users of the database to send feedback about this issue . before clustering all sequences
were masked against a library of vector sequences and t. cruzi repetitive elements , as described previously ( 22 ) .
annotated coding sequences from the reference genome , and other publicly available sequences were mapped against the genome scaffolds using blat .
sequences mapping to the same genomic regions were clustered together and multiple sequence alignments were obtained using phrap .
this initial clustering allowed us to group mrnas , ests and reference coding sequences to the reference genome assembly sequences .
but because allelic variants in the cl - brener genome were separated during assembly ( 12 ) , those initial clusters showed many instances of allelic variants separated into different alignments ( i.e. each mapping to its own contig ) . to obtain alignments between allelic variants , we merged alignments with highly similar consensus sequences ( by blast analysis ) . afterwards , and based on user feedback , we have also merged , splitted and re - analyzed many alignments .
users of tcsnp should also be aware of the fact that many sequences from the cl - brener genome assembly are located in contigs with assembly problems or may represent assembly artifacts . for sequences containing assembly warnings in the original genbank records ,
we have attached similar notes to the corresponding alignments in tcsnp to help users in the interpretation of the snp data .
multiple sequence alignments were scanned to identify polymorphic columns . to calculate the probability of these sites being true polymorphisms
as opposed to sequencing errors , we have used the software package polybayes , version 5 ( 13 ) . polybayes uses a bayesian statistical framework that relies on allele frequency , alignment depth and base quality values amongst other attributes to calculate a probability score .
because chromatogram trace data are not available for many of the sequences in this release , we have devised a scoring strategy that uses arbitrary base quality values .
sequence bases obtained from the t. cruzi cl - brener genome ( 19x shotgun coverage ) were arbitrarily assigned a base quality value of 40 ; those from genbank records , a value of 30 ( individual submissions ) ; and those from dbest , a value of 20 ( single - pass , unedited ) . as an example , using this scoring scheme , a single base from an est differing from two allelic variants of cl - brener reference sequence ( depth = 3 ) would give a probability of 0.22 of being a true snp ( see for example : http://snps.tcruzi.org/snps/view/4028216 ) . to analyze the effect of each snp on the corresponding protein product
, we noted the codon position of the snp in each reference coding sequence and evaluated the change introduced by the polymorphic base .
also , for a subset of the alignments ( those containing coding sequences of similar length , with indels being a multiple of 3 ) , we calculated dn and ds values ( 14 ) using bioperl 's population genetics modules ( 23 ) .
the tcsnp database is composed of a web application written in perl , running against a postgresql database .
the database schema is based on the genomics unified schema ( gus , http://gusdb.org ) with local customizations .
the web application has been developed using a model - view - controller architectural pattern , where the work of each layer is performed by a specialized perl component [ all components are available from cpan ( 20 ) ] .
access to the database from perl ( i.e. the model ) is done through a hybrid combination of ( i ) an abstraction of the database schema using perl 's dbix::class package and ( ii ) custom sql queries executed using perl 's database access interface ( dbi ) .
the controller component managing user 's requests and dispatching calls to other components is perl 's catalyst ( 21 ) .
a number of custom controller modules were developed , which contain the business logic of the tcsnp application . finally , the viewer component is perl 's template toolkit , which uses custom templates to render web pages using information provided by the controller .
the database runs on dedicated freebsd servers , with the catalyst web application running under the apache web server .
the reference genome sequence of the cl brener strain of t. cruzi was obtained from genbank using the umbrella accession number aahk00000000 ( july , 2005 ) . other t. cruzi sequences ( mrnas and ests )
were also obtained from genbank using custom entrez queries ( may , 2007 ) . before loading into the database ,
this was necessary because of the variations in how different authors write the names of strains in genbank submissions and publications .
cl brener strain appears in different genbank sequences as cl brener , cl - brener , clbrener , cl - brenner , cl brenner , cl brenner , or cl brener ( note the different capitalization , use of middle dash , spaces and the writing of the strain name using a single or a double n ) . because the database allows users to perform searches using strain names , it was important to reduce redundancy where possible .
in some cases , however , it was important to keep the distinction between similar strain names , for example to discriminate between cloned stocks and their parental uncloned strains .
as an example , we have kept caniii and caniii cl1 ( cl1 stands for clone 1 ) , and sc43 and sc43 cl1 as different
redundancy is still present , however , and further curation of strain names can be done .
before clustering all sequences were masked against a library of vector sequences and t. cruzi repetitive elements , as described previously ( 22 ) .
annotated coding sequences from the reference genome , and other publicly available sequences were mapped against the genome scaffolds using blat .
sequences mapping to the same genomic regions were clustered together and multiple sequence alignments were obtained using phrap .
this initial clustering allowed us to group mrnas , ests and reference coding sequences to the reference genome assembly sequences .
but because allelic variants in the cl - brener genome were separated during assembly ( 12 ) , those initial clusters showed many instances of allelic variants separated into different alignments ( i.e. each mapping to its own contig ) . to obtain alignments between allelic variants , we merged alignments with highly similar consensus sequences ( by blast analysis ) . afterwards , and based on user feedback , we have also merged , splitted and re - analyzed many alignments .
users of tcsnp should also be aware of the fact that many sequences from the cl - brener genome assembly are located in contigs with assembly problems or may represent assembly artifacts . for sequences containing assembly warnings in the original genbank records ,
we have attached similar notes to the corresponding alignments in tcsnp to help users in the interpretation of the snp data .
multiple sequence alignments were scanned to identify polymorphic columns . to calculate the probability of these sites being true polymorphisms
as opposed to sequencing errors , we have used the software package polybayes , version 5 ( 13 ) .
polybayes uses a bayesian statistical framework that relies on allele frequency , alignment depth and base quality values amongst other attributes to calculate a probability score .
because chromatogram trace data are not available for many of the sequences in this release , we have devised a scoring strategy that uses arbitrary base quality values .
sequence bases obtained from the t. cruzi cl - brener genome ( 19x shotgun coverage ) were arbitrarily assigned a base quality value of 40 ; those from genbank records , a value of 30 ( individual submissions ) ; and those from dbest , a value of 20 ( single - pass , unedited ) . as an example , using this scoring scheme , a single base from an est differing from two allelic variants of cl - brener reference sequence ( depth = 3 ) would give a probability of 0.22 of being a true snp ( see for example : http://snps.tcruzi.org/snps/view/4028216 ) . to analyze the effect of each snp on the corresponding protein product , we noted the codon position of the snp in each reference coding sequence and evaluated the change introduced by the polymorphic base .
also , for a subset of the alignments ( those containing coding sequences of similar length , with indels being a multiple of 3 ) , we calculated dn and ds values ( 14 ) using bioperl 's population genetics modules ( 23 ) .
national agency for the promotion of science and technology ( anpcyt , argentina ) ( grant pict 38209 ) ; and the university of san martn ( grant s05/22 ) . funding for open access charge : anpcyt .
Output:
| the tcsnp database ( http://snps.tcruzi.org ) integrates information on genetic variation ( polymorphisms and mutations ) for different stocks , strains and isolates of trypanosoma cruzi , the causative agent of chagas disease .
the database incorporates sequences ( genes from the t. cruzi reference genome , mrnas , ests and genomic sequences ) ; multiple sequence alignments obtained from these sequences ; and single - nucleotide polymorphisms and small indels identified by scanning these multiple sequence alignments .
information in tcsnp can be readily interrogated to arrive at gene sets , or snp sets of interest based on a number of attributes .
sequence similarity searches using blast are also supported .
this first release of tcsnp contains nearly 170 000 high - confidence candidate snps , derived from the analysis of annotated coding sequences .
as new sequence data become available , tcsnp will incorporate these data , mapping new candidate snps onto the reference genome sequences . |
PubmedSumm8832 | ***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:
| tissue proteolytic enzymes are currently believed to be critical to the pathogenesis of panacinar emphysema .
polymorphonuclear leukocytes ( polys ) have several enzymes including elastase and cathepsin g in their azurophil granules .
they have collagenase in their specific granules .
we have found that this collagenase is doubly latent .
it has the lysosomal type of latency that depends on the impermeability of the unit membrane that surrounds each specific granule .
in addition it has a latency that is converted to activity by proteolytic enzymes .
the cathepsin g of the azurophil granule is a potent activator of this latent collagenase once the collagenase is released from its membrane dependent latency .
thus latency of enzymes , the nature of the latency and accessibility of the latent enzymes to activating mechanisms must all be taken into account in any analysis of their contribution to pathogenesis of local lung disease .
equally important is that fact that polys are not a prominent cellular component of normal lung .
polys must be attracted to the lung by chemotactic peptides .
these peptides must be released by the interaction of inflammatory stimuli , such as smoke particles , with complement components or they must be provided by other sources . the hypothesis that lung damage in panacinar emphysema
is mediated by polys and their proteases is attractive and suggestive evidence supporting this is available .
however , more evidence that takes into full account the cell biology of the proteases any poly turnover in the lung are needed to extend the hypothesis and to form a rational basis for therapeutic and prophylactic measures.imagesfigure 1.figure 2.figure 3.figure 4.figure 6.figure 7.figure 8.figure 9 . |
PubmedSumm8833 | ***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: fatty liver disease is a very common condition , with a prevalence of 2030% in the adult population and 70% in diabetes patients . among patients who develop non - alcoholic steatohepatitis ( nash )
, half will evolve to fibrosis , 1015% to cirrhosis and 5.4% to hepatic insufficiency .
radiologists must report fatty liver disease because it may have serious long - term consequences if left untreated .
we searched our archive retrospectively , reviewed the literature and identified six patterns of liver steatosis : diffuse , geographic , focal , subcapsular , multifocal and perivascular .
diffuse forms may be graded subjectively according to severity ( mild , moderate , severe ) or quantitatively with magnetic resonance ( mr)-based methods .
therefore , previous knowledge of their cross - sectional appearance may prevent unwarranted investigations or allow non - invasive diagnosis .
ultrasound is the first - line imaging technique for the screening and follow - up of patients with chronic liver disease .
it is , therefore , important for radiologists to be aware of patterns of heterogeneous or focal forms of fatty deposition . on ultrasound , fatty liver
is hyperechoic compared with renal cortex and spleen , whereas fatty sparing is isoechoic or hypoechoic .
on unenhanced computed tomography ( ct ) , liver density less than 40 hounsfield units ( hu ) or a density difference of more than 10 hu between spleen and liver indicates fatty liver .
alternatively , liver parenchyma hypodensity relative to vessels establishes the presence of moderate to severe fatty liver disease . on portal phase contrast - enhanced ct with a standardised protocol
, a density difference greater than 25 hu between spleen and liver suggests fatty liver deposition .
ct with contrast material was previously thought to be less reliable in detecting fatty liver .
however , recent data suggest that portal phase contrast - enhanced ct using blood - subtracted hepatic attenuation may have a similar accuracy to or even greater accuracy than unenhanced ct in the diagnosis of fatty liver .
mr imaging ( mri ) allows measurement of fat and water proton signals and is considered the most accurate non - invasive technique for hepatic fat quantification .
chemical shift gradient - echo imaging is a widely available mri technique for fat detection and quantification .
fatty liver shows a signal drop on gradient echo t1-weighted out - of - phase images compared with in - phase images .
the dual - echo method results in underestimation of the fat fraction by only 2.9% compared with spectroscopy , the non - invasive gold standard .
it may have different levels of severity that can be determined by using quantification maps .
the presence of diffuse steatosis in a patient with hepatomegaly and an enlarged caudate - to - right lobe ratio should raise the possibility of nash .
fig .
d severe diffuse fatty liver disease . a ultrasound image in a 58-year - old man known for intraductal papillary mucinous neoplasm ( ipmn / ipmt ) of the pancreas and alcoholic pancreatitis showing a hyperechoic liver compared with the right renal cortex .
b ct , axial contrast - enhanced portal phase image shows a diffusely hypodense liver ( 42 hu ) compared with the spleen ( 113 hu ) ( > 25 hu difference ) .
mri , c axial t1-weighted in - phase and d out - of - phase images show an important signal drop of the liver on the opposed - phase image .
mr images were obtained on a 1.5-t mri system with tes of 2.2 and 4.5 for in- and out - of - phase images respectively a d severe diffuse fatty liver disease . a ultrasound image in a 58-year - old man known for intraductal papillary mucinous neoplasm ( ipmn / ipmt ) of the pancreas and alcoholic pancreatitis showing a hyperechoic liver compared with the right renal cortex .
b ct , axial contrast - enhanced portal phase image shows a diffusely hypodense liver ( 42 hu ) compared with the spleen ( 113 hu ) ( > 25 hu difference ) .
mri , c axial t1-weighted in - phase and d out - of - phase images show an important signal drop of the liver on the opposed - phase image .
mr images were obtained on a 1.5-t mri system with tes of 2.2 and 4.5 for in- and out - of - phase images respectively geographic fatty liver disease is a frequently encountered variant .
for example , fat accumulation sometimes occurs only in the right lobe ( fig . 2 ) .
one hypothesis to explain this distribution is that blood from the superior mesenteric vein containing lipogenic alimentary factors is preferentially distributed to the right lobe of the liver .
, fatty liver deposition can be distributed in territories previously affected by cholangitis ( fig .
fig . 2a , bgeographic fat accumulation limited to the right lobe of the liver .
mri of the liver in a 57-year - old woman known for multiple focal nodular hyperplasia .
a axial t1-weighted in - phase and b out - of - phase images show an important signal drop in the right lobe of the liver on opposed - phase imagefig
. mri of the liver in a 76-year - old man who had hepatico - jejunostomy for biliary duct trauma and stenosis followed by two episodes of cholangitis in 1997 and 2006 .
a axial t1-weighted in - phase and b out - of - phase images show an important signal drop on the opposed - phase image in a geographic distribution , affecting the hepatic dome more severely .
c subtraction confirms severe geographic fatty liver deposition a , bgeographic fat accumulation limited to the right lobe of the liver .
mri of the liver in a 57-year - old woman known for multiple focal nodular hyperplasia .
a axial t1-weighted in - phase and b out - of - phase images show an important signal drop in the right lobe of the liver on opposed - phase image a
mri of the liver in a 76-year - old man who had hepatico - jejunostomy for biliary duct trauma and stenosis followed by two episodes of cholangitis in 1997 and 2006 .
a axial t1-weighted in - phase and b out - of - phase images show an important signal drop on the opposed - phase image in a geographic distribution , affecting the hepatic dome more severely .
c subtraction confirms severe geographic fatty liver deposition focal fat deposition is slightly less common and can mimic other hepatic benign or malignant lesions on ultrasound and ct ( fig . 4 ) .
mri is very useful for making the diagnosis of focal hepatic steatosis , which appears isointense or hyperintense to liver on in - phase images and loses signal on out - of - phase images .
fat accumulation does not show diffusion restriction , which may also be useful to differentiate steatosis from other liver abnormalities .
moreover , focal fat accumulation tends to show wedge shaped margins , no mass effect on adjacent blood vessels or the biliary tree , sharp boundaries , and lobar or segmental distribution .
a ct , axial contrast - enhanced portal phase image in a 58-year - old woman shows a hypodense , mildly heterogeneous , cuneiform lesion in the posterior aspect of segment iv .
mri , b axial t1-weighted in - phase and c out - of - phase images show a signal drop within this lesion on the opposed - phase image focal fatty liver deposition .
a ct , axial contrast - enhanced portal phase image in a 58-year - old woman shows a hypodense , mildly heterogeneous , cuneiform lesion in the posterior aspect of segment iv .
mri , b axial t1-weighted in - phase and c out - of - phase images show a signal drop within this lesion on the opposed - phase image some regions of the liver are more prone to being affected by focal fat deposition .
those are the perivesicular and subcapsular regions abutting the hepatic hilum or falciform ligament in the area drained by the sapey s vein [ 7 , 11 ] .
the classical patterns of focal fatty liver deposition and sparing are linked to vascular anatomical variants that involve capsular veins , peribiliary veins , the cystic vein ( which drains perivesicular areas ) , and the right gastric vein ( which drains the anterior portion of segment i and the posterior portion of segment iv ) .
these veins can be the source of an aberrant venous draining system without portal inflow causing local haemodynamic anomalies that may lead to focal fatty liver deposition and sparing [ 11 , 13 ] .
d perivesicular fatty sparing . a ultrasound image in a 77-year - old woman who had nephrectomy for renal cell carcinoma shows a hyperechoic liver with hypoechoic perivesicular foci .
b ct , axial contrast - enhanced portal phase image shows a diffusely hypodense liver ( 57 hu ) in comparison with the spleen ( 135 hu ) with a perivesicular spared zone ( in segments iv and v ) .
mri , c axial t1-weighted in - phase and d out - of - phase images show an important signal drop of the liver on the opposed - phase image with the exception of a perivesicular spared zone a d perivesicular fatty sparing . a ultrasound image in a 77-year - old woman who had nephrectomy for renal cell carcinoma shows a hyperechoic liver with hypoechoic perivesicular foci .
b ct , axial contrast - enhanced portal phase image shows a diffusely hypodense liver ( 57 hu ) in comparison with the spleen ( 135 hu ) with a perivesicular spared zone ( in segments iv and v ) .
mri , c axial t1-weighted in - phase and d out - of - phase images show an important signal drop of the liver on the opposed - phase image with the exception of a perivesicular spared zone subcapsular fat deposition may present as small fat nodules ( fig . 6 ) or as a confluent peripheral region of fat confined to a subcapsular zone .
it may be caused by insulin added to the peritoneal dialysate in certain patients with renal failure and insulin - dependent diabetes .
subcapsular hepatocytes are exposed to a higher concentration of insulin than the rest of the liver in those patients .
because insulin promotes the esterification of free fatty acids into triglycerides , the peritoneal administration of insulin can result in subcapsular fat accumulation .
a axial contrast - enhanced portal phase ct image in a 58-year - old man with a neuro - endocrine tumour of the pancreas shows two small hypodense subcapsular hepatic lesions in segment v. mri , b axial t1-weighted in - phase and c out - of - phase images show a drop of signal within the two subcapsular lesions on the opposed - phase image a
a axial contrast - enhanced portal phase ct image in a 58-year - old man with a neuro - endocrine tumour of the pancreas shows two small hypodense subcapsular hepatic lesions in segment v. mri , b axial t1-weighted in - phase and c out - of - phase images show a drop of signal within the two subcapsular lesions on the opposed - phase image multifocal fatty liver deposition is another unusual pattern that can represent a difficult diagnostic challenge .
the differential diagnosis on ct and ultrasound may include metastasis , lymphoma , sarcoidosis , abscesses , candidiasis , haemangiomatosis and biliary hamartomas .
d multifocal fatty liver deposition . a ultrasound image in a 39-year - old woman with lymphoma and malignant thymoma with local pleural recurrence treated with radiotherapy and chemotherapy shows multiple nodular hyperechoic foci throughout the liver .
mri , c axial t1-weighted in - phase and d out - of - phase images show multiple lesions with signal drop on the opposed - phase image a d multifocal fatty liver deposition . a ultrasound image in a 39-year - old woman with lymphoma and malignant thymoma with local pleural recurrence treated with radiotherapy and chemotherapy shows multiple nodular hyperechoic foci throughout the liver .
mri , c axial t1-weighted in - phase and d out - of - phase images show multiple lesions with signal drop on the opposed - phase image a very unusual pattern of fatty liver disease is perivascular deposition .
halos of fat surround the hepatic veins , the portal veins , or both hepatic and portal veins .
. it may be difficult to differentiate perivascular fat deposition or perivascular sparing from periportal oedema , passive hepatic congestion and budd chiari syndrome on ct and ultrasound .
mri is useful for making this rare diagnosis by showing a signal intensity loss on opposed - phase images compared with in - phase images .
a ultrasound image in a 39-year - old man with a clinical suspicion of non - alcoholic fatty liver disease based on elevated liver enzymes shows a geographic area of fatty sparing parallel to the right hepatic vein .
b doppler image shows an absence of mass effect on the right hepatic vein a , b perivascular fatty sparing .
a ultrasound image in a 39-year - old man with a clinical suspicion of non - alcoholic fatty liver disease based on elevated liver enzymes shows a geographic area of fatty sparing parallel to the right hepatic vein .
it may have different levels of severity that can be determined by using quantification maps .
the presence of diffuse steatosis in a patient with hepatomegaly and an enlarged caudate - to - right lobe ratio should raise the possibility of nash .
fig .
d severe diffuse fatty liver disease . a ultrasound image in a 58-year - old man known for intraductal papillary mucinous neoplasm ( ipmn / ipmt ) of the pancreas and alcoholic pancreatitis showing a hyperechoic liver compared with the right renal cortex .
b ct , axial contrast - enhanced portal phase image shows a diffusely hypodense liver ( 42 hu ) compared with the spleen ( 113 hu ) ( > 25 hu difference ) .
mri , c axial t1-weighted in - phase and d out - of - phase images show an important signal drop of the liver on the opposed - phase image .
mr images were obtained on a 1.5-t mri system with tes of 2.2 and 4.5 for in- and out - of - phase images respectively a d severe diffuse fatty liver disease . a ultrasound image in a 58-year - old man known for intraductal papillary mucinous neoplasm ( ipmn / ipmt ) of the pancreas and alcoholic pancreatitis showing a hyperechoic liver compared with the right renal cortex .
b ct , axial contrast - enhanced portal phase image shows a diffusely hypodense liver ( 42 hu ) compared with the spleen ( 113 hu ) ( > 25 hu difference ) .
mri , c axial t1-weighted in - phase and d out - of - phase images show an important signal drop of the liver on the opposed - phase image .
mr images were obtained on a 1.5-t mri system with tes of 2.2 and 4.5 for in- and out - of - phase images respectively
for example , fat accumulation sometimes occurs only in the right lobe ( fig . 2 ) .
one hypothesis to explain this distribution is that blood from the superior mesenteric vein containing lipogenic alimentary factors is preferentially distributed to the right lobe of the liver .
geographic patterns may be secondary to an insult to the liver parenchyma . for example , fatty liver deposition can be distributed in territories previously affected by cholangitis ( fig .
mri of the liver in a 57-year - old woman known for multiple focal nodular hyperplasia .
a axial t1-weighted in - phase and b out - of - phase images show an important signal drop in the right lobe of the liver on opposed - phase imagefig
c severe geographic fatty liver deposition . mri of the liver in a 76-year - old man who had hepatico - jejunostomy for biliary duct trauma and stenosis followed by two episodes of cholangitis in 1997 and 2006 . a axial t1-weighted in - phase and
b out - of - phase images show an important signal drop on the opposed - phase image in a geographic distribution , affecting the hepatic dome more severely .
c subtraction confirms severe geographic fatty liver deposition a , bgeographic fat accumulation limited to the right lobe of the liver .
mri of the liver in a 57-year - old woman known for multiple focal nodular hyperplasia .
a axial t1-weighted in - phase and b out - of - phase images show an important signal drop in the right lobe of the liver on opposed - phase image a
mri of the liver in a 76-year - old man who had hepatico - jejunostomy for biliary duct trauma and stenosis followed by two episodes of cholangitis in 1997 and 2006 .
a axial t1-weighted in - phase and b out - of - phase images show an important signal drop on the opposed - phase image in a geographic distribution , affecting the hepatic dome more severely .
focal fat deposition is slightly less common and can mimic other hepatic benign or malignant lesions on ultrasound and ct ( fig . 4 ) .
mri is very useful for making the diagnosis of focal hepatic steatosis , which appears isointense or hyperintense to liver on in - phase images and loses signal on out - of - phase images .
fat accumulation does not show diffusion restriction , which may also be useful to differentiate steatosis from other liver abnormalities .
moreover , focal fat accumulation tends to show wedge shaped margins , no mass effect on adjacent blood vessels or the biliary tree , sharp boundaries , and lobar or segmental distribution .
a ct , axial contrast - enhanced portal phase image in a 58-year - old woman shows a hypodense , mildly heterogeneous , cuneiform lesion in the posterior aspect of segment iv .
mri , b axial t1-weighted in - phase and c out - of - phase images show a signal drop within this lesion on the opposed - phase image focal fatty liver deposition . a ct , axial contrast - enhanced portal phase image in a 58-year - old woman shows a hypodense , mildly heterogeneous , cuneiform lesion in the posterior aspect of segment iv .
mri , b axial t1-weighted in - phase and c out - of - phase images show a signal drop within this lesion on the opposed - phase image some regions of the liver are more prone to being affected by focal fat deposition .
those are the perivesicular and subcapsular regions abutting the hepatic hilum or falciform ligament in the area drained by the sapey s vein [ 7 , 11 ] .
the classical patterns of focal fatty liver deposition and sparing are linked to vascular anatomical variants that involve capsular veins , peribiliary veins , the cystic vein ( which drains perivesicular areas ) , and the right gastric vein ( which drains the anterior portion of segment i and the posterior portion of segment iv ) .
these veins can be the source of an aberrant venous draining system without portal inflow causing local haemodynamic anomalies that may lead to focal fatty liver deposition and sparing [ 11 , 13 ] .
d perivesicular fatty sparing . a ultrasound image in a 77-year - old woman who had nephrectomy for renal cell carcinoma shows a hyperechoic liver with hypoechoic perivesicular foci .
b ct , axial contrast - enhanced portal phase image shows a diffusely hypodense liver ( 57 hu ) in comparison with the spleen ( 135 hu ) with a perivesicular spared zone ( in segments iv and v ) .
mri , c axial t1-weighted in - phase and d out - of - phase images show an important signal drop of the liver on the opposed - phase image with the exception of a perivesicular spared zone a d perivesicular fatty sparing .
a ultrasound image in a 77-year - old woman who had nephrectomy for renal cell carcinoma shows a hyperechoic liver with hypoechoic perivesicular foci .
b ct , axial contrast - enhanced portal phase image shows a diffusely hypodense liver ( 57 hu ) in comparison with the spleen ( 135 hu ) with a perivesicular spared zone ( in segments iv and v ) .
mri , c axial t1-weighted in - phase and d out - of - phase images show an important signal drop of the liver on the opposed - phase image with the exception of a perivesicular spared zone
6 ) or as a confluent peripheral region of fat confined to a subcapsular zone .
it may be caused by insulin added to the peritoneal dialysate in certain patients with renal failure and insulin - dependent diabetes .
subcapsular hepatocytes are exposed to a higher concentration of insulin than the rest of the liver in those patients .
because insulin promotes the esterification of free fatty acids into triglycerides , the peritoneal administration of insulin can result in subcapsular fat accumulation .
a axial contrast - enhanced portal phase ct image in a 58-year - old man with a neuro - endocrine tumour of the pancreas shows two small hypodense subcapsular hepatic lesions in segment v. mri , b axial t1-weighted in - phase and c out - of - phase images show a drop of signal within the two subcapsular lesions on the opposed - phase image a
a axial contrast - enhanced portal phase ct image in a 58-year - old man with a neuro - endocrine tumour of the pancreas shows two small hypodense subcapsular hepatic lesions in segment v. mri , b axial t1-weighted in - phase and c out - of - phase images show a drop of signal within the two subcapsular lesions on the opposed - phase image
multifocal fatty liver deposition is another unusual pattern that can represent a difficult diagnostic challenge .
the foci are usually round or oval and may mimic multiple nodules . the differential diagnosis on ct and ultrasound may include metastasis , lymphoma , sarcoidosis , abscesses , candidiasis , haemangiomatosis and biliary hamartomas .
d multifocal fatty liver deposition . a ultrasound image in a 39-year - old woman with lymphoma and malignant thymoma with local pleural recurrence treated with radiotherapy and chemotherapy shows multiple nodular hyperechoic foci throughout the liver .
mri , c axial t1-weighted in - phase and d out - of - phase images show multiple lesions with signal drop on the opposed - phase image a d multifocal fatty liver deposition . a ultrasound image in a 39-year - old woman with lymphoma and malignant thymoma with local pleural recurrence treated with radiotherapy and chemotherapy shows multiple nodular hyperechoic foci throughout the liver .
mri , c axial t1-weighted in - phase and d out - of - phase images show multiple lesions with signal drop on the opposed - phase image
halos of fat surround the hepatic veins , the portal veins , or both hepatic and portal veins .
. it may be difficult to differentiate perivascular fat deposition or perivascular sparing from periportal oedema , passive hepatic congestion and budd chiari syndrome on ct and ultrasound .
mri is useful for making this rare diagnosis by showing a signal intensity loss on opposed - phase images compared with in - phase images .
a ultrasound image in a 39-year - old man with a clinical suspicion of non - alcoholic fatty liver disease based on elevated liver enzymes shows a geographic area of fatty sparing parallel to the right hepatic vein .
b doppler image shows an absence of mass effect on the right hepatic vein a , b perivascular fatty sparing .
a ultrasound image in a 39-year - old man with a clinical suspicion of non - alcoholic fatty liver disease based on elevated liver enzymes shows a geographic area of fatty sparing parallel to the right hepatic vein .
fatty liver deposition is a very common finding but it has many atypical patterns of distribution that can represent diagnostic pitfalls .
when an atypical form of fatty liver deposition is suspected on ultrasound or ct , mri may be used to confirm the diagnosis because of its ability to break down fat and water signal components .
Output:
| objectivefatty liver deposition is a very common finding , but it has many atypical patterns of distribution that can represent diagnostic pitfalls . the purpose of this pictorial essay is to review different patterns of fatty liver deposition and sparing.methodswe searched our archive retrospectively , reviewed the literature , and identified six patterns of liver steatosis.resultssteatosis may be diffuse , geographic , focal , subcapsular , multifocal or perivascular.conclusionsprevious knowledge of atypical patterns of steatosis distribution may prevent misdiagnosis of infiltrative disease or focal liver lesions .
when an unusual form of fatty liver deposition is suspected on ultrasound or computed tomography , magnetic resonance imaging may be used to confirm the diagnosis . |
PubmedSumm8834 | ***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 giant cell tumor , in which bcl-2 gene was expressed only in its malignant transformation , is a benign , primary skeletal neoplasm with variable biologic aggressiveness .
the correlation between giant cell tumor in hereditary multiple exostosis is still not clearly determined .
a 31-years - old female presented with pain and lump on her left wrist and a coexistence of non tender multiple lump in the right and left knee
. a wide excision of the tumor and reconstruction using non vascularized fibular graft was performed , followed by histopathology and immunohistochemistry of ext-1 and bcl-2 .
giant cell tumor and hereditary multiple exostosis also demonstrated associations of chromosomes 11 with a different pathological process .
giant cell tumor in hereditary multiple exostosis revealed positive ext-1 without bcl-2 expression . it still need more investigation to confirm the relationship between these tumors .
it often characterized by osteolytic destruction at the end of a long bone and large multinuclear cells in its histologic appearance .
it is benign in nature and known to be able to both recur and transform into malignancy , , .
the malignant subtype of gct is usually expressed some genes like the b - cell lymphoma 2 ( bcl-2 ) gene .
the gct was rarely found in coexistence with other benign lesion such as hereditary multiple exostosis ( hme ) , .
the reason behind that coexistence is still unclear , whether caused by either a transformation of hme or only considered as two separated lesions .
hereditary multiple exostosis is an autosomal dominant condition which characterized by the development of multiple exostosis and possess interfamilial and intrafamilial phenotypical variability in severity , size , and number of lesions .
this hme lesions are primarily caused by the presence of exostosin-1 ( ext-1 ) gene that occur in approximately 90% of cases .
the aim of this report is to identify the bcl-2 and ext-1 gene in gct with coexistence of hme .
it also served as a preliminary research to prove that the gct with the expression of ext-1 and bcl-2 in patients with hme tend to be more aggressive with high local recurrence and worse prognosis .
a 31-years - old female presented with pain and lump on her left wrist since 4 months ago . physical examination revealed a lump located on left wrist .
the size of the lump clinically was 5 cm by 6 cm with shiny skin , clear border , firm in consistency , and fixed to the bone ( fig .
her wrist extension and flexion was limited to 10 of flexion and 5 of extension due to pain and mass . on the right and left knees , we found non - tender multiple lumps ( fig .
1b ) . the x ray of left wrist revealed osteolytic lesion with some geographic patterns ( fig .
she had wide surgical excision of the tumor which extended to the wrist joint and 3 cm upper the tumor followed by reconstruction using non vascularized fibular graft .
we found multiple bony masses with clinical characteristics of multiple exostosis on the proximal site of fibular graft ( fig .
the excised part of the radius has replaced with non - vascularized fibular graft , then fixed with plate and screws .
histopathological finding revealed gct with an eosinophilic cytoplasm , round ovals nucleus , vesicular chromatin with small nucleus prominent , and a slight mitosis ( fig .
3 ) . immunochemistry finding revealed existence of ext-1 but no existence of bcl-2 ( fig .
the patient feels no pain , already returned to regular activities , range of motion return to 7599% and the grip strength is 100% ( fig .
the case presented a gct of the left wrist with another lesion of hme on the right and left knee .
this case was very rare because we were not able to find more cases in the literature matching this coexistence .
( 2002 ) mentioning a coexistence of giant cell tumor over the left leg , para - articular osteochondroma over the left hip and an idiopathic thrombocytopenic purpura ( itp ) .
a curettage of gct lesion was performed , followed by washing out the remainder with hot saline , then filled with autogenous iliac bone graft and cement .
( 2015 ) has reported a case of gct of proximal tibia in patient with history of multiple osteochondromatosis .
the tumor was resected , a skeletal reconstruction with gmrs prosthesis was performed , followed by soft tissue reconstruction with rotation flap .
histopathological examination revealed gct with area of fibrohistiocytic pattern and component of aneurysmal bone cyst .
the report also suggested a positive genetic polymorphism in the ext-2 gene . in this case , we suspected the existence of two tumors in one patient .
there was revealed a positive expression of ext-1 gene and negative expression of bcl-2 gene from gct mass of left wrist .
the cells giving positive reaction of anti - ext-1 with b chomogen method ( fig .
positive reaction was pointed by blue arrow , on the other hand , negative reaction was represented by red arrow .
positive control showed coloration on nucleus and cytoplasm , whereas no coloration on nucleus and cytoplasm was found on negative as seen on fig .
currently , ext-1 gene has considered as an important causative factor in hereditary multiple exostosis , , .
hereditary multiple exostosis is genetically heterogeneous with three loci on chromosomes 8q24.1 , 11p13 , and 19q .
the first ext-1 locus that located on chromosome 8 ( 8q24.1 ) was discovered by cook in 1993 , which also linked with chromosome 11q24 .
the distal end of 8q locus is responsible for the formation of hme and was identified as the ext-1 .
later on , a new gene on chromosome 11 ( 11p11 - 13 ) was identified as a locus for hme and named ext-2 .
a third locus on chromosome 19p , suspected of causing hme was named ext-3 , but it is considered to be a minor contributor to the actual formation of hme .
most of the ext-1 and ext-2 genes ( 80% ) prompt to mutation by nonsense , frameshift or splice - site mutations leading to premature termination of the ext proteins .
giant cell tumor of the bone is a benign , primary skeletal neoplasm with variable biologic aggressiveness that demonstrates telomeric associations of chromosomes 11 , 16 , 19 , 20 , and 21 , reduction of telomere length , marker chromosomes , double minutes , chromosome fragments , ring chromosomes , and polyploidy .
some gene that expressed in gct such as ip53 , h - ras , c - myc , mmp-9 , mib-1 and bcl-2 had important rules for malignant transformation .
we have also performed immunohistochemistry of bcl-2 for finding the apoptosis process in the tumor lesions .
bcl-2 is an anti - apoptosis protein whose overexpression contributes to the uncontrollable proliferation of gliomas and other neoplasm s .
it encodes an integral membrane protein ( 25 kda protein ) , mainly localized to inner mitochondrial membrane , endoplasmic reticulum and nuclear envelope .
the bcl-2 overexpression increases lifespan of b cells , maintains memory b cells , plasma cells and neurons by prolonging life span without cell division .
it also may participates in ion channel formation and alteration of membrane permeability that necessary for initiation of apoptosis .
( 2010 ) in their study reported a higher value of bcl-2 in malignant subtype of gct .
this implies that malignant transformation could trigger gct cells to express this marker more frequently , thus , it could be regarded as an indicator for malignant transformation and unfavorable clinical course .
( 1998 ) studied expression of regulatory apoptotic proteins in peripheral giant cell lesions containing osteoclast - like giant cells that showing only weak positivity for bcl-2 . in this case
the bcl-2 result is negative , revealing that the giant cell tumor was not transformed into malignant .
based on the results of this study , gct characterized as benign aggressive with negative bcl-2 gene expression and showed similarity with hme by a positive ext-1 gene expression .
a data based on ontology between hme and gct assuming that gct may arise from a transformation of hme .
giant cell tumor in hereditary multiple exostosis revealed positive ext-1 without bcl-2 expression . in this case , this coexistence revealed a probability of gct that arised from hme but did not showed malignant transformation .
Output:
| highlightsthe giant cell tumor is a benign , primary skeletal neoplasm with variable biologic aggressiveness.a coexistence with hereditary multiple exostosis with expression of ext-1 is very rare.bcl-2 gene is expressed only in malignant transformation of the giant cell tumor.the correlation between giant cell tumor and hereditary multiple exostosis is still not clearly determined.the case revealed giant cell tumor in hereditary multiple exostosis with positive ext-1 without bcl-2 expression . |
PubmedSumm8835 | ***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: lymphangiomas are rare benign tumors that are preferentially located in the head and neck in children ( 1 ) .
lymphangiomas in the peritoneal cavity are extremely rare occurring most commonly in the mesentery , followed by the omentum , mesocolon , and retroperitoneum .
the etiology is unclear , but they are considered primarily to congenital in origin ( 2 ) .
we report the case of a young woman with appendicular pain caused by a cystic lymphangioma of the right iliac fossa : a rare but possible differential diagnosis .
a 17-year - old female patient presented with a dull abdominal pain in the right iliac fossa and flank of a 1-month duration .
an abdominal examination revealed hyperactive bowel sounds and tenderness during palpation in the central abdominal quadrant and right iliac fossa in mc burney point .
neoplastic markers ( afp , cea , ca 19 - 9 , ca 15 - 3 , ca125 , tps ) were negative .
axial and coronal t2-weighted tse images showed the presence of a fluid - filled cystic lesion in the retrocaecl adipose tissue .
an ultrasonographic and ct scan of the abdomen revealed the presence of a cystic mass ( max diameter 60 mm ) in the retrocaecal adipose tissue that was in proximity of the caecum , appendix and ileum .
in addition , the ct scan revealed the presence of multiple hypodense formations in the body and tail of pancreas . during the hospital
the exam revealed in the retrocaecl adipose tissue the presence of a fluid - filled formation with a diameter of 60 mm that appeared indissociable from the caecum for the presence of a tissue connection ( fig 1 ) .
other cystic lesions ( communicating with pancreatic duct ) were present in the whole pancreas and in the right kidney .
fluid - filled cystic lymphangioma with polycyclic edge and internal septa ( intraoperative specimen ) the patient underwent exploratory surgery : at laparotomy a yellowish oval formation with a diameter of 6 cm was found arising from the mesentery of terminal ileum with partial adhesion of the appendix .
the lesion had a cystic aspect and was fluid - filled ( fig 2 ) .
the patient has been followed - up for two years with semestral clinical examination and abdominal eco scan and no recurrence occurred .
intra - abdominal mesenteric lymphangioma is an uncommon tumor that usually manifestes in early adulthood .
this tumor has an incidence of approximately 1/20,000 and 1/250,000 hospital admissions , and it is more frequent in men than women with a m / f ratio of 3:1 ( 3 ) . in intraperitoneal sites , the small bowel mesentery ( 70% )
is the commonest localization , with 5060% of all cysts located in the ileal mesentery .
( 4 ) the etiology of mesenteric lymphangioma is considered to be congenital , with abnormal embryonic development of the lymphatic system causing sequestration of lymphatic tissue ( 1 ) : infact in our patient also other cystic lesions ( kidney and pancreas ) were found at abdomen ct / mri .
radiological investigations are a useful diagnostic tool , but definitive diagnosis is confirmed by histopathology after a complete surgical resection .
( 5 ) at immunochemistry : the lining mesothelial cells are immunoreactive for cytokeratin and negative for factor viiiis .
double staining with prox1 and cd31 is the most reliable method for characterizing lymphangioma endothelial cells.(6 )
Output:
| pain of the right iliac fossa in young girls can relate to several pathologies of the gastrointestinal and genitor - urinary tract . on the other hand , lymphangiomas in the peritoneal cavity are extremely rare .
we report the case of a young woman with pain in the right iliac fossa caused by a cystic lymphangioma . a 17-year - old caucasian female patient presented with abdominal pain in the right iliac fossa and flank of a 1-month duration .
the patient was apyrexic and laboratory tests were negative .
ct / mri of abdomen showed a cystic mass ( max diameter 60 mm ) in the retrocaecl adipose tissue in connection with the caecum and appendix .
the patient underwent a total excision of the lesion and appendicectomy .
histopathological examination was consistent with the diagnosis of mesenteric lymphangioma .
this case shows a rare but possible cause of right iliac fossa pain in young women to be considered in the differential diagnosis . |
PubmedSumm8836 | ***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: baseline sera samples of 1,400 mexican american persons enrolled in the san antonio family heart study ( 29 ) were screened for the presence of neutralizing antibodies to ad36 by serum neutralization assay as described .
subsequently , seropositivity was evaluated for association with measures of adiposity available at baseline and 10 years later .
the study was initiated in 1991 with the goal of investigating the genetic factors influencing cardiovascular disease and related quantitative risk factors in mexican american individuals from san antonio , texas .
multigenerational families were ascertained from largely hispanic neighborhoods of san antonio via a single adult mexican american proband with a sufficient number of first - degree relatives to be eligible .
body weight , body fat , fasting glucose , and insulin determined at baseline and at 10-year follow - up visit were used for analyses .
baseline body composition was determined by the bioimpedance method using a valhalla bio - impedance analyzer ( valhalla scientific , san diego , ca ) .
the 10-year follow - up body composition also was determined by a bioimpedance analyzer from xitron technologies ( san diego , ca ) .
plasma glucose was measured using an abbott v / p analyzer , and serum concentrations of insulin were measured using commercial radioimmunoassay kits ( diagnostic products ) .
presence of neutralizing antibodies in serum was determined by the constant virus - decreasing serum method as described ( 22 ) .
this is a labor - intensive assay but a highly specific and sensitive gold standard to determine neutralizing antibodies .
ad36 required for the assay was originally obtained from american type culture collection ( cat # vr913 ) and was plaque - purified and propagated in a549 cells ( human lung cancer cell line ) ( 3,4 ) .
the statistical analyses for baseline measures were performed with the r package blr ( bayesian linear regression ) ( 30,31 ) to account for the degrees of genetic similarity between subjects within a pedigree and can adjust for covariates in the regression models ( see supplementary materials for details ) .
the data set comprises 153 pedigrees ( with most participants belonging to large multigenerational pedigrees and a few participants being members of small pedigrees or singletons ) .
bmi , body fat percentage , fasting glucose , and insulin were adjusted for age and sex .
table 2 lists means and sds of the differences in baseline indices of adiposity and glycemic control between ad36 seropositive and seronegative subjects . in the table
we also list the probability that the alternative hypothesis ( h1 : ad36 infection increases adiposity or h1 : ad36 infection improves glycemic control ) is true .
the statistical analyses for longitudinal data were performed with the r package pedigreemm ( pedigree - based mixed - effect models ) ( 32 ) ( see supplementary materials for details ) .
the measurements on adiposity and glycemic control at three time points ( baseline , 5 years , and 10 years past the baseline ) were jointly modeled in the mixed - effect model . the genetic similarity between subjects within a pedigree
consistent with the previous analyses for baseline measures , bmi , body fat percentage , fasting glucose , and insulin were adjusted for age and sex .
p values were based on one - tailed tests according to our hypotheses about the association of ad36 with obesity and glycemic control .
furthermore , to gain better insight , we also examined the associations of ad36 infection with bmi , body fat percentage , fasting glucose , and insulin for different subgroups of sex and bmi . despite a continuous measure
, bmi is commonly categorized as normal weight , overweight , or obese ( bmi kg / m : < 25 , 2530 , and > 30 , respectively ) .
glycemic control as indicated by the levels of fasting glucose or insulin is expected to deteriorate with age in the elderly or even the middle - aged ( 33,34 ) .
a lower increase in fasting glucose or insulin values based on the longitudinal observations over the 10-year period was used to indicate less deterioration of glycemic control .
baseline sera samples of 1,400 mexican american persons enrolled in the san antonio family heart study ( 29 ) were screened for the presence of neutralizing antibodies to ad36 by serum neutralization assay as described .
subsequently , seropositivity was evaluated for association with measures of adiposity available at baseline and 10 years later .
the study was initiated in 1991 with the goal of investigating the genetic factors influencing cardiovascular disease and related quantitative risk factors in mexican american individuals from san antonio , texas .
multigenerational families were ascertained from largely hispanic neighborhoods of san antonio via a single adult mexican american proband with a sufficient number of first - degree relatives to be eligible .
body weight , body fat , fasting glucose , and insulin determined at baseline and at 10-year follow - up visit were used for analyses .
baseline body composition was determined by the bioimpedance method using a valhalla bio - impedance analyzer ( valhalla scientific , san diego , ca ) .
the 10-year follow - up body composition also was determined by a bioimpedance analyzer from xitron technologies ( san diego , ca ) .
plasma glucose was measured using an abbott v / p analyzer , and serum concentrations of insulin were measured using commercial radioimmunoassay kits ( diagnostic products ) .
presence of neutralizing antibodies in serum was determined by the constant virus - decreasing serum method as described ( 22 ) .
this is a labor - intensive assay but a highly specific and sensitive gold standard to determine neutralizing antibodies .
ad36 required for the assay was originally obtained from american type culture collection ( cat # vr913 ) and was plaque - purified and propagated in a549 cells ( human lung cancer cell line ) ( 3,4 ) .
the statistical analyses for baseline measures were performed with the r package blr ( bayesian linear regression ) ( 30,31 ) to account for the degrees of genetic similarity between subjects within a pedigree and can adjust for covariates in the regression models ( see supplementary materials for details ) .
the data set comprises 153 pedigrees ( with most participants belonging to large multigenerational pedigrees and a few participants being members of small pedigrees or singletons ) .
bmi , body fat percentage , fasting glucose , and insulin were adjusted for age and sex .
table 2 lists means and sds of the differences in baseline indices of adiposity and glycemic control between ad36 seropositive and seronegative subjects . in the table
we also list the probability that the alternative hypothesis ( h1 : ad36 infection increases adiposity or h1 : ad36 infection improves glycemic control ) is true .
the statistical analyses for longitudinal data were performed with the r package pedigreemm ( pedigree - based mixed - effect models ) ( 32 ) ( see supplementary materials for details ) .
the measurements on adiposity and glycemic control at three time points ( baseline , 5 years , and 10 years past the baseline ) were jointly modeled in the mixed - effect model . the genetic similarity between subjects within a pedigree
consistent with the previous analyses for baseline measures , bmi , body fat percentage , fasting glucose , and insulin were adjusted for age and sex .
p values were based on one - tailed tests according to our hypotheses about the association of ad36 with obesity and glycemic control .
furthermore , to gain better insight , we also examined the associations of ad36 infection with bmi , body fat percentage , fasting glucose , and insulin for different subgroups of sex and bmi . despite a continuous measure
, bmi is commonly categorized as normal weight , overweight , or obese ( bmi kg / m : < 25 , 2530 , and > 30 , respectively ) .
glycemic control as indicated by the levels of fasting glucose or insulin is expected to deteriorate with age in the elderly or even the middle - aged ( 33,34 ) . a lower increase in fasting glucose or insulin values based on the longitudinal observations over the 10-year period
at baseline , men and women were almost 40 years of age on average and had a mean bmi in the overweight category ( 29.15 6.38
their mean fasting glucose and insulin levels were toward the upper limit of the normal range .
of the 834 women , and of the 566 men , 132 ( 15.8% ) and 72 ( 12.7% ) , respectively , were seropositive for ad36 . to avoid any potential confounding effect of antidiabetic drugs on the variation in glucose and insulin levels , diabetic individuals ( 174 seronegative [ 14.5% ] and 31 seropositive [ 15.2% ] )
were not included in the analyses of glycemic indices . a separate analysis for glycemic indices of diabetic and nondiabetic individuals
was conducted ( the diabetes status was regarded as a covariate adjusted in the model ) , which was presented in the supplementary materials .
baseline characteristics ( mean sd ) compared with their seronegative counterparts , seropositive men and women were more likely to have greater body fat percentage ( table 2 ) .
bmi subgroup analyses indicated that ad36 seropositivity was associated with better baseline glycemic control in the normal - weight group ( bmi 25 kg / m ) . when the bmi subgroups were separated by sex , seropositive normal - weight women , but not men , had lower baseline fasting glucose and insulin levels ( table 2 ) .
differences in baseline indices of adiposity and glycemic control between ad36 seropositive and seronegative subjects seropositive men and women of all bmi , when analyzed together , showed a greater body fat percentage compared with seronegative counterparts ( table 3 ) . from the bmi subgroup analyses ,
the overweight and obese seropositive men had a significant greater bmi compared with the overweight and obese seronegative men .
longitudinal data analyses for bmi and body fat percentage men and women of all bmi , when analyzed together , showed lower fasting insulin levels for the seropositive group compared with the seronegative counterpart ( table 4 ) .
the bmi / sex subgroup analyses indicated that mainly the seropositive normal - weight men and women and the overweight men contributed to this association .
obese seropositive subjects did not show significantly different fasting glucose or insulin levels compared with their seronegative counterparts .
longitudinal data analyses for fasting glucose and insulin in nondiabetic subjects note that only nondiabetic individuals were included in the analyses of fasting glucose and insulin . however , when the analyses were conducted by including diabetic and nondiabetic individuals , but adjusting for the diabetes status , the findings were similar ( supplementary table 2 ) .
ad36 seropositivity was associated with lower fasting glucose and insulin levels in only normal - weight men and women ( supplementary table 2 ) .
thus , despite diabetes status , ad36 is associated with better glycemic profile , as we previously reported ( 13 ) .
at baseline , men and women were almost 40 years of age on average and had a mean bmi in the overweight category ( 29.15 6.38
their mean fasting glucose and insulin levels were toward the upper limit of the normal range .
of the 834 women , and of the 566 men , 132 ( 15.8% ) and 72 ( 12.7% ) , respectively , were seropositive for ad36 . to avoid any potential confounding effect of antidiabetic drugs on the variation in glucose and insulin levels , diabetic individuals ( 174 seronegative [ 14.5% ] and 31 seropositive [ 15.2% ] )
were not included in the analyses of glycemic indices . a separate analysis for glycemic indices of diabetic and nondiabetic individuals
was conducted ( the diabetes status was regarded as a covariate adjusted in the model ) , which was presented in the supplementary materials .
baseline characteristics ( mean sd ) compared with their seronegative counterparts , seropositive men and women were more likely to have greater body fat percentage ( table 2 ) .
bmi subgroup analyses indicated that ad36 seropositivity was associated with better baseline glycemic control in the normal - weight group ( bmi 25 kg / m ) . when the bmi subgroups were separated by sex , seropositive normal - weight women , but not men , had lower baseline fasting glucose and insulin levels ( table 2 ) .
seropositive men and women of all bmi , when analyzed together , showed a greater body fat percentage compared with seronegative counterparts ( table 3 ) . from the bmi subgroup analyses ,
the overweight and obese seropositive men had a significant greater bmi compared with the overweight and obese seronegative men .
longitudinal data analyses for bmi and body fat percentage men and women of all bmi , when analyzed together , showed lower fasting insulin levels for the seropositive group compared with the seronegative counterpart ( table 4 ) .
the bmi / sex subgroup analyses indicated that mainly the seropositive normal - weight men and women and the overweight men contributed to this association .
obese seropositive subjects did not show significantly different fasting glucose or insulin levels compared with their seronegative counterparts .
longitudinal data analyses for fasting glucose and insulin in nondiabetic subjects note that only nondiabetic individuals were included in the analyses of fasting glucose and insulin . however , when the analyses were conducted by including diabetic and nondiabetic individuals , but adjusting for the diabetes status , the findings were similar ( supplementary table 2 ) .
ad36 seropositivity was associated with lower fasting glucose and insulin levels in only normal - weight men and women ( supplementary table 2 ) .
thus , despite diabetes status , ad36 is associated with better glycemic profile , as we previously reported ( 13 ) .
the results confirm a cross - sectional association of ad36 infection with greater adiposity , as reported by several earlier studies ( 2227 ) . more importantly , this is the first report to show the longitudinal association of ad36 infection with adiposity and glycemic control .
the key finding of this study is that , as hypothesized , natural ad36 infection is associated with greater adiposity and less deterioration in glycemic control in hispanic men and women over time .
clearly , even a longitudinal association does not establish causality , and interpretation of these findings within the context of this study and in relation to other studies with ad36 is required .
overall , ad36 seropositivity was associated with greater adiposity and attenuated deterioration in better glycemic control , both cross - sectionally and longitudinally ( supplementary table 1 ) .
interestingly , further analyses revealed that the association of ad36 seropositivity with glycemic control and adiposity may be mainly contributed by two different subgroups , women with bmi 25 ( for glycemic control ) and men with bmi > 25 ( for adiposity ) , respectively . in animal models ,
the dual effect of ad36 on adiposity and glycemic control ( 6,7 ) appears similar to that of the thiazolidinedione class of antidiabetic drugs ( 20 ) , which increase adiposity but improve diabetes .
however , very recent vitro data indicate that unlike the action of the thiazolidinediones , the two effects of ad36 may be separable ( 7,16 ) .
the dichotomy of association of ad36 seropositivity with adiposity and glycemic control with two separate subgroups also suggests that the adipogenic and glycemic associations of ad36 infection may not be interdependent .
when men and women were analyzed together , ad36 seropositivity was associated with lower fasting insulin levels and greater body fat percentage over time . however , when analyzed separately , women appear to mainly contribute to the association with lower fasting insulin , whereas men appear to mainly contribute to the association with greater adiposity .
animal data indicate that adiponectin , an important insulin - sensitizing adipokine , may be a key player in mediating the insulin - sensitizing effect of ad36 ( 7 ) .
also , ad36 infection is associated with greater adiponectin levels in humans ( 16 ) .
adiponectin levels are higher in women compared with men ( 35 ) , which may facilitate a greater effect of ad36 on glycemic control in that sex .
conversely , adiponectin levels decrease in obesity or with a high - fat diet ( 36 ) , which may explain a subdued association of ad36 with better glycemic control in obese subjects .
although it is unclear why some sex and bmi subgroups did not show significant associations with ad36 infection , it could potentially indicate the contribution of unknown factors specific to these subgroups .
importantly , there is no information about other potential factors such as diet or exercise , which may influence adiposity or glycemic control in this population . how genetic and environmental factors can modulate the phenotypic effect of a virus
this virus increases the susceptibility of an individual to crohn disease only in the presence of a mutation in host gene atg16l1 and in the presence of commensal bacteria ( 37 ) .
similarly , factors related to ad36 infection , such as the virulence , the time lapsed after exposure to infection , and host factors , including race-/ethnicity - specific response to infection , severity of infection , and other lifestyle factors pertinent to this population may vary in subgroups and may collectively shape the phenotypic association to ad36 infection .
the first step toward understanding such genetic and nongenetic contributors of the metabolic associations of ad36 is to identify the subgroup differences .
although the results are consistent with our expectations based on previous reports by us and others ( 2,7,13,38,39 ) , the seropositivity - based differences in adiposity and glycemic control are modest in magnitude .
moreover , we investigated the association of ad36 seropositivity with adiposity and glycemic control in three bmi subgroups and both sexes .
this required the adjustment for multiple comparisons . following the commonly used guidelines on statistical reporting ( 40 )
however , if a conservative bonferroni correction is applied to the multiple testing ( 2 sexes 3 bmi categories 4 traits 2 types of analysis [ baseline and longitudinal ] = 48 tests ) , the p value for significance should be considered to be approximately 0.001 . none of our results reach this level of statistical significance , but such an adjustment is likely overly conservative given the correlated nature of the phenotypic variables . in any case , caution when interpreting these results is warranted .
bmi is a continuous variable and an argument could be made against stratifying by obesity level for analyses .
however , to reflect clinical relevance of our findings , we selected the three categories of bmi that are used extensively . also , a recent study suggested that weight gain over time may depend on baseline adiposity ( 41 ) .
therefore , we used bmi subgroup analyses , which revealed some interesting insight about the contribution of individual bmi categories to the results . neutralizing antibodies to viruses
therefore , it is possible that subjects deemed seronegative at baseline may have experienced seroconversion later during the 10-year follow - up period .
this would presumably bias the comparison against the current findings ( by including such seroconverted subjects in the seronegative category ) .
the significance was noted in the ad36 seropositive groups , despite this possibility and despite the long follow - up duration .
although screening for neutralizing antibodies is highly resource - intensive , determining antibody status at the end of the follow - up period may strengthen the association further . despite these limitations
, this study is an important initial step in unraveling our understanding of how some pathogens may chronically interact with metabolic pathways .
although this study indicates an association , and not causation , taken together with previous in vitro and in vivo data , and with human cross - sectional data , these associations render more plausible the idea that in humans ad36 increases adiposity and improves glycemic control .
importantly , in specific subgroups , ad36 seropositivity may be a protective factor for hyperglycemia or insulin resistance .
if so , then this is potentially a property that could be harnessed to improve diabetes , as demonstrated by the experimental ad36 infection of mice with diet - induced hyperglycemia ( 7 ) .
however , e4orf1 , a viral protein that is necessary and sufficient for the antihyeprglyemic effect of ad36 ( 15 ) , may be used to develop an antidiabetic agent .
improvement in glycemic control predicted by natural ad36 infection in humans conceptually supports the potential of the ad36 e4orf1 protein to improve glycemic control in humans .
a recent study reported another potential implication of determining ad36 infection status . in response to a reduced energy diet ,
ad36 seropositive adults lose more weight and have improved insulin sensitivity and reduced hepatic steatosis compared with seronegative individuals ( 39 ) .
importantly , the results advance the possibility that in addition to genetic , physiological , and behavioral factors , certain asymptomatic infections may lastingly influence human metabolism . a deeper understanding of these under - recognized factors may help in designing treatment or prevention strategies for such metabolic disorders .
although the results are consistent with our expectations based on previous reports by us and others ( 2,7,13,38,39 ) , the seropositivity - based differences in adiposity and glycemic control are modest in magnitude .
moreover , we investigated the association of ad36 seropositivity with adiposity and glycemic control in three bmi subgroups and both sexes .
this required the adjustment for multiple comparisons . following the commonly used guidelines on statistical reporting ( 40 )
if a conservative bonferroni correction is applied to the multiple testing ( 2 sexes 3 bmi categories 4 traits 2 types of analysis [ baseline and longitudinal ] = 48 tests ) , the p value for significance should be considered to be approximately 0.001 .
none of our results reach this level of statistical significance , but such an adjustment is likely overly conservative given the correlated nature of the phenotypic variables . in any case , caution when interpreting these results is warranted .
bmi is a continuous variable and an argument could be made against stratifying by obesity level for analyses .
however , to reflect clinical relevance of our findings , we selected the three categories of bmi that are used extensively . also , a recent study suggested that weight gain over time may depend on baseline adiposity ( 41 ) .
therefore , we used bmi subgroup analyses , which revealed some interesting insight about the contribution of individual bmi categories to the results . neutralizing antibodies to viruses
therefore , it is possible that subjects deemed seronegative at baseline may have experienced seroconversion later during the 10-year follow - up period .
this would presumably bias the comparison against the current findings ( by including such seroconverted subjects in the seronegative category ) .
the significance was noted in the ad36 seropositive groups , despite this possibility and despite the long follow - up duration .
although screening for neutralizing antibodies is highly resource - intensive , determining antibody status at the end of the follow - up period may strengthen the association further . despite these limitations
, this study is an important initial step in unraveling our understanding of how some pathogens may chronically interact with metabolic pathways .
although this study indicates an association , and not causation , taken together with previous in vitro and in vivo data , and with human cross - sectional data , these associations render more plausible the idea that in humans ad36 increases adiposity and improves glycemic control .
importantly , in specific subgroups , ad36 seropositivity may be a protective factor for hyperglycemia or insulin resistance .
if so , then this is potentially a property that could be harnessed to improve diabetes , as demonstrated by the experimental ad36 infection of mice with diet - induced hyperglycemia ( 7 ) .
however , e4orf1 , a viral protein that is necessary and sufficient for the antihyeprglyemic effect of ad36 ( 15 ) , may be used to develop an antidiabetic agent .
improvement in glycemic control predicted by natural ad36 infection in humans conceptually supports the potential of the ad36 e4orf1 protein to improve glycemic control in humans .
a recent study reported another potential implication of determining ad36 infection status . in response to a reduced energy diet ,
ad36 seropositive adults lose more weight and have improved insulin sensitivity and reduced hepatic steatosis compared with seronegative individuals ( 39 ) .
importantly , the results advance the possibility that in addition to genetic , physiological , and behavioral factors , certain asymptomatic infections may lastingly influence human metabolism . a deeper understanding of these under - recognized factors may help in designing treatment or prevention strategies for such metabolic disorders .
Output:
| objectivead36 , a human adenovirus , increases adiposity but improves glycemic control in animal models . similarly , natural ad36 infection is cross - sectionally associated with greater adiposity and better glycemic control in humans .
this study compared longitudinal observations in indices of adiposity ( bmi and body fat percentage ) and glycemic control ( fasting glucose and insulin ) in ad36-infected versus uninfected adults.research design and methodsbaseline sera from hispanic men and women ( n = 1,400 ) were screened post hoc for the presence of ad36-specific antibodies .
indices of adiposity and glycemic control at baseline and at 10 years past the baseline were compared between seropositive and seronegative subjects , with adjustment for age and sex .
in addition to age and sex , indices of glycemic control were adjusted for baseline bmi and were analyzed only for nondiabetic subjects.resultsseropositive subjects ( 14.5% ) had greater adiposity at baseline , compared with seronegative subjects .
longitudinally , seropositive subjects showed greater adiposity indices but lower fasting insulin levels .
subgroup analyses revealed that ad36-seropositivity was associated with better baseline glycemic control and lower fasting insulin levels over time in the normal - weight group ( bmi 25 kg / m2 ) and longitudinally , with greater adiposity in the overweight ( bmi 2530 kg / m2 ) and obese ( bmi > 30 kg / m2 ) men .
statistically , the differences between seropositive and seronegative individuals were modest in light of the multiple tests performed.conclusionsthis study strengthens the plausibility that in humans , ad36 increases adiposity and attenuates deterioration of glycemic control .
panoptically , the study raises the possibility that certain infections may modulate obesity or diabetes risk . a comprehensive understanding of these under - recognized factors is needed to effectively combat such metabolic disorders . |
PubmedSumm8837 | ***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 injuries have a considerable impact on the population 's health in terms of mortality , morbidity and disability121 ) .
trauma is the major cause of death for all age groups in most countries as well as in korea .
approximately half of all trauma deaths are associated with head injury , and more than 60% of traffic accidental deaths are due to head injury323 ) .
some patients who survive the primary injury are frequently left with significant neurological deficit and often require prolonged hospitalization or long - term care .
this situation would result in extended loss of productive function and a prohibitive cost for the country48 ) . as a general rule ,
referring the several available statistics , death rate from traumatic injuries does not identify head injuries , although their incidence reflects geographical differences and trends over time in the frequency of trauma deaths as a whole11 ) .
epidemiologic study of head injury in korea is very important because tremendous increase in the number of traffic accidents has been observed with its rapid industrial and economic growth .
korea had one of the world 's fastest growing economies from the early 1970s to the late 1990s , and remains one of the fastest growing developed countries in the 2000s .
it was n't until 2010 that the korea trauma data bank committee was founded within korean society of neurotrauma for epidemiologic study18 ) .
consequently the authors tried to outline the trend of incidence of head injury using traffic accident statistical database from 1970 to 2012 and seven reports of hospital based head injury .
the aim of the present study is to estimate the incidence of head injury based on traffic accident statistics and to describe the incidence trends and the impacts of rapid industrialization on head injury epidemiology in korea over the period 19702012 including both of developing and developed terms .
it is of limited value that reports of head injuries are carried out by clinicians .
because the several different specialists are responsible for head injuries of different severities with varying admission and transfer policies , it is not easy to put these reports into an epidemiological setting . furthermore , most head injuries admitted to hospital are mild , but many clinical reports are produced by neurosurgeons who focus only on the 510% of severe or complicated injuries that are transferred to them .
therefore it is very demanding to acquire the total number of head injuries in korea .
our concern is not to know the total number of head injuries but to understand the trend of epidemiology on head injury before and after industrialization .
it was n't until 2010 that the korea trauma data bank committee was founded within korean society of neurotrauma for the purpose of injury prevention , clinical research and policy development on head injury .
consequently the authors tried to outline the trend of incidence of head injury and to understand epidemiologic effects of rapid industrialization on head injury using traffic accident statistical database from 1970 to 2012 and seven reports of hospital based head injury .
the first is the police road accident database and the second is the integrated road accident database , the latter being an aggregated database from police , insurance companies and mutual aid associations .
the latter is more reasonable and realistic but has data only from 2007 not including developing stage .
lee16 ) estimated the incidence of head injury by reviewing seven hospital based reports ( table 1 ) and applying to national traffic accident statistics .
analyzing the cause of head injury on those reports by hospitals , the traffic accident was about 62.5% of all head injuries .
he made approximate calculations of the incidence of head injury by a formula h = t/0.625 ( h : the total number of head injury , t : the total number of patients due to traffic accidents ) . in the same way we estimated the incidence of head injury from 1970 to 2012 and plotted a line graph for easy interpretation of the trend of the incidence and the mortality on head injury .
we also investigated gross national income ( gni ) per capita quoting the data reported by world macroeconomic research10 ) and the population pyramid produced by statistics korea over the same period . and
we tried to investigate how the structure of population and the growth of gni by industrialization make on impact on epidemiology of head injury .
referring to the result of traffic accident statistical database by the korea road traffic authority , the number of head injury patients due to motor vehicle accidents was 42830 in 1970 , 111641 in 1980 , 324229 in 1990 , 426984 in 2000 , and 344565 in 2012 ( https://taas.koroad.or.kr/ ) . consequently using the above estimation formula performed by lee
, the total number of patients with head injury would be 68528 in 1970 , 178625 in 1980 , 518766 in 1990 , 683174 in 2000 and 551304 in 2012 . according to the material produced by statistics korea , the population of korea was 32240827 in 1970 , 38123775 in 1980 , 43295704 in 1991 , 47008111 in 2000 , and 50004441 in 2012 ( http://www.kostat.go.kr/ ) .
accordingly the annual incidence rate of head injury per 100000 would be 130.2 in 1970 , 315.2 in 1980 , 614.3 in 1991 , 517.9 in 1998 , and 467.1 in 2012 .
we plotted all the calculated data of annual incidence on head injury in the linear graph from 1970 through 2012 to estimate the trend of the incidence of head injury ( fig .
it was stabilized in 1990s with some fluctuations and then started to decline in 2000s . the age specific data on traffic accidents revealed different appearance by age groups .
the age group of 20s and 30s represented highest incidence , which reached a peak in 2000 and then declined gradually . on the contrary ,
2 ) . as a result of traffic accident , according to the traffic accident statistics
the total number of death was 3051 in 1970 , 5608 in 1980 , 13429 in 1991 , 10236 in 2000 and 5392 in 2012 .
taking into account of the total population of korea in each year , the annual mortality rate per 100000 would be 9.5 in 1970 , 14.7 in 1980 , 31.0 in 1991 , 21.8 in 2000 , and 10.8 in 2012 .
we draw all the data of annual mortality on traffic accidents in the linear graph from 1970 through 2012 to understand the trend of the mortality ( fig .
the mortality trend per 100000 population showed gradual increase until 1991 . and after that time it has been declining with some changes . between 1990 and 2012 ,
the number of road fatalities decreased by 62% , while the number of the injured decreased by only 12.4% .
although there was transient increase in around 1996 , as a whole age specific mortality trends declined gradually with some fluctuation except the age group over 65 .
on the contrary it was slightly increasing in the age group over 65 ( fig .
world macroeconomic research announced gni per capita in korea was 302 dollars in 1970 , 1777 dollars in 1980 , 5509 dollars in 1990 , 12127 dollars in 2000 , and 25120 dollars in 2012 ( http://www.kushnirs.org/macroeconomics/ ) . during 19702013 gni per capita in korea grew exponentially by 26416 dollars ( in 88.4 times ) to 26718 dollars ( fig .
the average annual growth of gni per capita in korea was 614.3 dollars or 203.2% .
data on the incidence figures for head injury was lacking in korea excluding some hospital based reports .
statistics by national health insurance databank did not provide information on low income and pre - industrial stage .
therefore the authors had no choice but to use traffic accident statistical database from 1970 to 2012 to outline the trend of incidence of head injury and tried to understand epidemiologic impacts of rapid industrialization on head injury .
the reported annual incidence of head injury has varied widely owing to different study methods , case definitions , time periods and geographic locations although many studies are based primarily or exclusively on hospitalized cases and mortality3 ) .
differences in study methods of head injury may result in divergent estimates of numbers and make inter - study comparison difficult .
however when inclusion and exclusion criteria are considered , the relative incidences and trends are congruent .
since the korea trauma data bank system has problems to perform our epidemiological purpose13 ) , we employed lee16 ) 's estimation in this article that the traffic accident was about 62.5% of all head injuries based on reviewing seven hospital based reports6111314161820 ) .
this estimation has a minor problem that those hospital reports were performed in the short term and early stage between 1966 and 1987 .
however this would not be trouble as the aim of this study was to assess the trend of incidence rather than actual incidence for head injury over the period 19702012 . during the 1970s and the 1980s the incidence trend of head injury revealed constant increase . at that time civic consciousness of keeping the road traffic law was lacking .
according to world macroeconomic research , gni per capita in korea was 302 dollars in 1970 , 649 dollars in 1975 , and 1777 dollars in 1980 .
however we started to accelerate industrialization in 1980s to break out of low income stage .
as a result of rapid industrialization gni per capita had increased to 2495 dollars in 1985 , 4766 dollars in 1988 ( the year of seoul olympic ) , and 6,608 dollars in 1990 .
especially korea has observed a very rapid increase in motorization due to the development of automobile manufacturing industry in 1980s and 1990s . in spite of more rapid increase of in the number of motor vehicles ,
the incidence of head injury was stabilized in 1990s with some fluctuations and then continued to decline in 2000s .
the mortality trend per 100000 population showed gradual increase until 1991 , which peaked in 1991 at 13429 . since then , road deaths have decreased with some fluctuations and were halved in 2004 .
this important decrease is due in part to the several measures of reinforcement on road traffic laws , which include the compulsory wearing of front seatbelts in 1990 , nation - wide implementation of speed enforcement cameras since 1997 and enforcement against drunk driving in 1998 . in taiwan and united states ,
the number of motorcycle - related injuries declined considerably by 33% after the implementation of the motorcycle helmet law25 ) .
becoming high - income people , civic consciousness on traffic safety was much improved . between 1990 and 2012 ,
the rate of decrease for the mortality has been more rapid than the incidence of head injury .
this means that the severity of accidents has diminished more rapidly than their occurrence owing to strengthening safety policy25 ) .
in addition , korea made great and rapid strides in the health care delivery system especially on head injury .
various diagnostic and treatment modalities have been introduced to improve the outcome of head injury .
neurosurgical intensive care unit ( nicu ) was set up on a nation - wide scale to manage severe traumatic brain injury in 1960s , 1970s . at present ,
monitoring of icp , brain oxygen , and cerebral blood flow is available for better outcome at nicu . in terms of treatment modalities ,
induced hypothermia , barbiturate coma therapy , and hyperosmotic therapy can be beneficial for severe traumatic brain injury .
both of age - associated incidence and mortality trends display peak in 2140 age groups because they are most energetic during life .
contrary to young age , both of incidence and mortality trends of old age show slightly increasing tendency in spite of high income stage and satisfactory quality of medical care .
age is an important factor influencing outcome after severe head injury . in general , the older the victim is , the higher the probability of a poor outcome is924 ) .
older patients have been reported to have a markedly higher complication and death rates , which might be involved in the age - dependent mortality in trauma victims720 ) .
in addition , seeing the incidence and mortality rate was increasing in old age , it was necessary to understand 4-stage population pyramids of demographic transition model in korea ( fig . 6 ) .
demographic transition refers to the transition from high birth and death rates to low birth and death rates as a country develops from a pre - industrial to an industrialized economic system .
population pyramid of 1960 in korea come under stage one , pre - industrial society , death rates and birth rates are high and roughly in balance .
population pyramid of 1980 is equivalent to stage two , that of a developing country , the death rates drop rapidly due to improvements in food supply and sanitation .
population pyramid of 1995 falls under stage three , birth rates decrease due to access to contraception , increases in wages , urbanization , a reduction in subsistence agriculture . population pyramid of 2010 is applicable to stage four .
this would be the one of major reasons why incidence and mortality rate of the old age was continuously increasing .
with respect to incidence of head injury in this study , population of ages from 51 to 60 shows most dramatic increase in incidence , whereas the fatality is highest in population of ages more than 65 . on this peculiar finding
although we could not investigate about preexisting disease with head injury in old patients in this study , according to report from the japan neurotrauma data bank , the older group had a significantly higher rate of preexisting disease24 ) .
furthermore , alteration in the pathophysiological response , which is related to the development of secondary brain injury in the aging brain , probably contributes to more severe and irreversible brain damage in older patients , and is thus associated with poor outcomes24 ) .
epidemiological studies on head injury are required to initiate appropriate preventive measures and to plan necessary services .
however , in korea there has been few nationwide epidemiologic survey on head injury . at
long last , the korea trauma data bank committee for head injury began its formal activity in 2010 .
however , since it has still lots of incomplete or incomprehensible data and less specified items for cause of injury , we need to make much more improvements to neuro - trauma data bank for more nation - wide project on epidemiology of head injury1318 ) .
although at the moment epidemiologic study of head injury is an under - researched in korea , investigating the traffic accident statistic data analysis and reviewing some medical reports , the results of this study support the following fact .
in korea during the low income and pre - industrial stage , rapid industrialization especially on very rapid motorization cause considerable increase in mortality and incidence of head injury . during the high income and post - industrialized stage , despite rapid increase in the number of motor vehicles the incidence of head injury gradually declined and the mortality dropped more rapidly than injuries .
however , in spite of preventive measures of traffic accidents and satisfactory quality of medical care , the old age groups revealed rather slight increase in both of the mortality and incidence of head injury owing to the large aging population and the declining birth rate shown by population pyramid .
Output:
| objectivethe aim of the present study is to estimate the incidence trend of head injury and the mortality based on traffic accident statistics and to investigate the impacts of rapid industrialization and economic growth on epidemiology of head injury in korea over the period 19702012 including both pre - industrialized and post - industrialized stages.methodswe collected data of head injury estimated from traffic accident statistics and seven hospital based reports to see incidence trends between 1970 and 2012 .
we also investigated the population structure and gross national income ( gni ) per capita of korea over the same period .
the age specific data were investigated from 1992 to 2012.resultsthe incidence of head injury gradually rose in the 1970s and the 1980s but stabilized until the 1990s with transient rise and then started to decline slowly in the 2000s .
the mortality grew until 1991 but gradually declined ever since .
however , the old age groups showed rather slight increase in both rates .
the degree of decrease in the mortality has been more rapid than the incidence on head injury.conclusionin korea during the low income stage , rapid industrialization cause considerable increase in the mortality and the incidence of head injury . during the high income stage ,
the incidence of head injury gradually declined and the mortality dropped more rapidly than the incidence due to preventive measures and satisfactory medical care .
nevertheless , the old age groups revealed rather slight increase in both rates owing to the large population structure and the declining birth rate . |
PubmedSumm8838 | ***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 hypothalamus is thought to play an important role in migraine pathogenesis [ 14 ] .
it is possible that periodic central disturbance of hypothalamic activity or labile threshold could account for the periodicity of the migraine attack .
it also provides a mechanism by which emotional disturbances could be mediated by pathways from the limbic system to the hypothalamus .
almost 60% of patients with migraine report symptoms of elation , irritability , depression , hunger , thirst , or drowsiness during the 24 h preceding headache , which also suggests a hypothalamic site of origin .
it has been suggested that if neuronal hyperexcitability and cortical spreading depression during migraine attack are part of the pathophysiology of the disorder , then aura is not the initiating event but rather is initiated by subcortical changes .
the suprachiasmatic nucleus ( scn ) is a possible subcortical origin of this changes , suggesting that a migraine attack might be an attempt at a drastic resetting of the biological clock in response to its previous decompensation .
compared with the environmental cycle of 24 h , the human biological pacemaker has an intrinsic periodicity of 25.7 hours . the conversion between the intrinsic rhythm and the environmental rhythm is known as
the environmental agents that are able to synchronize the endogenous circadian clock are known as
zeitgebers , among them the most influential is the change in luminosity between day and night .
photic entrainment is mainly mediated by a direct retinal - hypothalamic pathway that conveys to the scn information about the level of ambient light .
photic information relayed from the scn to the pineal gland is closely reflected there in the secretion of melatonin , which is probably the strongest biological marker of the circadian rhythm in humans .
melatonin is absent during the day in human beings and its nocturnal secretion is the main biological event signaling to the organism when it is night . once melatonin is synthesized in the pineal gland , it is quickly released , generating a blood melatonin rhythm reminiscent of that seen in the gland .
being an amphiphilic molecule , melatonin is capable of entering every cell in the organism ; additionally , it readily crosses all morphophysiological barriers , including the blood brain barrier and the placenta .
melatonin is enzymatically - degraded in the liver to 6-hydroxymelatonin and finally excreted in the urine as 6-sulphatoxymelatonin ( amt6s ) .
urine analysis is widely used as a measure of melatonin secretion , since it is correlated with the nocturnal profile of plasma melatonin secretion .
the advantages of urinary metabolite measurement are substantial , particularly the non - invasive nature of fluid collection , the ability to perform very long - term studies and the feasibility of studies in circumstances where blood sampling is difficult .
substantial evidence points to melatonin as playing a role in the regulation of circadian rhythms , sleep , and headache .
an interictal decrease in the levels of nocturnal plasma melatonin and an alteration of the urinary amt6s excretion throughout the ovarian cycle have also been described in migraine patients [ 14 , 15 ] .
furthermore , seasonal variations in daily melatonin secretion have been reported , patients with migraine being more likely to have headache during the bright arctic summer season [ 16 , 17 ]
. these data prompted us to test the hypothesis of decreased levels of melatonin during migraine attacks , assessing amt6s levels in a large consecutive series of patients with migraine , comparing with controls .
the study was performed from february to december 2006 , at albert einstein hospital , so paulo , brazil .
the inclusion criteria were : patients with migraine and controls subjects of both sex , aged 1865 years , able to understand the consent form and explanations given by the research team , and with satisfactory diuresis .
migraine was defined according to international classification of headache disorders diagnostic criteria , second edition .
the exclusion criteria were : chronic diseases , instable medical condition , secondary headache , continuous usage of any kind of medication , drug addiction or alcohol abuse .
the patients who remained aroused with light exposure during the night of urine collection were also excluded .
all subjects provided written consent for the experimental procedure approved by the local ethics committee ( federal university of so paulo and albert einstein hospital , so paulo , brazil ) .
subjects were asked to collect urine into a plastic container from 8:00 p.m. to 8:00 a.m. of the next day ( 12-h period ) .
female patients were advised to collect the samples at least 5 days away from the beginning or the end of menses .
the patients were asked to provide information regarding the presentation or not of a migraine headache on the day of urine collection .
sample s volumes were recorded and 5-ml aliquots were stored frozen at 20c until analysis .
amt6s has been found to be extremely stable without preservative for at least 5 days at room temperature and for at least 2 years at 20c and no special precautions were necessary during sample collection .
amt6s was measured by quantitative elisa ( bhlmann laboratories , allschwil , switzerland ) . at a dilution of 1:200 ,
50 l of urine sample was assayed directly ; where necessary , samples were re - assayed at dilution of 1:400 . the chi - square test ( ) ( without yates correction ) was used for categorical data comparisons .
mean differences of continuous measurements were tested by the student s t test ( t ) followed by the mann
whitney test , which without exception did not show any discrepant results ( only the parametric tests results will be reported ) .
the pearson s product - moment correlation coefficient ( r ) was used to assess the relationship between two continuous variables .
a p value of less than 0.05 was considered to indicate statistical significance ; all tests were two - tailed .
ninety - five percent confidence intervals ( ci ) were calculated for the difference between means .
all statistical analyses were performed on a personal computer with the statistical package spss 11.5.1 for windows .
the chi - square test ( ) ( without yates correction ) was used for categorical data comparisons .
mean differences of continuous measurements were tested by the student s t test ( t ) followed by the mann
whitney test , which without exception did not show any discrepant results ( only the parametric tests results will be reported ) .
the pearson s product - moment correlation coefficient ( r ) was used to assess the relationship between two continuous variables .
a p value of less than 0.05 was considered to indicate statistical significance ; all tests were two - tailed .
ninety - five percent confidence intervals ( ci ) were calculated for the difference between means .
all statistical analyses were performed on a personal computer with the statistical package spss 11.5.1 for windows .
48 were excluded : 12 patients did not correctly provide their urine samples , 3 refused to take part in the study , 19 did not give reliable headache information and 17 had at least one exclusion criteria .
the remaining 220 subjects were in accordance with inclusion criteria . among them , 146 had migraine and 74 were control subjects .
there were no statistically significant differences between controls and patients with migraine regarding the mean age [ 38.4 9.0 vs. 38.5 11.2 , t(218 ) = 0.7 , 95% ci = 3.0 to 2.8 , p = 0.946 ] and sex [ 78 vs. 81% of women , (1 ) = 0.18 ; p = 0.669 ] . among patients with migraine ,
their urinary amt6s concentration was significantly lower than in the urine of patients without pain [ 14.0 7.3 vs. 49.4 19.0 ; t(143 ) = 15.1 ; 95% ci = 40.0 to 30.8 ; p < 0.001 ] .
however , there was no significant difference in the amt6s concentration of patients with migraine without pain on the day of their urine samples collection and controls [ 49.4 19.0 vs. 42.5 27.9 ; t(140 ) = 1.7 ; 95% ci = 1.2 to 14.8 ; p = 0.094 ] ( fig .
1mean amt6 s concentration according to the diagnosis mean amt6 s concentration according to the diagnosis migraine with aura was observed in 24% of the patients .
there was no significant difference in the amt6s concentration of patients with migraine with and without aura [ 32.3 21.5 vs. 30.5 22.9 ; t(144 ) = 0.52 ; 95% ci = 10.9 to 6.4 ; p = 0.604 ] .
claustrat et al . were the first to demonstrate lower plasma melatonin levels in samples from migraine patients compared with controls .
migraine patients without depression had lower levels than controls , but migraineurs with superimposed depression exhibited the greatest melatonin deficiency .
murialdo et al . also found nocturnal urinary melatonin to be significantly decreased throughout the ovarian cycle of migraine patients without aura compared with controls . during the luteal phase ,
when melatonin levels should normally increase , migraine patients showed a less pronounced change when compared with controls .
brun et al . studied urinary melatonin in women with migraine without aura attacks associated with menses and controls .
melatonin levels throughout the cycle were significantly lower in the migraine patients than in controls .
in the control group , melatonin excretion increased significantly from the follicular to the luteal phase , whereas no difference was observed in the migraine group .
lowered melatonin levels in patients with insomnia were observed compared with those without insomnia , and a phase delay in the melatonin peak in patients versus controls . to our knowledge , our study is the first to demonstrate reduction in melatonin levels during migraine attacks , not depending on the migraine type .
however , patients with migraine that did not present headache in the day of the urine sample collection did not have lower amt6s levels when compared with controls . in our opinion , two possible explanations could be made to this fact : first , the hypothalamic disturbance may occur only during attacks , mainly in the prodromal phase , so patients in the interictal period will not have reduction of melatonin levels .
the other possible explanation is that all patients with migraine could have lower levels of amt6s , but patients in the interictal phase could have a compensatory increase in melatonin levels .
Output:
| substantial evidence points to melatonin as playing a role in the regulation of circadian rhythms , sleep , and headache disorders .
the objective of the study was to assess 6-sulphatoxymelatonin ( amt6s ) levels in a large consecutive series of patients with migraine , comparing with controls .
a total of 220 subjects were evaluated146 had migraine and 74 were control subjects .
urinary samples were collected into the same plastic container since 8:00 p.m. to 8:00 a.m. of the next day ( 12-h period ) and amt6s was measured with quantitative elisa technique . among patients with migraine ,
53% presented pain on the day of the urine samples collection .
their urinary amt6s concentration was significantly lower than in the urine of patients without pain [ 14.0 7.3 vs. 49.4 19.0 ; t(143 ) = 15.1 ; 95% ci = 40.0 to 30.8 ; p < 0.001 ] .
there was no significant difference in the amt6s concentration of patients with migraine without pain on the day of their urine samples collection and controls [ 49.4 19.0 vs. 42.5 27.9 ; t(140 ) = 1.7 ; 95% ci = 1.2 to 14.8 ; p = 0.094 ] . to our knowledge
, this is the first study to demonstrate reduction in melatonin levels during attacks in episodic and chronic migraine . |
PubmedSumm8839 | ***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 visual system is specialized to extract features from complex natural scenes that have a unique statistical structure ( simoncelli and olshausen , 2001 ; felsen et al . , 2005a ) , including edges and contours that change in space and time across the field of view .
although neurons in the primary visual cortex ( v1 ) respond best to local image features that fall within their receptive fields ( rfs ) , their responses are strongly modulated by stimuli placed in the surrounding regions of visual space ( blakemore and tobin , 1972 ; nelson and frost , 1978 ; allman et al . , 1985 ; gilbert and wiesel , 1990 ) .
typically , stimulating the surround suppresses responses to stimuli in the rf ( jones et al .
, 2003 ; ozeki et al . , 2009 ; adesnik et al . , 2012 ) , and this suppression is more pronounced when using natural surround images than when using their phase - scrambled versions devoid of complex structure ( guo et al . , 2005 ) .
visual circuits are thus particularly sensitive to integrating salient image components across natural scenes , which may contribute to contour integration and pop - out phenomena at the perceptual level ( knierim and van essen , 1992 ) .
concomitantly , surround modulation by natural images alters the firing rate distribution of individual neurons , whereby their responses become more selective and sparse ( vinje and gallant , 2000 , 2002 ; haider et al . ,
sparse codes are considered efficient , because they are able to transfer more information with fewer spikes ( olshausen and field , 2004 ) .
taken together , surround modulation contributes to contextual processing of sensory information and increases the efficiency of neural representations for natural scenes ( sachdev et al . , 2012 ) .
how do neural circuits become specialized to integrate and efficiently represent information from complex natural scenes , which contain image features that extend beyond the rf of any individual neuron ?
neurons in v1 are feature selective already at eye opening ( hubel and wiesel , 1963 ; blakemore and van sluyters , 1975 ; chapman and stryker , 1993 ; krug et al . , 2001 ;
, 2001 ; rochefort et al . , 2011 ; ko et al . , 2013
however , little is known about the development of surround modulation and its dependence on early sensory experience , and how this impacts the ability to encode complex natural scenes .
surround modulation is mediated by excitatory and inhibitory interactions at different stages of the mature visual pathway , including the retina ( olveczky et al .
2006 ) and visual cortex ( stettler et al . , 2002 ; angelucci and bressloff , 2006 ; girardin and martin , 2009 ; ozeki et al . , 2009 ; haider et al . , 2010 ;
, 2012 ; nienborg et al . , 2013 ; vaiceliunaite et al . ,
2013 ) . since both excitatory and inhibitory circuits refine after eye opening ( frgnac and imbert , 1984 ; katagiri et al . , 2007 ;
, 2011 ; ko et al . , 2013 ) and are susceptible to changes in visual experience ( ruthazer and stryker , 1996 ; zufferey et al . , 1999 ;
2004 ) , the effectiveness of surround modulation may be expected to change during postnatal development .
the extent to which this may improve the processing of full field natural scenes is , however , unknown . in this study , we show that circuits mediating surround modulation require sensory experience to become preferentially sensitive to natural stimulus statistics across the rf and its surround . in mature mouse v1 , neuronal firing to natural movies presented to the rf became more selective when costimulating the surround with natural movies than with phase - scrambled movies lacking the higher - order statistical regularities of natural scenes .
in contrast , this preferential sensitivity of center - surround interactions for natural scenes was absent in immature , visually naive v1 after eye opening and in mature animals that were reared without visual input .
mechanistically , the surround - induced increase of response selectivity was mediated by transient membrane potential hyperpolarization that coincided with moments of greatest depolarization during rf stimulation .
these transient hyperpolarizing events were most effective in limiting spiking during full - field natural movie stimulation in adult v1 , consistent with the increased effectiveness of the natural surround stimuli in improving response selectivity .
therefore , normal visual experience is required for the refinement of neuronal circuits that contribute to the selective coding of natural scenes by spatially integrating information from the entire field of view .
to study the effectiveness of surround modulation during postnatal development , we carried out in vivo whole - cell recordings from individual neurons in cortical layer 2/3 of monocular v1 in immature mice with limited visual experience ( 15 days after eye opening , p14p19 , n = 18 from 7 mice ) and in visually mature mice with at least 18 days of normal visual experience ( p32p40 , n = 21 from 10 mice ) . to determine the exact rf size of each recorded neuron
, we alternated the presentation of a naturalistic movie within apertures of increasing size ( isoluminant gray surround ) and the corresponding surround ( annulus ) regions ( figure 1a ; see experimental procedures ) . in
both mature and immature v1 , neuronal firing was stimulus size dependent ( figure 1b ) .
responses first increased and then decreased with increasing aperture size , while response rate decreased for the corresponding surround stimuli ( figure 1b , see figure legend for details ) . the rf size defined by the aperture diameter at which neurons exhibited a maximal response without a significant response to the corresponding annulus stimulus was similar for the two age groups ( figure 1e ; mean sem , mature , 29.9 10 ; immature , 35.3 18 , p = 0.26 , t test ) . while responses decreased significantly during full - field stimulation with natural movies ( rf + natural surround ; figures 1c and 1d ) compared to stimulation of the rf alone ( p < 0.01 for both mature and immature mice , paired t test ) , they were suppressed more in mature v1 ( figure 1f , mature , 71.9% 3.6% ; immature , 35.3% 15.6% , p = 0.019 , t test ) .
these results show that neurons in immature v1 exhibit surround suppression within a few days after eye opening , but that the suppressive effect of the surround becomes stronger with age . to determine how the developmental strengthening of surround suppression influences the selectivity of neuronal responses
, we computed a measure that captures the distribution of spiking across stimulus repetitions ( here referred to as selectivity , also known as lifetime sparseness ; vinje and gallant , 2002 ; lehky et al . , 2005 ; tolhurst et al . , 2009 ;
response selectivity increased significantly during natural surround stimulation compared to stimulation of the rf alone ( figure 1 g ; p < 0.01 , paired t test ) , and this increase was significantly greater in mature animals ( mature , 7.5% 1.1% ; immature , 3.0% 1.1% , p = 0.008 , t test ) . a reduced spike rate and increased selectivity only add to the efficiency of a neuronal representation if the information about the stimulus is adequately maintained ( laughlin , 2001 ; vinje and gallant , 2002 ) .
hence , the amount of information per spike should increase to compensate for fewer evoked spikes . in both age groups , costimulating the surround significantly increased the information per spike ( see experimental procedures ) relative to the stimulation confined to the rf ( figure 1h , p < 0.01 , paired t test ) .
this increase tended to be higher in mature than in immature v1 ( mature , 41.9% 6.3% ; immature , 26.2% 8.2% , p = 0.2 , t test ) , but the effect did not reach significance .
very similar results were obtained in a separate data set using juxtacellular single - cell recordings ( figure s1 available online ) , indicating that any alterations of the intracellular milieu caused by the whole - cell recording technique did not influence the results .
these age - dependent effects of the surround on firing rate suppression were not influenced by any differences in rf size or absolute firing rate between of neurons recorded in the two age groups ( figure s2 ) .
taken together , these data indicate that visual circuits are capable of spatial integration already at eye opening , but that surround modulation becomes more effective at suppressing firing and increasing response selectivity to natural scenes with age . in adult monkey v1 ,
the effectiveness of surround modulation depends on the higher - order structure of natural scenes ( e.g. , extended contours ) , because responses to natural images in the rf are suppressed less when randomizing the phase of natural images in the surround ( guo et al . , 2005 ) .
we therefore tested whether neurons in mature mouse v1 also exhibit the dependency of rf - surround interactions on the statistical properties of surround stimuli .
we compared how responses to the natural movie presented in the rf were altered by costimulating the surround either with the same natural movie ( rf + natural surround ) or with the phase - randomized version of the same movie ( rf + phase - randomized surround , figure 2a ) .
note that the phase randomization only removes the higher - order structure in natural images without altering their contrast or spatial frequency composition ( see experimental procedures ) .
accordingly , full - screen presentations of natural and phase - randomized stimuli evoked similar activity levels in both age groups ( figure s3 ) . for the following analysis
, we only included neurons whose responses were significantly suppressed in at least one of the surround conditions ( mature , 21/21 cells ; immature , 13/18 cells ; see experimental procedures ) .
in mature v1 , costimulation of the surround with both natural and phase - randomized stimuli reduced firing rates significantly ( figure 2b ; p = 9 10 , one - way anova ) , increased response selectivity ( figure 2c ; rf + natural surround , 7.5% 1.1% , p < 0.001 ; rf
+ phase - randomized surround , 3.7% 0.9% , p < 0.001 ; t test ) and mutual information per spike ( figure 2d ; rf + natural surround , 41.8% 7.4% , p < 0.001 ; rf + phase - randomized surround , 20.6% 6.2% , p <
importantly , however , stimulating the surround with natural movies decreased firing rates significantly more than phase - randomized surround movies ( figure 2b ; p < 0.001 , paired t test ) .
this led to significantly greater increases in both selectivity and mutual information per spike during natural compared to phase - randomized surround stimulation ( figures 2c and 2d ; p < 0.001 and p = 0.005 , respectively , paired t test ) .
thus , neurons in mature v1 are sensitive to the higher - order regularities of natural stimuli extending beyond the rf boundary , which makes their responses more selective and informationally efficient .
we next determined whether the increased sensitivity of v1 neurons for natural surround stimuli is already apparent within a few days after eye opening .
in immature mice , the costimulation of the rf with either natural or phase - randomized surround stimuli generated significant spike rate suppression ( figures 2e and 2f , p = 0.0007 , one - way anova ) , increased response selectivity ( figure 2 g , natural surround , 4.7% 1.3% , p < 0.001 ; phase - randomized surround , 4.3% 1.8% , p < 0.001 ; t test ) , and information transmitted per spike ( figure 2h , natural surround , 43.2% 7.8% , p < 0.001 ; phase - randomized surround , 40.7% 12.8% ,
however , neither the amount of response suppression nor the increase in response selectivity and information per spike was significantly different between the two types of surround stimuli ( figures 2f2h ; p = 0.17 , p = 0.72 and p = 0.67 , respectively ; paired t test ) .
thus , in contrast to experienced animals , neurons in immature v1 did not differentiate between naturalistic and phase - scrambled stimuli in the surround , suggesting that early circuits mediating surround modulation are not yet preferentially sensitive for higher - order structure of natural scenes extending beyond the rf .
we next investigated whether the age - dependent increase in the sensitivity of center - surround interactions for natural scenes can be explained by differences in subthreshold membrane potential dynamics during different stimulus conditions ( figures 3a and 3f ) .
previous reports indicate that surround stimulation leads to more hyperpolarized membrane potential ( vm ) relative to rf stimulation alone ( haider et al .
, 2010 , 2013 ) , which is partly attributed to increased inhibition in the cortical network ( haider et al . , 2010 ; adesnik et al . , 2012 ;
however , when averaged over the entire stimulation period , we found that costimulation of the surround with either natural or phase - scrambled movies slightly depolarized the median absolute vm in immature and mature mice ( figures 3b and 3h ; p = 0.017 and p < 0.0001 , respectively ; friedman s test ) .
because it is unclear how such small average differences in vm could contribute to changes in the spiking response selectivity , we focused our analysis on how vm temporal dynamics are altered by surround stimulation .
we quantified moment - to - moment differences in vm between rf and full - field stimulation for each neuron ( vm = vmrf+surround vmrf ; see experimental procedures ) .
both natural and phase - randomized surround stimuli induced hyperpolarizing ( negative vm ) and depolarizing ( positive vm ) vm changes relative to rf stimulation alone ( figures 3c and 3 g ) .
plotting the median vm of each cell against its average change in firing rate revealed that vm was strongly correlated with the firing rate suppression during full - field stimulation in mature , but not in immature mice ( figures 3d and 3i ; see figure legend for details ) .
moreover , the distribution of vm was shifted to more negative values during natural than phase - randomized surround stimulation in mature v1 ( figure 3d , p = 0.027 , wilcoxon rank sum test ) , but not in immature v1 ( figure 3i , p = 0.6 , wilcoxon rank sum test ) .
how could relatively small differences in vm between natural and phase - randomized surround stimulation lead to pronounced differences in firing rate suppression incurred by these surround stimuli in mature v1 ? to address this question , we determined the dependency of vm on the particular membrane potential value ( relative to spike threshold ) elicited by the rf stimulus at each time point during movie presentation ( vmrf ) .
strikingly , in both age groups , vm exhibited a negative linear dependency on membrane depolarization during rf stimulation : neurons were relatively most hyperpolarized during rf + surround stimulation ( negative vm ) specifically at times when vmrf was closest to spiking threshold ( figures 3e and 3j ) . which mechanisms underlie the pronounced surround - induced relative hyperpolarization when the vm is most depolarized during rf stimulation ?
surround stimulation has been shown to increase synaptic inhibition ( haider et al . , 2010 , 2013 ;
we therefore tested the influence of chloride ( cl)-mediated conductances on the inverse relationship between vm and vmrf .
we performed whole - cell recordings using an elevated cl concentration in the intracellular solution ( [ cl]i , see experimental procedures ) to modify the reversal potential of gabaa - mediated conductances ( figure 4a ) .
compared to data recorded with the normal cl - concentration ( figure 3e ) , recordings with elevated [ cl]i revealed a rightward shift of vm values in both natural and phase - randomized surround conditions at all values of vmrf ( figure 4b ) .
these data suggest that an increased cl conductance during surround stimulation at least in part contributes to the negative relationship of vm and vmrf .
the cl conductance may also account for the depolarizing effect of surround costimulation ( positive vm values , figure 4b ) at very hyperpolarized levels of vmrf , if these fall below the reversal potential for gabaa - mediated conductances .
given that the increased cl conductance is most likely mediated by gabaa receptors , we explored the likely sources of gabaergic inputs by targeting parvalbumin ( pv ) and somatostatin ( som ) inhibitory interneurons with whole - cell recordings ( figures 4c and 4d ; see experimental procedures ) .
we found that firing rates of pv and som neurons were on average only slightly but significantly reduced by costimulation of the surround relative to stimulation of the rf alone , irrespective of the surround stimulus type ( figure 4e).the relative firing rate decrease was smaller in both pv and som cells compared to putative pyramidal ( pyr ) cells during either surround stimulus condition ( figure 4f , rf + natural surround , pyr - pv p = 8 10 ; pyr - som p = 8 10 ; rf + phase - scrambled surround , pyr - pv p = 0.01 ; pyr - som p = 0.01 , mann - whitney u test ) .
since pv and som cells maintained relatively high firing rates during rf + surround stimulation , both interneuron classes can be expected to contribute to the increased inhibition of pyr cells during surround stimulation .
importantly , neither pv nor som cells were preferentially selective for the natural and phase - randomized surround stimuli ( figure 4f , pv p = 0.12 and som p = 0.14 , for rf + natural versus rf + phase - randomized surround , paired t test ) .
this is consistent with the observation that the rightward shift of the vm and vmrf relationship after elevating [ cl]i was not associated with a change in the slope of the relationship ( figure 4b ) , suggesting that surround stimuli of different statistics cause no major difference in the average increase of cl conductance .
these data further imply an additional involvement of other , most likely excitatory conductances , suggesting that surround suppression is rooted in the modulation of temporally balanced excitation and inhibition ( ozeki et al . , 2009 ) .
our results thus far suggest that the increased response suppression and selectivity of putative pyramidal neurons during rf + natural surround stimulation in mature mice could not be explained by a net difference in the amount of inhibition during the two surround conditions . instead
, our results raise the possibility that the timing of inhibition may be important for this selective suppression , because the difference in vm between natural and phase - randomized surround stimulation was largest at most depolarized vmrf ( i.e. , closest to spike threshold ) in mature mice ( figure 5c ; see also figure 3e ) . to examine the timing of surround - induced hyperpolarization in more detail
, we determined the temporal progression of vm before the occurrence of a spike during rf stimulation ( see experimental procedures ) . at times preceding action potential firing events during rf stimulation ( corresponding to instances when the vm is most depolarized , figure 5c ) , natural surround stimuli hyperpolarized the vm more than phase - randomized surround stimuli ( figures 5a , 5c , and s4d ) .
this difference in the relative hyperpolarization between natural and phase - randomized surround ( vm difference ) was significantly larger in mature mice compared to immature mice ( figures 5a5c and s4h ) , both when vm was binned relative to vmrf ( p = 0.006 , t test ) and relative to rf spike time ( p = 0.0004 , t test ) .
these findings are consistent with the greatest spike rate suppression during natural surround stimulation in mature v1 ( figures 2b and 3d ) , and suggest that suppression is caused by time - locked vm hyperpolarization that curtails spike generation at moments of largest vm depolarization . accordingly , natural surround stimulation significantly reduced the likelihood that large - amplitude , depolarizing synaptic events ( > 3 mv change within 5 ms , see experimental procedures ) triggered a spike in mature v1 ( figure 5d ; rf versus rf + natural surround , p = 1 10 ; rf + natural surround versus rf + phase - randomized surround , p = 0.01 ; kruskal - wallis test and post hoc mann - whitney u test ) , but not in immature v1 ( figure 5e ; p = 0.19 , kruskal - wallis test ) , even though the number of large - amplitude events did not differ between the stimulus conditions ( figures 5f and 5 g ; p = 0.34 and p = 0.59 for mature and immature mice , respectively ; kruskal - wallis test ) .
interestingly , even in instances of action potential firing during surround stimulation , the vm during rf + natural surround stimulation was more hyperpolarized prior to spike generation compared to rf + phase - randomized surround stimulation in mature mice ( figure s4 ) , suggesting that the relative magnitude of excitation and inhibition governs spike generation during full - field stimulation . taken together ,
natural surround stimuli most effectively recruit precisely timed hyperpolarization to increase the selectivity of spiking to stimuli in the rf .
the results thus far suggest that there is an age - dependent increase in sensitivity of visual circuits for features in natural movies extending beyond the rf , which confers greater response selectivity to neurons in v1 . to determine whether this increased sensitivity for the statistical structure of full - field natural scenes depends on visual experience during development , we carried out recordings in mature mice that were reared in the dark until p32p40 and therefore never experienced normal visual input
. the estimated rf size did not differ significantly between the dark - reared , immature , and normal mature mice ( p = 0.65 , one - way anova ; figure s5 ) . similar to immature and mature animals ,
costimulation of the surround suppressed neuronal responses and increased their selectivity in dark - reared mice ( figures 6a and 6b ; firing rate change rf + natural surround , 60.7% 7.9% , p < 0.001 ; rf + phase - randomized surround , 52.3% 10.3% , p < 0.001 , n = 15 ; t test ) , indicating that the capacity of visual circuits for surround modulation was maintained and not disrupted by rearing animals devoid of visual experience .
importantly , however , we observed no significant differences between the effects of the natural and phase - randomized surrounds on responses to stimuli in the rf ( figure 6b ) in terms of firing rate ( rf + natural versus rf + phase - randomized surround , p = 0.33 , paired t test ) , response selectivity ( p = 0.23 , paired t test ) , or information transmitted per spike ( p = 0.88 , paired t test ) . differences in the level of spike suppression were not related to differences in absolute firing rates in any age group ( figure s6 ) .
the indifference of dark - reared v1 neurons to the statistical properties of surround stimuli was also reflected at the level of subthreshold membrane potential dynamics ( note that the cellular sensitivity for spiking to membrane potential changes was comparable to the other age groups ; figure s5 ; azouz and gray 2003 ) .
the median vm in dark - reared mice was not significantly altered by costimulation of rf and surround ( figures 6c and 6d , n = 19 ; p = 0.33 ; friedman s test ) .
similar to normally reared , mature mice , there was a strong dependence of vm ( figure 6e ) on the level of vm depolarization during stimulation of the rf alone ( figures 6 g and 6h ) .
however , the distribution of vm was not different between natural and phase - randomized surround stimulation conditions ( figure 6f , p = 0.21 , wilcoxon rank sum test ) , and vm at most depolarized vm during rf stimulation was not significantly different when costimulating the surround with natural and phase - randomized stimuli ( figures 6 g and 6h ) in dark - reared v1 , similar to the observations in immature v1 ( figures 3f3j ) .
accordingly , while the likelihood of spiking during large - amplitude depolarizing events ( which were unaltered in frequency of occurrence across conditions ; figure 6j ; p = 0.82 , kruskal - wallis test ) was reduced , it was not significantly different between the two surround conditions ( figure 6i ; p = 0.18 , kruskal - wallis test across all conditions ) . these findings are consistent with a similar level of firing rate suppression by phase - randomized and natural surround stimuli ( figure 6b ) in these visually inexperienced but mature animals .
thus , the emergence of neuronal sensitivity for image features extending beyond the rf boundaries requires visual experience after eye opening .
our findings provide evidence for a progressive developmental refinement of visual processing to the global statistics of the natural environment , as hypothesized previously ( olshausen and field , 1996 ; berkes et al . , 2011 ; sachdev et al . ,
v1 we observed developmental improvements in coding efficiency for natural scenes after eye opening ( increased response selectivity and mutual information rate ) , which was brought about by an increased neuronal sensitivity for natural scene statistics in the rf surround , but not for surround stimuli lacking the statistical regularities of natural scenes .
this emergence of efficient processing of natural stimuli was dependent on sensory experience , because it was absent in animals reared without visual input . in cat and monkey v1 , costimulation of rf and
its surround with naturalistic stimuli leads to more sparse and efficient responses than during stimulation of the rf alone ( vinje and gallant , 2000 ; haider et al . ,
similarly , we found that in mature mouse v1 , the full - field naturalistic movie was most effective for reducing spike rate and increasing selectivity and information per spike , consistent with the idea that neural codes are constrained by the same factors across mammalian species ( i.e. , energy consumption and information transmitted ) .
our findings reveal the existence of circuit mechanisms for improving coding efficiency beyond that provided by the filter characteristics of the rf alone ( olshausen and field , 1996 ; david et al . , 2004 ; felsen et al . , 2005b ) , which depend on the specific structure of natural scenes spanning the rf and its surround . while phase sensitivity of the surround in general has been suggested before ( guo et al . , 2005 ;
, 2007 ; xu et al . , 2005 ) , we show that the sensitivity to the spatiotemporal stimulus correlations across rf and surround is a plausible mechanism for improving neuronal selectivity . at the population level in mouse v1 ,
recent experiments indicate on the one hand that surround suppression is orientation tuned ( self et al . , 2014 ) and on the other hand that the representations of natural stimuli are sparser than those of phase - scrambled stimuli ( froudarakis et al . , 2014 )
our data not only suggest a circuit mechanism for this increased coding efficiency of natural scenes but also reveal its developmental dependency .
importantly , while surround suppression was apparent albeit weaker already in the first days after eye opening , the surround - induced increase in response selectivity and information per spike were unspecific to the statistical properties of the surround stimuli in these visually inexperienced mice .
the circuit mechanisms for increasing response selectivity are therefore present but not yet sensitive to detect the higher - order stimulus correlations of natural scenes in the immature visual pathway .
moreover , neurons in dark - reared , mature v1 were also indifferent to the statistics of surround stimuli . visual experience , therefore , may be required to promote the refinement of neuronal circuits to detect congruent information across the field of view , which leads to improved response selectivity of mature v1 neurons for features embedded in full - field natural scenes .
we note , however , that this refinement may not only depend on visual experience , as dark - rearing may also delay the development of visual circuits ( fagiolini et al .
, 1994 ; iwai et al . , 2003 ; espinosa and stryker , 2012 ) .
cortical inhibition likely plays a role in surround - induced response suppression in v1 ( haider et al .
our results extend this idea by revealing how costimulation of the rf surround affects membrane potential dynamics to suppress neuronal firing ; while the average membrane potential was altered little by surround stimulation , the principal effect of the surround was to counteract membrane depolarization generated by stimulation of the rf alone . specifically , we observed an experience - dependent increase of relative membrane hyperpolarization by natural surround stimuli at times of large depolarizing events during rf stimulation .
this hyperpolarization was partly mediated by an increased cl conductance , most likely through gabaa receptors .
yet the average firing rates of pv and som interneurons , although slightly reduced by surround stimulation , were not different between natural compared to phase - randomized surround stimulation in mature v1 .
hence , the preferential sensitivity for natural scene statistics in the surround was not mediated by a relative increase of inhibitory tone .
rather , we identified transient increases in membrane hyperpolarization during natural relative to phase - randomized surround stimulation , particularly at times that coincided with moments of greatest depolarization during rf stimulation .
these temporal differences in the magnitude of hyperpolarization resulted in increased spike suppression , and thereby increased the response selectivity for features in full - field natural scenes in mature v1 , but not in the immature or visually deprived v1 .
therefore , our results suggest that sensory experience during maturation exerts a prominent influence on the recruitment of inhibition particularly with respect to its timing relative to potential firing events to generate more selective coding of visual features embedded in natural scenes .
our results are broadly consistent with observations in cat v1 , where there is a transient increase of inhibition during surround suppression with drifting grating stimuli ( ozeki et al . , 2009 ) , which ultimately results in an overall reduction of both excitatory and inhibitory conductances when the circuit reaches a balanced state .
our results , however , underscore the importance of transient hyperpolarization prior to spiking events as a mechanism for effective surround suppression during ongoing stimulation with natural movies .
a probable explanation for this difference is that the statistical properties of grating stimuli are much narrower than that of the naturalistic stimuli used in our study .
the continuous variation of spectrotemporal content of naturalistic movies may prevent cortical circuits ever reaching a stable state of balanced excitation and inhibition that is observed when using narrowband grating stimuli .
these results suggest a possible functional role for the elaboration of both excitatory and inhibitory intracortical circuits , which are susceptible to changes in sensory experience in the period after eye opening ( ruthazer and stryker , 1996 ; zufferey et al . , 1999 ;
, 2001 ; chattopadhyaya et al . , 2004 ; katagiri et al . , 2007 ; ko et al . , 2013 )
we propose that circuit connectivity is shaped by exposure to the statistical structure of the natural environment ( e.g. , extended contours or edges ) after the onset of vision , which increases the effectiveness of surround modulation when viewing naturalistic stimuli to which animals are typically exposed .
our data suggest that visual experience optimizes spiking output by refining the timing and magnitude of inhibition recruited by the surround . in conclusion ,
our results support the idea that visual circuits mature in an experience - dependent manner to become sensitive to the statistical structure of natural stimuli extending beyond the boundaries of the rf . while the basic rf properties are established by the time of eye opening ( hubel and wiesel , 1963 ; blakemore and van sluyters 1975 ; chapman and stryker , 1993 ; krug et al . , 2001 ; white et al . , 2001 ;
, 2011 ; ko et al . , 2013 ) , efficient representations of natural stimulus features in terms of selectivity , information transfer , and energy consumption ( barlow , 1961 ; simoncelli and olshausen , 2001 ; laughlin , 2001)are not inherent to sensory circuits but require visual experience to develop .
all experimental procedures were licensed and performed in accordance with institutional and national animal welfare guidelines .
data were obtained from c57bl/6 mice aged postnatal day ( p ) 1419 ( immature age group , n = 7 ) or p32p40 ( mature age group n = 10 ; dark - reared age group n = 8) . for dark rearing ,
mice were initially anaesthetized with a mixture of fentanyl ( 0.05 mg / ml ) , midazolam ( 5.0 mg / kg ) , and medetomidin ( 0.5 mg / kg ) .
anesthesia was maintained with a low concentration of isoflurane ( typically 0.5% mixed with o2 ) delivered by a small nose cone .
the position and size of a neuron s rf were determined in similar way as described before ( jones et al . , 2001 , 2002 ) .
first , rf center position was mapped with pseudorandomized sparse noise stimulus sequence ( white and black flashing patches on an isoluminant gray background ) .
then , the rf radius was estimated by determining a circular area of half - maximal spike responses to the same pseudorandomized sparse noise stimulus .
next , we presented the naturalistic movie within an aperture centered on the rf , surrounded by an isoluminant gray ( see supplemental experimental procedures ) .
these apertured naturalistic movies were interleaved with a naturalistic movie shown in the surrounding annulus of the same size ( i.e. , center not stimulated ) .
we explicitly used the naturalistic movie in this procedure ( rather than a grating stimulus ) to achieve best estimates , because rf radius and surround effects are dependent on contrast , which is constantly fluctuating in movies , but not in grating stimuli .
the radius of the aperture and the surrounding annulus were systematically varied ( typically 0.4 to 2 times the originally estimated rf radius in 5 steps ) .
the aperture size that elicited the strongest response ( firing rate ) , but no significant response to the annulus stimulus of the corresponding size , was defined as the rf size ( jones et al . , 2001 ;
ozeki et al . , 2009 ) ( see figure 1b ) . mean and distribution of rf sizes obtained in this way were very similar for the three experimental groups ( figure s5 ) .
next , the naturalistic movie was presented in one of the following ways : in the rf condition , the naturalistic movie was presented within a rf - sized aperture , masking all portions of the movie outside the calculated rf with an isoluminant gray screen . to ensure a smooth transition to the surround ,
linear alpha - blending ( 0.3/ ) was applied at the border of the rf and gray surround . in the natural surround condition ,
the naturalistic movie was shown full - field . in the phase - randomized surround condition ,
the natural movie was shown in the central aperture , while the phase - randomized movie covered all the surrounding portions of the screen . to determine the influence of the surround alone ,
after each stimulus presentation , a constant gray screen was shown for 1,000 ms .
each condition was typically presented 11 times , and the first repetition was discarded from the analysis to eliminate onset - related effects .
cells were included for further analysis if during at least one movie frame if any of the two rf + surround conditions elicited a significant response modulation ( p < 0.01 , randomized two - sided t test ) .
there were no significant differences in the cortical recording depth between the age groups ( range , 85430 m beneath cortical surface ; 212 15 , 207 20 , and 198 17 m , mean sem , for mature , immature , and dark - reared mice , respectively ; p = 0.86 ; one - way anova ) .
in short , pipettes were advanced into the cortex at 40 angle with a high positive pressure until the electrode tip was at the depth of approximately 100 m ( corresponding to superficial layer 2/3 ) .
the resistance of the pipettes was typically 68 m , which were filled with a solution containing 110 mm potassium gluconate , 4 mm nacl , 40 mm hepes , 2 mm atp - mg , and 0.3 mm gtp - nacl ( adjusted to ph 7.2 with koh , 290 mosm ) . for experiments with elevated cl reversal potential , 5 mm of potassium gluconate was replaced by 5 mm kcl in the internal solution .
the membrane potential was filtered at 50 hz ( humbug ) and digitized at 10 khz ( national instruments , usa ) .
pv and som cells were targeted for whole - cell recordings in different transgenic mouse lines ( pv - gfp mice , meyer et al . , 2002 ; gin mice , oliva et al . , 2000
, 2010 ; hofer et al . , 2011 ) , using either 30 m alexa fluor 594 or alexa fluor 488 ( life technologies , uk ) in the internal solution .
the targeted cells and patch pipettes were visualized using a custom - built two - photon microscope in the green and red channels with excitation at 880 and 930 nm , respectively .
all analysis was performed with built - in or custom - made functions in matlab ( mathsworks , usa ) .
selectivity index ( si ) and mutual information ( mi ) were calculated as described before ( haider et al .
, 2010 ; borst and theunissen , 1999 ) and are explained in detail in the supplemental experimental procedures .
moment - to - moment differences in vm ( vm ) between rf and rf + surround conditions for each neuron were calculated in frame - wide bins ( 33 ms , figures 3d and 3i ) or 1 ms bins ( figures 3e and 3j ) from spike - removed traces ( spikes removed at spike threshold , see below ) .
the mean vm during either surround stimulation for each frame was plotted either against the mean vm relative to spiking threshold ( 5 mv binning ) or against the relative time before firing a spike ( 500 ms to 1 ms in 50 ms bins ) during the rf stimulation .
the membrane potential preceding a spike was first identified , and the membrane potential value at which the second derivative of the membrane potential was maximal was defined as threshold .
analysis of depolarizing events was carried out by quantifying the number and size of transient positive membrane deflections .
events were detected with a moving window ( bin width 5 ms ) with an amplitude threshold of 3 mv .
an individual event was regarded to have triggered a spike if the peak amplitude of the event was followed by an action potential .
statistical significance for repeated measurements of the same cell with different stimuli was assessed using the paired student s t test and anova for reaped measurements ( parametric data ) or wilcoxon sign - rank test and friedman s test ( nonparametric data ) .
m.p . and t.d.m .- f . conceived of the experiments and wrote the paper . e.s . , y.h . , and m.p .
Output:
| summaryat eye opening , neurons in primary visual cortex ( v1 ) are selective for stimulus features , but circuits continue to refine in an experience - dependent manner for some weeks thereafter . how these changes contribute to the coding of visual features embedded in complex natural scenes remains unknown .
here we show that normal visual experience after eye opening is required for v1 neurons to develop a sensitivity for the statistical structure of natural stimuli extending beyond the boundaries of their receptive fields ( rfs ) , which leads to improvements in coding efficiency for full - field natural scenes ( increased selectivity and information rate ) .
these improvements are mediated by an experience - dependent increase in the effectiveness of natural surround stimuli to hyperpolarize the membrane potential specifically during rf - stimulus epochs triggering action potentials .
we suggest that neural circuits underlying surround modulation are shaped by the statistical structure of visual input , which leads to more selective coding of features in natural scenes . |
PubmedSumm8840 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: we adopted tada ( for transmission and de novo association ) , a weighted , statistical model integrating de novo , transmitted and case - control variation .
tada uses a bayesian gene - based likelihood model including per gene mutation rates , allele frequencies , and relative risks of particular classes of sequence changes .
because no aggregate association signal was detected for inherited mis3 variants , they were not included in the analysis .
for each gene , variants of each class were assigned the same effect on relative risk . using a prior probability distribution of relative risk across genes for each class of variants ,
the model effectively weighted different classes of variants in this order : de novo lof > de novo mis3 > transmitted lof , and allowed for a distribution of relative risks across genes for each class . the strength of association was assimilated across classes to produce a gene - level bayes factor ( bf ) with a corresponding false discovery rate or fdr q - value .
this framework increases the power compared to use of de novo lof alone ( extended data fig .
tada identified 33 autosomal genes with an fdr < 0.1 ( table 1 ) and 107 genes with an fdr < 0.3 ( supplementary tables 2 and 3 and extended data fig .
15 ( 45.5% ) are known asd risk genes ; 11 have been reported previously with mutations in asd patients but were not classed as true risk genes owing to insufficient evidence ( suv420h1 , adnp , bcl11a , and cacna2d3 , cttnbp2 , gabrb3 , cdc42bpb , aph1a , nr3c2 , setd5 , trio ) ; and 7 are completely novel ( ash1l , mll3 , etfb , naa15 , myo9b , mib1 , vil1 ) .
adnp mutations have recently been identified in 10 patients with asd and other shared clinical features .
two of the newly discovered genes , ash1l and mll3 , converge on chromatin remodeling .
mib1 encodes an e3 ubiquitin ligase critical for neurogenesis and is regulated by mir-137 , a microrna that regulates neuronal maturation and is implicated in risk for schizophrenia . when the wes data from genes with fdr < 0.3 were evaluated for the presence of deletion copy number variants ( such cnvs are functionally equivalent to lof mutations ) , 34 cnvs meeting quality and frequency constraints ( supplementary information )
< 0.1 , three contained deletion cnvs mapping to three asd subjects and one parent .
of the 74 genes meeting the criterion 0.1 fdr < 0.3 , about a third could be false positives .
deletion cnvs were found in 14 of these genes and the data supported risk status for 10 of them ( extended data table 1 , extended data fig .
the risk from deletion cnvs , as measured by the odds ratio , is comparable to that from lof snv in cases versus controls or transmission of lof from parents to offspring .
inherent in our conception of the biology of asd is the notion that there is variation between genes in their impact on risk : for a given class of variants ( e.g. , lof ) , some genes have large impact , others smaller , and still others have no effect at all .
yet mis - annotation of variants , among other confounds , can produce false variant calls in subjects ( supplementary information ) .
these confounds can often be overcome by examining the data in a manner orthogonal to gene discovery .
for example , females have greatly reduced rates of asd relative to males ( a so - called female protective effect ) .
consequentially , and regardless of whether this is diagnostic bias or biological protection , females have a higher liability threshold , requiring a larger genetic burden before being diagnosed .
a corollary is that if a variant has the same effect on autism liability in males as it does in females , that variant will be at higher frequency in female asd cases compared to males .
importantly , the magnitude of the difference is proportional to risk as measured by the odds ratio ( or ) ; hence , the effect on risk for a class of variants can be estimated from the difference in frequency between males and females .
genes with fdr < 0.1 show profound female enrichment for de novo events ( p=0.005 for lof , p=0.004 for mis3 ) , consistent with de novo events having large impact on liability ( or 20 ; extended data fig .
genes with fdr between 0.1 and 0.3 , however , show substantially less enrichment for female events , consistent with a modest impact for lof variants ( or range 2 - 4 , whether transmitted or de novo ) and little to no effect from mis3 variants .
the results are consistent with inheritance patterns , lof mutations in fdr < 0.1 genes are rarely inherited from unaffected parents while those in the 0.1 < fdr < 0.3 group are far more often inherited than de novo . by analyzing the distribution of relative risk over inferred asd genes ,
the estimate relies on the balance of genes with multiple de novo lof mutations versus those with only one : the larger the number of asd genes , the greater proportion that will show only one de novo lof .
while there are many more genes to be discovered , many will have a modest impact on risk compared to the genes in table 1 .
fdr < 0.3 gene sets are strongly enriched for genes under evolutionary constraint ( p=3.010 , fig . 1a , supplementary table 4 ) , consistent with the hypothesis that heterozygous lof mutations in these genes are asd risk factors .
indeed over 5% of asd subjects carry de novo lof mutations in our fdr < 0.3 list .
we also observed that genes in the fdr < 0.3 list had a significant excess of de novo lof events detected by the largest schizophrenia wes study to date ( p=0.0085 , fig .
1a ) , providing further evidence for overlapping risk loci between these disorders and independent confirmation of the signal in the gene sets presented here .
we found significant enrichment for genes encoding mrnas targeted by two neuronal rna - binding proteins : fmrp ( also known as fmr1 ) , mutated or absent in fragile x syndrome ( p=1.2010 , 34 targets , of which 11 are corroborated by an independent data set ) , and , rbfox ( rbfox1/2/3 ) ( p=0.0024 , 20 targets , of which 12 overlap with fmrp ) , with rbfox1 shown to be a splicing factor dysregulated in asd ( fig .
these two pathways expand the complexity of the asd neurobiology to post - transcriptional events , including splicing and translation , both of which would sculpt the neural proteome .
we found nominal enrichment for human orthologs of mouse genes encoding synaptic ( p=0.031 ) and postsynaptic density ( psd ) proteins ( p=0.046 , fig .
enrichment analyses for interpro , smart , or pfam domains ( fdr < 0.05 and a minimum of 5 genes per category ) reveal an overrepresentation of dna / histone - related domains : 8 genes encoding proteins with interpro zinc finger ( znf ) fyve phd domains ( 142 such annotated genes in the genome ; fdr=7.610 ) , and five with pfam su(var)3 - 9 , enhancer - of - zeste ( set ) domains ( 39 annotated in the genome ; fdr=8.210 ) . to implicate additional genes in risk for asd , we use a model called dawn .
dawn evokes a hidden markov random field framework to identify clusters of genes that show strong association signal and highly correlated co - expression in a key tissue and developmental context .
previous research suggests human mid - fetal prefrontal and motor - somatosensory neocortex is such a critical nexus for risk , thus we evaluated gene co - expression data from that tissue together with tada scores for genes with fdr < 0.3 . because this list is enriched for genes under evolutionary constraint , we generalized dawn to incorporate constraint scores ( supplementary information ) .
when ( a ) tada results , ( b ) gene co - expression in mid - fetal neocortex , and ( c ) constraint scores are jointly modeled , dawn identifies 160 genes that plausibly affect risk ( fig .
moreover , the model parameter describing evolutionary constraint is an important predictor of clusters of putative risk genes ( p=0.018 ) .
a subnetwork obtained by seeding the 160 dawn genes within a high - confidence protein - protein interactome confirmed that the putative genes are enriched for neuronal functions .
we kept the largest connected component , containing 95 seed dawn genes , 50 of which were in the fdr < 0.3 gene set .
2 ) . we visualized the enriched pathways and biological functions for each of these clusters on canvases ( extended data fig .
many of the previously known asd risk genes fall in cluster c3 , including genes involved in synaptic transmission and cell - cell communication .
many tada and dawn genes in this cluster interact tightly with other transcription factors , histone modifying enzymes and dna binding proteins .
five tada genes in the cluster c2 are bridged to the rest of the network through mapt , inferred by dawn .
the enrichment results for c2 indicate that genes implicated in neurodegenerative disorders could also play a role in neurodevelopmental disorders .
to implicate additional genes in risk for asd , we use a model called dawn .
dawn evokes a hidden markov random field framework to identify clusters of genes that show strong association signal and highly correlated co - expression in a key tissue and developmental context .
previous research suggests human mid - fetal prefrontal and motor - somatosensory neocortex is such a critical nexus for risk , thus we evaluated gene co - expression data from that tissue together with tada scores for genes with fdr < 0.3 . because this list is enriched for genes under evolutionary constraint , we generalized dawn to incorporate constraint scores ( supplementary information ) .
when ( a ) tada results , ( b ) gene co - expression in mid - fetal neocortex , and ( c ) constraint scores are jointly modeled , dawn identifies 160 genes that plausibly affect risk ( fig .
moreover , the model parameter describing evolutionary constraint is an important predictor of clusters of putative risk genes ( p=0.018 ) .
a subnetwork obtained by seeding the 160 dawn genes within a high - confidence protein - protein interactome confirmed that the putative genes are enriched for neuronal functions .
we kept the largest connected component , containing 95 seed dawn genes , 50 of which were in the fdr < 0.3 gene set .
2 ) . we visualized the enriched pathways and biological functions for each of these clusters on canvases ( extended data fig .
many of the previously known asd risk genes fall in cluster c3 , including genes involved in synaptic transmission and cell - cell communication .
many tada and dawn genes in this cluster interact tightly with other transcription factors , histone modifying enzymes and dna binding proteins .
five tada genes in the cluster c2 are bridged to the rest of the network through mapt , inferred by dawn .
the enrichment results for c2 indicate that genes implicated in neurodegenerative disorders could also play a role in neurodevelopmental disorders .
amongst critical synaptic components found mutated in our study are voltage - gated ion channels involved in fundamental processes including propagation of action potentials ( e.g. , nav1.2 channel ) , neuronal pacemaking , and excitability - transcription coupling ( e.g. , cav1.3 channel ) ( fig .
we identified , 4 lof and 5 mis3 variants in scn2a ( nav1.2 ) , 3 mis3 in cacna1d ( cav1.3 ) , 2 lof in cacna2d3 ( -auxiliary subunits of l - type voltage - gated ca channels , including cav1.3 ) . remarkably , three de novo mis3 variants in scn2a hit residues mutated in homologous genes in patients with other syndromes , including brugada syndrome ( scn5a ) or epilepsy disorders ( scn1a ) ( p.r379h and p.r937h ) .
these arginines , as well as the threonine mutated in p.t1420 m , cluster to the p - loops forming the ion selectivity filter , in proximity of the inner ring ( deka motif ) ( fig .
because homologous channels mutated in these arginines do not conduct inwards na currents , p.r379h and p.r937h might have similar effect .
two de novo cacna1d variants ( p.g407r and p.a749 g ) hit positions proximal to residues mutated in patients with primary aldosteronism and neurological deficits ( fig .
the reported mutations interfere with channel activation and inactivation . amongst variants found in cases , p.a59v maps to the nscate domain , also important for ca - dependent inactivation , while p.s1977l and p.r2021h co - cluster in the c - terminal proline - rich domain , the site of interaction with shank3 , a key psd scaffolding protein .
mutations in rims1 and rimbp2 , which can associate with cav1.3 , were found in our cohort ( but with an fdr.0.3 ) .
chromatin remodeling involves histone - modifying enzymes ( encoded by histone modifier genes , hmgs ) and chromatin remodelers ( readers ) that recognize specific histone post - translational modifications ( ptms ) and orchestrate their effects on chromatin .
our gene set is enriched in hmgs ( 9 hmgs out of 152 annotated in histome , fisher 's exact test , p=2.210 ) .
histone - lysine n - methytransferase activity ( 5 genes out of 41 so annotated ; fdr=2.210 ) highlights this as a prominent pathway .
lysines on histones 3 and 4 can be mono- , di- , or tri - methylated , providing a versatile mechanism for either activation or repression of transcription . of 107 tada genes ,
five are set lysine methyltransferases , four are jumonji ( jmjc ) lysine demethylases , and two are readers ( fig .
rbfox1 co - isolates with h3k4me3 , and our dataset is enriched in targets shared by rbfox1 and h3k4me3 ( p=0.0166 , fig . 1a , supplementary table 4 ) .
some de novo missense variants targeting these genes map to functional domains ( extended data fig .
, we extended our analyses in search of additional de novo variation in the cases of the case - control sample . by sequencing complete parent - child trios for many chd8 variants , five variants were found to be de novo , two of which affect essential splice sites and cause loss of function by exon skipping or activation of cryptic splice sites in lymphoblastoid cells ( fig .
3b ) . given the role of hmgs in transcription , we reasoned that tada genes might be interconnected through transcription routes .
we searched for a connected network ( seeded by 9 tada hmgs ) in a transcription factor interaction network ( chea ) .
we found that 46 tada genes are directly interconnected in a 55-gene cluster ( extended data fig .
8) ( p=0.002 ; 1,000 random draws ) , for a total of 69 when including all known hmgs ( fig .
4 ) ( p=0.001 ; 1,000 random draws ) . examining the human gene mutation database we found that the 107 tada genes included 21 candidate genes for intellectual disability , 3 for epilepsy , 17 for schizophrenia , 9 for congenital heart disease and 6 for metabolic disorders ( fig . 5 ) .
complementing earlier reports , asd subjects show a clear excess of de novo lof mutations over expectation , with a pile - up of such events in a handful of genes .
while this handful has a large effect on risk , most asd genes have much smaller impact .
this gradient emerges most strikingly from the contrast of risk variation in male and female asd subjects . unlike some earlier studies , but consistent with expectation
, the data also show clear evidence for effect of de novo missense snv on risk ; for risk generated by lof variants transmitted from unaffected parents ; and for the value of case - control design in gene discovery .
indeed , by integrating data on de novo , inherited and case control variation , the yield of asd gene discoveries was doubled over what would be obtained from a count of de novo lof alone .
almost uniformly asd genes show large constraint against variation , a feature we exploit to implicate other genes in risk .
three critical pathways for typical development are damaged by risk variation : ( 1 ) chromatin remodeling , ( 2 ) transcription and splicing , and , ( 3 ) synaptic function .
chromatin remodeling controls events underlying the formation of neural connections , including neural neurogenesis and neural differentiation , and relies on epigenetic marks as histone ptms .
here we provide extensive evidence for hmgs and readers in sporadic asd , implicating specifically lysine methylation and extending the mutational landscape of the emergent asd gene chd8 to missense variants .
risk variation also hits multiple classes and components of synaptic networks , from receptors and ion channels to scaffolding proteins .
because a wide set of synaptic genes is disrupted in idiopathic asd , it seems reasonable to conjecture that altered chromatin dynamics and transcription , induced by disruption of relevant genes , leads to impaired synaptic function as well .
de novo mutations in asd , intellectual disability and schizophrenia cluster to synaptic genes , and synaptic defects have been reported in models of these disorders .
integrity of synaptic function is essential for neural physiology , and its perturbation could represent the intersection between diverse neuropsychiatric disorders .
dna was obtained , and exomes were captured and sequenced . after variant calling qc was performed : duplicate subjects and incomplete families were removed ; and subjects with extreme genotyping , de novo , or variant rates were removed . following cleaning , 3,871 subjects with asd remained .
de novo and transmission / non - transmission were obtained for trio data ( published de novo from 825 trios were incorporated ) .
this path led to the tada analysis , which found 33 asd risk genes with q < 0.1 ; and 107 with q < 0.3 .
the multiple lof test ( red ) is a restricted version of tada that uses only the de novo lof data .
tada ( blue ) models de novo lof , de novo mis3 , lof variants transmitted / not transmitted and lof variants observed in case / control samples . the sample size ( n ) indicates either ( i ) n trios , for which we record de novo and transmitted variation , or ( ii ) n trios , for which we record only de novo events , plus n cases and n controls . left panel , variants in affected subjects ; right panel , unaffected subjects . for the counts ,
we only focus on de novo lof and mis3 variants , transmitted / un - transmitted and case / control lof variants .
these variant counts are normalized by the length of coding regions of each gene and sample size of each dataset ( |trio|+|case| for left panel , |trio|+|control| for the right panel ) .
the deletions are displayed in red if with unknown inheritance , in grey if inherited , and in black in un unaffected subjects .
frequency of de novo ( dn ) and transmitted ( tr ) variants per sample in males ( black ) and females ( white ) for genes with q < 0.1 ( upper panel ) , q < 0.3 ( central panel ) , or all tada genes ( lower panel ) .
the p values were determined by a one - tailed permutation test ( * p < 0.5 ; * * p < 0.01 ; * * * p < 0.01 ) .
p - values using mouse - genome - informatics / mammalian - phenotype ( mgi - mp , blue ) , kyoto encyclopedia of genes and genomes pathways ( kegg , red ) , and gene ontology biological processes ( go , yellow ) are indicated .
mis3 are in black , lof in red , and variants identified in other disorders in grey ( fig . 5 ) .
jmjc , jumonji c domain ; jmjn , jumonji n domain ; jmjc , phd , plant homeodomain ; arid , at - rich interacting domain ; set , su(var)3 - 9 , enhancer - of - zeste , trithorax domain ; fyr n , fy - rich n - terminal domain ; fyr c , fy - rich c - terminal domain ; pwwp , pro - trp - trp - pro domain ; hmg , high mobility group box ; aws , associated with set domain ; bromo , bromodomain ; bah , bromo adjacent homology .
edges indicate transcription regulator ( source node ) and its gene targets ( target node ) based on chea network .
count of deletion copy number variants , inferred from sequence , for asd subjects and those unaffected by asd .
number of subjects and family status : 849 asd without family information ; 1467 asd subjects in families ; 2766 unaffected parents ; 319 unaffected siblings of asd subjects ; 373 unaffected subjects without family information .
no parents in this count were affected ; 7 parents in the study were affected , none carried a cnv reported in the table and these subjects did not enter the calculation .
tr - asd = transmitted to asd subject from carrier parent ; nt = parent a carrier but cnv not transmitted to affected child ; tr - not - asd = parent transmits a cnv to an unaffected child . to compute the odds ratio we count the number
a of affected carriers , b unaffected carriers ( including parents ) , c affected subjects who do not have the cnv , and
one parent transmits the cnv to an affected and unaffected offspring ; to obtain the total count of controls with a cnv , subtract one .
both genes are hit by the same cnv ( 1 asd and 2 unaffected subjects ) .
Output:
| summarythe genetic architecture of autism spectrum disorder involves the interplay of common and rare variation and their impact on hundreds of genes .
using exome sequencing , analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry - matched or parental controls implicates 22 autosomal genes at a false discovery rate ( fdr ) < 0.05 , and a set of 107 autosomal genes strongly enriched for those likely to affect risk ( fdr < 0.30 ) . these 107 genes , which show unusual evolutionary constraint against mutations , incur de novo loss - of - function mutations in over 5% of autistic subjects .
many of the genes implicated encode proteins for synaptic , transcriptional , and chromatin remodeling pathways . these include voltage - gated ion channels regulating propagation of action potentials , pacemaking , and excitability - transcription coupling , as well as histone - modifying enzymes and chromatin remodelers , prominently histone post - translational modifications involving lysine methylation / demethylation . |
PubmedSumm8841 | ***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 july 2004 , an update of treatment guidelines for hypercholesterolemia was published by the national cholesterol education program adult treatment panel ( ncep - atp iii).1 this document reviews the results of the most recent clinical trials and assessed their implications for cholesterol management .
therapeutic lifestyle changes were emphasized as an essential modality in clinical management of dyslipidemia , and the benefit of cholesterol - lowering therapy was confirmed in high - risk patients .
the atp iii low - density lipoprotein ( ldl ) cholesterol treatment goals and endpoints for theraputic lifestyle changes and drug therapy in different risk categories are summarized in table 1 .
ldl cholesterol is the primary target of cholesterol - lowering therapy with agents such as 3-hydroxy-3-methylglutaryl coenzyme a ( hmg - coa ) reductase inhibitors ( commonly referred to as statins ) .
the clinical use of these drugs for primary or secondary prevention in patients with hypocholesterolemia has significantly reduced morbidity and mortality associated with coronary heart disease ( chd).27 unfortunately , a number of these agents can reduce ldl cholesterol levels by only 30% to 35% , which may not bring many subjects to their ncep - atp iii goals.8 moreover , the higher - potency agents ( simvastatin , lovastatin , atorvastatin ) have extensive extrahepatic tissue penetration and show potential drug interactions that may have remarkable safety implications.9 rosuvastatin , the most recently approved hmg - coa reductase inhibitor , has demonstrated a potent lipid - lowering effect associated with a good tolerability profile and a lower risk of pharmacokinetic interactions .
this statin is a hydrophilic compound with poor penetration in extrahepatic tissue , and it does not seem to exhibit significant cytochrome ( cyp ) p450 drug interactions , as do several of the other hmg - coa reductase inhibitors.10 this reviews the pharmacologic and pharmacokinetic properties of rosuvastatin , comparing its efficacy and safety with other that of currently available hmg - coa reductase inhibitors .
statins are natural , fungus resultant , mevinic acid derived ( simvastatin , lovastatin , pravastatin ) , or synthetic , heptenoic acid derived ( atorvastatin , cerivastatin , fluvastatin).11 rosuvastatin is a synthetic hmg - coa reductase inhibitor belonging to a new novel series of methanesulfonamide pyrimidine and n - methanesulfonyl pyrrole - substituted 3,5-dihydroxy-6-heptenoates ( heptenoic acid - derivative combined with a pyrimidine and sulfonamide group ) .
the enzyme inhibition is reversible , competitive with the substrate hmg - coa and noncompetitive with the cosubstrate nicotinamide - adenine dinucleotide phosphate ( nadph ) .
its low lipophilicity is conferred by the addition of a stable polar methane sulfonamide group as a hydrophilic moiety besides the characteristic statin pharmacophore.1012 the ldl cholesterol - lowering effect of statins is derived from their inhibitory action on hmg - coa reductase in the hepatocytes .
these compounds directly bind in a tight and reversible manner to a specific binding site on the hmg - coa reductase enzyme .
moreover , rosuvastatin and atorvastatin were found to have additional bonding interactions at the enzyme complex as compared to other statins .
the addition of a methane sulfonamide group to the rosuvastatin molecule , even though it increases hydrophilicity , results in enhanced interaction with the hmg - coa enzyme and leads to a more potent enzyme inhibition , owing to the appearance of ionic binding interactions.1013 rosuvastatin shows a very high affinity for the active site of the hmg - coa reductase , four times greater than the affinity of the natural substrate hmg - coa for the enzyme . the high affinity and tight binding of rosuvastatin to hmg - coa reductase leads to a slow recovery of enzyme activity after removal of free inhibitor .
in fact , hepatic cholesterol synthesis in rats was found to be inhibited by 62% at 7 hours after oral dosing compared to 7% and 13% for atorvastatin and simvastatin , respectively.13,14 the binding properties of this statin for the target enzyme are reflected in the drug concentration needed to block 50% of sterol synthesis in the rat hepatocyte ( ic50 ) .
the mean ic50 of rosuvastatin in primary rat hepatocytes ( 0.16 nm on log scale ) is significantly lower than the mean ic50 of other statins ( 1.16 for atorvastatin , 2.74 for simvastatin , 3.78 for fluvastatin , and 6.93 for pravastatin ) .
therefore rosuvastatin was found to be a significantly more potent inhibitor of hepatocyte sterol synthesis than any of the statins currently available.14,15 moreover , rosuvastatin is significantly less lipophilic than other hmg - coa reductase inhibitors except pravastatin.16 hepatocyte concentrations of drug are not influenced by the statin lipophilicity because active uptake occurs , but differences in lipophilicity of statins are related to their penetration into extrahepatic tissues .
cerivastatin , the most lipophilic agent of this class , shows a very great penetration in extrahepatic tissues , is the most potent inhibitor of vascular smooth muscle proliferation , and had the largest number of cases of rhabdomyolysis . on the contrary , pravastatin , the most hydrophilic statin ,
has a rhabdomyolysis rate which is approximately one - third that of lovastatin and does not show a dose - related increase in the risk of muscle toxicity as with lovastatin.10,16,17
the oral bioavailability of rosuvastatin is approximately 20% , or rather lower than cerivastatin ( which has a bioavailability of 60% ) , but higher than lovastatin and simvastatin , and comparable to that of pravastatin , fluvastatin , and atorvastatin .
food is known to reduce rosuvastatin s rate of absorption by 20% , but the extent of absorption is unchanged . the peak plasma concentration ( cmax ) of 6.1 ng / ml is reached at 5 hours after a single oral dose of 20 mg .
prolonged dosing with 20 mg once daily leads to a steady state cmax of 9.7 ng / ml , which occurs 3 hours after dosing .
in pharmacokinetic trials , the cmax and the area under the concentration time curve ( auc024 ) demonstrated an approximately linear relation throughout the dosage range of 5 to 80 mg after single and seven daily doses .
steady state tmax ranged from 3 to 5 hours , and it was longer than other currently available statins ( with tmax values usually lower than 3 hours).10,18 at steady state , the mean volume of distribution for rosuvastatin is about 130 l , and it is tightly bound in a reversible manner to plasma proteins ( 88% ) , while other statins are more than 95% protein bound except pravastatin ( which is approximately 50% bound).11 metabolism of rosuvastatin and its interactions with cytochrome p450 isoenzymes were evaluated in vitro using human hepatic microsomes .
no significant inhibitory effect was noted on cyp1 a2 , 2c9 , 2c19 , 2d6 , 2e1 , and 3 a4 activity .
the most potent inhibition was found against the cyp2c9 , but the enzyme activity was reduced by only 10%.19 the metabolism of rosuvastatin via cultured human hepatocytes ( 3% to 50% over 3 days ) produces an n - desmethyl - metabolite and a 5s - lactone product .
the n - desmethyl - metabolite is 7-fold less potent than rosuvastatin for inhibition of hmg - coa reductase activity.10 the slow metabolism and the limited inhibitory effect of rosuvastatin on cyp isoenzymes suggest that it is unlikely to cause any significant pharmacokinetic interactions with other drugs metabolized by hepatic cyp isoenzymes . on the contrary , lovastatin , simvastatin , and atorvastatin are extensively metabolized by cyp3 a4 , and inhibitors of this enzymatic system ( such as itraconazole ) were found to increase serum concentrations of these statins by several - fold , with an increased risk of muscle toxicity.19,20 recovery of rosuvastatin is primarily via the fecal route of elimination : approximately 70% of absorbed dose is eliminated via bile secretion , and 30% via renal excretion .
the circulating plasma half - life of rosuvastatin is about 20 hours.10,16 statins are effective inhibitors of p - glycoprotein , which is cell membrane - associated and transports many drug substrates across the intestinal wall .
inhibition of p - glycoprotein may influence the pharmacokinetic and pharmacodynamic properties of drugs that are substrates of this transporter , and may lead to other important drug drug interactions .
lovastatin , simvastatin , and atorvastatin are very potent inhibitors of p - glycoprotein in higher concentrations , and show important drug
drug interactions with digoxin , which is transported by p - glycoprotein.21,22 to date there are no data available assessing whether rosuvastatin is an inhibitor or a substrate for p - glycoprotein .
itraconazole is a potent inhibitor of cyp3 a4 and p - glycoprotein , and is known to interact with other statins . in two randomized , double - blind , placebo - controlled trials the effect of itraconazole on the pharmacokinetics of rosuvastatin was evaluated in 26 healthy volunteers . in these studies ,
the coadministration of itraconazole produced only modest increases in plasma concentrations of rosuvastatin , which are unlikely to be of clinical relevance.23 lipid - lowering therapy is frequently requested for the treatment of hypocholesterolemia associated with antiretroviral drugs in patients with human immunodeficiency virus ( hiv ) infection .
particularly , protease inhibitors ( pi ) are extensively metabolized by hepatic cyp 3a4 and concomitant use of statins could lead to significant drug drug interactions with increased risk of drug toxicity .
because pharmacokinetic studies have demonstrated that the rosuvastatin metabolism is not dependent on cyp 3a4 isoenzyme , its use could be considered in pi - treated subjects owing to the low risk of pharmacological interactions . in an open - label , randomized , prospective study
we have evaluated over at least 12 months the efficacy and safety of rosuvastatin , pravastatin , and atorvastatin in 94 hiv - infected subjects on a stable pi - based antiretroviral therapy and presenting hypocholesterolemia . during the 12-month follow - up all administered statins showed a favorable tolerability profile , and patients plasma hiv viral load
particularly , no significant increases in serum levels of creatine phosphokinase ( cpk ) or liver function tests were reported.24 however , two recent studies showed potential pharmacokinetic interactions between rosuvastatin and pis .
a prospective study assessed drug drug interactions of rosuvastatin with atazanavir / ritonavir and fosamprenavir / ritonavir in 6 hiv - negative healthy adult volunteers . compared to baseline , auc024 and cmax of rosuvastatin increased by 213% and 600% , respectively , when given with atazanavir / ritonavir , while coadministration with fosamprenavir / ritonavir did not significantly affect plasma concentrations of the statin .
therefore , atazanavir / ritonavir significantly increases the plasma levels of rosuvastatin , most likely by increasing its oral bioavailability , but the clinical significance of this pharmacokinetic interaction is unknown.25 an open - label , prospective study evaluated drug - drug interaction between rosuvastatin and lopinavir / ritonavir in 15 hiv - negative healthy adult volunteers .
rosuvastatin auc024 and cmax were unexpectedly increased 2.1- and 4.7-fold , respectively , when given in combination with the pi , and there was 1 asymptomatic elevation in serum levels of cpk and liver function tests .
therefore , rosuvastatin and lopinavir / ritonavir should be used with caution until the safety and appropriate dosing of this combination have been demonstrated in larger populations.26
rosuvastatin was found to be highly efficacious in reducing plasma ldl cholesterol levels and favorably modifying the other lipid and apolipoprotein parameters in patients with hypercholesterolemia in both short - term and long - term clinical trials .
moreover , in pairwise comparisons , rosuvastatin showed a significantly higher efficacy in reducing ldl cholesterol than milligram - equivalent doses of other statins currently available .
dosing of rosuvastatin ranging from 1 to 80 mg daily over 6 weeks has resulted in ldl - cholesterol reductions compared with the baseline values from 34% to 65% , and the ldl cholesterol reduction at the probable starting dose range ( 5 to 10 mg ) was 43% to 51%.27 in a direct comparative trial , rosuvastatin or atorvastatin was administered to patients with familial heterozygous hypercholesterolemia .
subjects were randomized to either 20 mg of rosuvastatin or atorvastatin and the dose was doubled at 6-week periods until all patients reached the maximum dose of 80 mg for both drugs at weeks 12 to 18 .
decreases in ldl cholesterol concentrations were significantly greater for rosuvastatin compared with atorvastatin at all time points , and 61% of patients taking rosuvastatin reached target goals according to ncep - atp ii guidelines , compared to 46% of those taking atorvastatin.28 the stellar study29 was a 6-week , open - label , randomized , multicenter trial comparing rosuvastatin with atorvastatin , pravastatin , and simvastatin across dose ranges for reduction of ldl cholesterol , changes in other lipid parameters , and achievement of ncep - atp iii ldl - cholesterol goals . after a 6-week dietary lead - in period , 2431 adult subjects with hypercholesterolemia were randomized to therapy with rosuvastatin ( 10 , 20 , 40 , or 80 mg daily ) , atorvastatin ( 10 , 20 , 40 , or 80 mg daily ) , simvastatin ( 10 , 20 , 40 , or 80 mg daily ) , or pravastatin ( 10 , 20 , or 40 mg daily ) .
at the end of 6-weeks follow - up , across - dose analyses showed that rosuvastatin 10 to 80 mg reduced ldl cholesterol by a mean of 8.2% more than atorvastatin 10 to 80 mg , 26% more than pravastatin 10 to 40 mg , and 12%18% more than simvastatin 10 to 80 mg ( all p < 0.001 ) .
mean percent changes in high - density lipoprotein ( hdl ) cholesterol levels were + 7.7% to + 9.6% compared with + 2.1% to + 6.8% in all other groups . moreover , rosuvastatin reduced total cholesterol significantly more than all comparators , and triglycerides significantly more than simvastatin and pravastatin .
the ncep - atp iii ldl cholesterol goals were achieved by 82% to 89% of subjects treated with rosuvastatin 10 to 40 mg compared with 69% to 85% of patients treated with atorvastatin 10 to 80 mg , and drug tolerability was comparable across treatments.29 effects of statins at different dosages in lowering ldl cholesterol levels are summarized in table 2 .
a substudy of the stellar trial assessed non - hdl cholesterol , apolipoprotein ( apo ) b , and lipid and apolipoprotein ratios that included both atherogenic and antiatherogenic lipid components in 2,268 patients with hypercholesterolemia .
all participants were randomized to therapy with rosuvastatin ( 10 , 20 , 40 , or 80 mg daily ) , atorvastatin ( 10 , 20 , 40 , or 80 mg daily ) , simvastatin ( 10 , 20 , 40 , or 80 mg daily ) , or pravastatin ( 10 , 20 , or 40 mg daily ) for 6 weeks . at the end of follow - up , rosuvastatin reduced non - hdl cholesterol , apo b , and all lipid and apolipoprotein ratios assessed significantly more than milligram - equivalent doses of atorvastatin , and milligram - equivalent or higher doses of simvastatin and pravastatin ( all p < 0.002).30 a post - hoc subanalysis of the stellar trial evaluated the effects of maximal doses of rosuvastatin and atorvastatin on ldl cholesterol and small dense ldl ( sldl ) cholesterol levels in 271 hyperlipidemic patients .
all participants were randomized to therapy with rosuvastatin 40 mg daily or atorvastatin 80 mg daily for 6 weeks .
rosuvastatin was significantly more effective than atorvastatin in reducing ldl cholesterol , sldl cholesterol , total cholesterol / hdl cholesterol ratio , and non - hdl cholesterol , even though the magnitude of these differences was modest , and both statins caused similar decreases in triglyceride levels.31 two studies have evaluated the efficacy of rosuvastatin therapy after a 52-week follow - up . in the first randomized , double - blinded , multicenter study , 412 subjects with elevated ldl cholesterol levels received fixed doses of rosuvastatin ( 5 or 10 mg daily ) or atorvastatin ( 10 mg daily ) for 12 weeks , followed by dose adjustements up to 80 mg if the ncep - atp iii goals were not met .
both doses of rosuvastatin resulted in greater ldl cholesterol reductions than atorvastatin at 12 weeks ( 46% and 50% , respectively , versus 39% ; p < 0.001 for both groups ) and 52 weeks ( 47% and 53% , respectively , versus 44% ; p < 0.05 and p < 0.001).32 in a similarly designed trial , 477 patients with hypocholesterolemia received fixed doses of rosuvastatin ( 5 or 10 mg daily ) , pravastatin ( 20 mg ) , or simvastatin ( 20 mg ) for 12 weeks followed by 40 weeks of liberal - dose titration up to 80 mg for rosuvastatin and simvastatin and 40 mg for pravastatin . after 52 weeks , more rosuvastatin - treated subjects achieved the ncep - atp iii ldl cholesterol goals ( 88% and 87.5% , respectively ) than recipients of pravastatin ( 60% ) or simvastatin ( 73%).33 in recent years , some evidence has suggested that the quality rather than the quantity of ldl produces a direct influence on cardiovascular risk .
there are at least four major subspecies of ldl particles , and the predominance of sldl has been associated with a significantly higher risk of coronary artery disease.34 to date , only few studies have directly investigated if rosuvastatin may alter ldl size and subclasses , but this statin seems modulate significantly ldl size and subclasses towards less atherogenic particles as well as the ldl particle number , as indirectly measured by the levels of apo b.35 the jupiter trial36 was a randomized , double - blind , placebo - controlled study designed to compare whether rosuvastatin ( 20 mg daily ) versus placebo would reduce major cardiovascular events in 17,802 apparently healthy patients with low to normal ldl cholesterol levels but elevated c - reactive protein ( crp ) levels .
notably , this trial was prematurely interrupted after a median follow - up of 1.9 years based on unequivocal evidence of a reduction in cardiovascular morbidity and mortality in rosuvastatin - treated patients .
the rates of first major cardiovascular events ( defined as non - fatal myocardial infarction , nonfatal stroke , hospitalization for unstable angina , arterial revascularization procedure , or confirmed death from cardiovascular causes ) were 0.77 and 1.36 per 100 person - years of follow - up in the rosuvastatin and placebo groups , respectively ( p < 0.00001).36 in an analysis of 15,548 subjects participating in the jupiter trial ( 87% of full cohort ) , patients allocated to rosuvastatin who achieved ldl cholesterol less than 1.8
mmol / l had a 55% reduction in rate of vascular events , and those achieving crp less than 2 mg / l a 62% reduction .
particularly , in rosuvastatin - treated patients achieving both ldl cholesterol less than 1.8 mmol / l and crp less than 2 mg / l , a 65% reduction in vascular events was recorded.37
the hmg - coa reductase inhibitors are overall very safe , especially in light of the ability of this drug class to reduce morbidity and mortality . however , the withdrawal of cerivastatin because of excess cases of fatal rhabdomyolysis has raised awareness of this otherwise very rare complication of treatment , and there is an appropriately enhanced concern about adverse effects associated with these drugs . from 1997 to 2000
there were 387 cases of rhabdomyolysis associated with cerivastatin therapy , which represented about 50% of all of the cases spontaneously reported in association with statin therapy over this period . in comparison , simvastatin was responsible for 24% of the total , atorvastatin for 11% , and pravastatin for 9% . in a recent report using us data , there were 0.15 cases of death from rhabdomyolysis per million prescriptions for all statins , but 3.16 cases per million prescriptions for cerivastatin alone .
the relative high number of cases of rhabdomyolysis for cerivastatin may be related to its greater lipophilicity and penetration in extrahepatic tissues , as described previously.38,39 however , a population - based cohort study found that the use of statins in general was associated with a greater risk of myopathy than nonuse , but the absolute risk of myopathy was minimal.40 a review of rosuvastatin s pooled safety data demonstrated that incidence of adverse events was comparable to those of the other statins .
the most frequently reported adverse events ( incidence > 5% ) during rosuvastatin therapy in the controlled phase ii / iii trials included pharyngitis ( 12.2% ) , pain ( 6.7% ) , headache ( 6.6% ) , flu syndrome ( 5.3% ) , and myalgia ( 5.1% ) .
the frequency of elevation in alanine amino - transferase ( alt ) was 0.5% , and the incidence of myopathy ( cpk levels > 10 times upper limit of normal ( uln ) with muscle symptoms including weakness , aching , or tenderness ) was 0.2% .
all cases of myopathy occurred in patients treated with 80 mg daily and cpk elevations resolved following withdrawal of rosuvastatin.41 a retrospective matched cohort study compared the incidence rates of hospitalization associated with rhabdomyolysis , myopathy , renal or hepatic dysfunction , and of inhospital death , among over 48,000 initiators of rosuvastatin and other statins .
this study found no difference between rosuvastatin and the other statins in the incidence of hospitalization because of renal or hepatic dysfunction , or death , while the absolute incidence rates of rhabdomyloysis and myopathy were reassuringly low among all statin initiators but remain too small for firm conclusions to be drawn on any difference between the statins .
particularly , incidence rate per 1000 person - years of rhabdomyolysis was 0.1 among subjects taking rosuvastatin and 0.06 among those taking other statins , while incidence rate of myopathy was 0.2 among rosuvastatin - treated subjects and 0 among other statin initiators.42 the safety and tolerability of rosuvastatin were evaluated using data from 16,876 patients who received rosuvastatin 5 to 40 mg daily in a multinational phase ii / iii / iiib / iv program .
adverse events irrespective of causality assessment occurred in 52.1% of patients receiving rosuvastatin and 51.8% of those receiving placebo . in all controlled clinical trials with comparator statins , rosuvastatin
5 to 40 mg was associated with an adverse event profile similar to profiles for atorvastatin 10 to 80 mg , simvastatin 10 to 80 mg , and pravastatin 10 to 40 mg . clinically significant elevations in alt were uncommon in the rosuvastatin and comparator groups , and elevated cpk levels more than 10 times laboratory uln occurred in 0.3% of patients receiving rosuvastatin or other statins .
myopathy possibly related to treatment was reported in 0.03% of patients taking rosuvastatin at doses of 5 to 40 mg .
the frequency of dipstick - positive proteinuria at a rosuvastatin dose 5 to 40 mg was comparable to that seen with other statins , and the occurrence of proteinuria was not predictive of acute or chronic renal disease .
however , both short- and long - term rosuvastatin treatments were associated with small increases in estimated glomerular filtration rate.43 an observational cohort study was designed to monitor the postmarketing safety of rosuvastatin using prescription - event monitoring .
the cohort comprised 11,680 patients with a median period of treatment of 9.8 months , and rosuvastatin was found to be reasonably well tolerated .
myalgia was the most common reason for stopping rosuvastatin and the most frequently reported clinical event .
a 2.5-fold increase in the rate of abnormal liver function tests was observed for patients started on rosuvastatin 40 mg daily compared with those started on 10 mg daily , while no case of rhabdomyolysis was reported in this cohort.44
recent data have show multiple mechanisms for statins in reducing the risk of cardiovascular diseases . in particular ,
the hmg - coa reductase inhibitors reduce the incidence of ischemic heart disease , improve endothelial function , reduce left ventricular hypertrophy and adverse remodeling , slow atherosclerotic process , and reduce serum levels of pro - inflammatory cytokines.45 recently , the in vitro effects of statins on peripheral blood mononuclear cells and fibroblast - like synoviocytes were analyzed in 25 patients with rheumatoid arthritis and in 20 healthy blood donors . in fibroblast - like cells stimulated with atorvastatin
a significant downregulation of proinflammatory cytokine ( interleukin-6 ) and chemokine ( interleukin-8 ) expression was detected , showing a marked in vitro anti - inflammatory activity of atorvastatin in rheumatoid arthritis , including a systemic effect on a pathogenic cd4 + t cell population and a local effect on fibroblast - like synoviocytes.46 moreover , simvastatin and atorvastatin inhibited the crp - induced chemokine secretion , intercellular adhesion molecule ( icam-1 ) upregulation , and migration in human adherent monocytes , through the inhibition of hmg - coa reductase - extracellular signal - regulated kinase 1/2 pathway.47 the effect of rosuvastatin on plasma inflammation markers , endogenous nitric oxide synthase inhibitor levels , and reactive oxygen species generated by circulating leukocytes was evaluated in normotensive and in spontaneously hypertensive rats . in the experimental conditions ,
rosuvastatin lessened pro - inflammatory cytokines , increased interleukin-4 levels , and reduced reactive oxygen species production in circulating monocytes of spontaneously hypertensive rats.48 the effect of rosuvastatin on crp expression in stimulated human hepatocytes was also investigated .
experimental results showed a direct inhibitory effect of rosuvastatin on interleukin-6-induced expression of crp in human hepatoma cells and primary human hepatocytes .
statins may reduce c - reactive protein levels by inhibiting its production in the liver rather than by exerting systemic anti - inflammatory effects.49 the anti - inflammatory properties of rosuvastatin and other hmg - coa reductase inhibitors may have a great clinical utility in addition to their effects on atherogenic lipoproteins , and certainly require further laboratory and clinical in - depth examination .
the most appropriate algorithm for pharmacologic therapy in patients with hypocholesterolemia is summarized in figure 2 .
rosuvastatin could be considered a second - generation hmg - coa reductase inhibitor with unique pharmacokinetic and pharmacodynamic properties .
its chemical structure allows additional hmg - coa reductase enzyme - binding interactions that cause tighter binding , and in vitro studies have shown a substantial active transport into hepatocytes , with the lowest ic50 for sterol synthesis in liver cells . as a consequence ,
rosuvastatin at dosages ranging from 10 to 80 mg daily has demonstrated superior efficacy in lowering ldl cholesterol levels compared to milligram - equivalent dosages of atorvastatin , simvastatin , and pravastatin .
moreover , the lower lipophilicity of rosuvastatin is associated with poor penetration in extrahepatic tissues such as human umbilical vein endothelial cells and fibroblasts , with a lower risk of muscle toxicity .
rosuvastatin metabolism is characterized by a low potential for cytochrome p450 involvement and a lower risk of drug drug interactions with other drugs extensively metabolized by this hepatic pathway .
this statin was usually well tolerated and the safety profile was comparable to that of other statins currently available , and has shown significant anti - inflammatory effects in experimental conditions . in this context
Output:
| rosuvastatin represents the latest inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a ( hmg - coa ) reductase introduced in clinical practice for the treatment of hypercholesterolemia . in comparative trials , across dose
ranges this statin reduced low - density lipoprotein ( ldl ) cholesterol and total cholesterol significantly more than atorvastatin , simvastatin , and pravastatin , and triglycerides significantly more than simvastatin and pravastatin . in healthy subjects with normal ldl cholesterol and elevated c - reactive protein , rosuvastatin treatment significantly decreased the incidence of cardiovascular events .
its chemical and pharmacokinetic properties ( with a low lipophilicity and poor capacity to inhibit cytochrome p450 enzymes ) suggest a very limited penetration in extrahepatic tissues with a lower risk of muscle toxicity and unlike metabolically mediated drug drug interactions .
this article reviews the most recent data on the pharmacologic and clinical properties of rosuvastatin , in order to enable the correct use of this statin for the treatment of hypercholesterolemia . |
PubmedSumm8842 | ***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 chinese giant salamander ( a. davidianus ) belonging to one of the most primitive orders caudata , family cryptobranchidae , is the largest extant amphibian species in the world and found only in china , .
it was called babyfish mainly lives in chinese interior water area . being crown as a living fossil from 350 million years ago , so it is considered to be a valuable model in edible value , medical value , view value , science value and so on .
the chinese giant salamander is classified as critically endangered by the international union for conservation of nature and natural resources ( iucn ) red list of threatened species , is a class ii on the national list of protected animals in china .
nonetheless , only a limited number of transcriptomes from a. davidianus have been sequenced so far , , , , . meanwhile , the genetic information and gene sequences about the chinese giant salamander in public databases are also scanty .
here we performed de novo transcriptome assembly for a. davidianus by next - generation sequencing .
the obtained transcriptomic data will be useful for further studies of the genomes evolution of a. davidianus may have represented transition steps from aquatic to terrestrial life .
the healthy a. davidianus were obtained from a farm located in luan chuan ( henan province , china ) .
organ tissues including spleen , liver , muscle , kidney , skin , testis , gut and heart collected from three - year - old ( 3y ) male a. davidianus immediately after dissection , washed in sterile pbs .
animals tissues sample for rna extraction were snap - frozen in liquid nitrogen and stored at 80 c for further analysis .
all experiments were performed in strict accordance with the animal protection law of china , and were approved by the review committee for the use of animal subjects of henan university of science and technology .
the a. davidianus were pooled from 8 tissues ( spleen , liver , muscle , kidney , skin , testis , gut and heart ) and used for total rnas library construction .
rna - seq libraries were generated using the truseq rna - seq sample prep kit according to the manufacturer 's protocol ( illumina inc . , san diego , ca ) .
first and second strand cdna synthesis were followed by end - repair and adenosines were added to the 3ends .
adapters were ligated to the cdna and 200 25 bp fragments were gel purified and enriched by pcr .
the libraries were quantified using bioanalyzer 2100 ( agilent technologies , santa clara , ca ) and run on the illumina hiseq2500 platform ( illumina inc . ) .
a total of 15,398,997,600 bp were obtained from sequencing libraries . after cleaning and quality checks , the de novo assembly of all sequencing data using the trinity program .
it generated 158,103 all - transcripts with an average length of 810 bp and an n50 of 1659 bp ; and 132,912 all unigenes were achieved with an average length of 690 bp and an n50 of 1263 bp ( table 1 ) .
of these , 34,075 were > 1 kb and 21,855 > 1 kb , respectively .
we annotated the all 71,443 unigenes to nr , nt , cdd , swissprot , trembl , pfam , kegg , kog and go databases .
a microsatellite program misa was also used to identify and localize microsatellite motifs.table 1summary of a. davidianus assembly statistics.table 1indexa .
davidianus unigenesall number158,103132,912length 500 bp59,71542,327length 1000 bp34,07521,855n50 length1659 bp1263 bpn90 length285 bp262 bpmax length16,067 bp16,067 bpminor length201 bp201 bpall length128,175,999 bp91,713,308 bpmean length810 bp690 bp summary of a. davidianus assembly statistics .
the healthy a. davidianus were obtained from a farm located in luan chuan ( henan province , china ) .
organ tissues including spleen , liver , muscle , kidney , skin , testis , gut and heart collected from three - year - old ( 3y ) male a. davidianus immediately after dissection , washed in sterile pbs .
animals tissues sample for rna extraction were snap - frozen in liquid nitrogen and stored at 80 c for further analysis .
all experiments were performed in strict accordance with the animal protection law of china , and were approved by the review committee for the use of animal subjects of henan university of science and technology .
the a. davidianus were pooled from 8 tissues ( spleen , liver , muscle , kidney , skin , testis , gut and heart ) and used for total rnas library construction .
rna - seq libraries were generated using the truseq rna - seq sample prep kit according to the manufacturer 's protocol ( illumina inc .
first and second strand cdna synthesis were followed by end - repair and adenosines were added to the 3ends .
adapters were ligated to the cdna and 200 25 bp fragments were gel purified and enriched by pcr .
the libraries were quantified using bioanalyzer 2100 ( agilent technologies , santa clara , ca ) and run on the illumina hiseq2500 platform ( illumina inc . ) .
a total of 15,398,997,600 bp were obtained from sequencing libraries . after cleaning and quality checks , the de novo assembly of all sequencing data using the trinity program .
it generated 158,103 all - transcripts with an average length of 810 bp and an n50 of 1659 bp ; and 132,912 all unigenes were achieved with an average length of 690 bp and an n50 of 1263 bp ( table 1 ) . of these , 34,075 were > 1 kb and 21,855 > 1 kb , respectively .
we annotated the all 71,443 unigenes to nr , nt , cdd , swissprot , trembl , pfam , kegg , kog and go databases .
a microsatellite program misa was also used to identify and localize microsatellite motifs.table 1summary of a. davidianus assembly statistics.table 1indexa .
davidianus unigenesall number158,103132,912length 500 bp59,71542,327length 1000 bp34,07521,855n50 length1659 bp1263 bpn90 length285 bp262 bpmax length16,067 bp16,067 bpminor length201 bp201 bpall length128,175,999 bp91,713,308 bpmean length810 bp690 bp summary of a. davidianus assembly statistics .
Output:
| next - generation technologies for determination of genomics and transcriptomics composition have a wide range of applications .
andrias davidianus , has become an endangered amphibian species of salamander endemic in china .
however , there is a lack of the molecular information . in this study
, we obtained the rna - seq data from a pool of a. davidianus tissue including spleen , liver , muscle , kidney , skin , testis , gut and heart using illumina hiseq 2500 platform .
a total of 15,398,997,600 bp were obtained , corresponding to 102,659,984 raw reads .
a total of 102,659,984 reads were filtered after removing low - quality reads and trimming the adapter sequences .
the trinity program was used to de novo assemble 132,912 unigenes with an average length of 690 bp and n50 of 1263 bp .
unigenes were annotated through number of databases .
these transcriptomic data of a. davidianus should open the door to molecular evolution studies based on the entire transcriptome or targeted genes of interest to sequence . the raw data in this study can be available in ncbi sra database with accession number of srp099564 . |
PubmedSumm8843 | ***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: hibernoma is a very rare fatty tumor that originates from remaining brown fat after one 's fetal stage .
fetal brown tissue is known to be found from pelvic limb , scapular region , axilla , collum , abdominal etc . , and observed from a mass , gradually increasing in size .
so far , there was hardly a case of a malignant tumor , and it is established as a ground rule to treat such conditions by a total resection of affected parts .
the following study reports about hibernoma that developed from a patient with a history of neurilemmoma and discussion of literature .
a 49-year - old man presented with a mass on his back which had been growing for several months . a year ago , he had his previous visit with symptoms of a stiff shoulder on his right scapular region that had last for a few months . at that time
, he underwent chest x - ray and thoracic mri and discovered a paraspinal mass on the right side of third thoracic vertebra .
1 ) after being diagnosed as neurilemmoma from a biopsy , and was observed for external proceedings without any abnormal findings . when neurilemmoma was first discovered , there was a mass found from the right back , yet the size was small and mri showed no hints of invasive remark .
the patient visited our hospital for further workup after the size of the mass increased gradually .
clinically , the oval - shaped mass on the patient 's back was visible to the naked eye .
the size was approximately 1273 cm , and there were no other abnormal findings such as change of color , ecchymosis , fossula formation etc . during a physical exam , there was local heat sense found around the mass , but there were no tenderness , or any neurologic abnormal findings such as motor paralysis or hypoesthesia . for a detailed examination of the mass ,
a thoracic mri was performed . from the result , a mass with an approximate size of 1273 cm was found within the right paraspinal muscle , with a clear margin .
it was lobulated , and appeared to be stronglyheterogenous from both t1 , t2 myelogram . in the operating room
after the incision , the vertical center from the sixth cervical vertebra to the fourth thoracic vertebra was desquamated to the subcutaneous tissues by skin incision .
the mass was yellowish brown , located at the intersection where the connection part of cervical vertebrae and thoracic vertebrae , and surrounded by numerous blood vessels .
being careful not to injure any neurovascular structures around the mass , a resection of the entire mass was performed , followed by scrupulous hemostasis .
the mass was 13.66.02.2 cm in size , and appeared to be encapsulated with irregular borders of yellow and brown colors.there were no hemorrhage or necrosis , and the cross - section of the mass was observed to be multi - lobulated ( fig .
histologically , it was a typical hibernoma , where polygonal and multivacuolated adipose cells , along with abundant granular cytoplasm , were divided into minute reticulin fiber septum and arranged into a form of lobules ( fig .
4 ) thoracic tomography performed after the operation showed only a small amount of undercurrent body fluid , without other specific findings such as tumor remnants .
the operated area did not have peculiar symptoms or infection , and the patient is now outpatient observation after discharge without particular complications .
the following hibernoma was accompanied by the history of neurilemmoma , and since several studies in the past reported related chromosome abnormality to these two types of tumor , additional chromosome test was carried out for checkup ; the result appeared to be normal without any abnormal findings .
hibernoma is a benign tumor that originates from remnants of brown fat tissue . because its cells resembled the cells of hibernating animals , gery first used the term " hibernoma " in 1914 .
from then , hibernoma has been a rare type of tumor , reported by only around 160 cases globally , and 10 cases nationally2,4 ) .
it commonly develops in one 's adolescence or twenties , and slightly appears more in women than in men1 ) . due to the vascular activity of the mass , the skin that covers
when diagnosing hibernoma , mri , angiography , and needle biopsy play an important role : it shows lower signal than subcutaneous fat at t1 weighted mri , increased heterogenous signal in t2 weighted mri , noticeably increased build - up from gadolinium imaging1 ) , and a distinguished image from a typical fat mass on fat suppression imaging because of its uncontrolled fat .
mri can be helpful in checking the size of the mass , vessel conditions , or any permeated parts in terms of radiation beforethe operation .
however , it is hard to actually diagnose through radiation results alone , because other tumors including fibroma , neural fibroma , polymorphic lipoma , and positive lipoblastoma display the same findings as hibernoma . at lipoma and hibernoma 's mri
, lipoma shows equivalent signal strength while hibernoma 's signal is presented with dysplasia on the inner parts due to its vascular fiber structure .
hibernoma is not composed of one particular structure , but a mixture of traditional lipoma and hibernoma component , two complex tumors are integrated as one .
if the composition of brown fat is higher than the other , it displays lower signal in t1 image and higher signal in t2 image1,8 ) .
because hibernoma shows strengthened vessel structure due to the copious blood distribution , it can be easily distinguished from the mass that has low blood vessel distribution , including simple lipoma , fibroma , neural fibroma and etc , yet it still requires a specialized method to distinguished it from liposarcoma . knowing the vessel distributionaround the surrounding area can be helpful before planning resection7 ) .
although definite diagnosis before the operation is possible via needle biopsy in most cases , it is recommended to avoid needle biopsy if there are too many vessels formed around the mass , which may result in excessive bleeding9 ) . in this case , the mass was a painless tumor according to the physical exam , only with a slight heat sensation around the mass area .
mri findings showed clear difference from a simple lipoma , which has similar signal strength to subcutaneous fat tissue , and seen from heterogenous aspects and high vessel distribution , the tumor had to be distinguished from low grade liposarcoma and angiolipoma8 ) .
there was a case of malignant hibernoma in the past , but in most of cases , it can be treated sufficiently by resection alone , with few sequelae . however , in terms of abundant vessel distribution of hibernoma , sometimes it can be hard to remove the tumor entirely .
hematoma may result after operation , and resection alone can not totally eliminate the possibility of malignancy in terms of histology .
therefore , performing a total resection reduces the chance of the recurrence of tumor remnants . after the operation , extra procedure is required to prevent hemostasis .
if there is a nutrition vessel found , embolization of the vessel is required to minimize the bleeding that may occur during the actual operation4,5,6 ) . in 1994 , fredrik et al . presented seven case reports in total , including three previous case reports , about chromosome abnormalities occurring in hibernoma patients3 ) .
thus , it is generally thought that hibernoma patients have a structural abnormalityof chromosome 11 's long arm , including 11q13 .
also , numerous neurilemmoma are discovered in type 2 neurofibromatosis , caused by a problematic sex chromosome . for the following patient in this case
actual chromosome test results proved that this patient had a normal karyotype without unusual number of chromosomes or structural disorder .
this case report presents a case of hibernoma that occurred in a patient who previously had an operation for neurilemmoma .
it was a rare case of two tumors presenting at the same time , which is hard to find in previous literature .
after diagnosis , thepatient was treated with total resection of each tumor , and upon observation showed no post - op complications or sequelae .
one should keep in mind that if hibernoma is identified via imaging tests and biopsy in future cases , the tumor can be fully treated by total resection , and that excessive bleeding may occur due to surrounding blood vessels formed anew . such knowledge and guidelines will benefit in additional chromosome examination of a hibernoma patient , and diagnosis and additional data collection .
Output:
| hibernoma is a very rare , benign soft fatty tumor that derived from remnants of fetal brown tissue .
the following case of hibernoma break out occurred from a patient who had received surgical resection of neurilemmoma .
there has never been a case that reported about hibernoma accompanied by neurilemmoma .
it is anticipated that this experience would be helpful to other physicians who are interested in this rare type of tumor . |
PubmedSumm8844 | ***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: neurologic development during infancy and childhood depends on physical health and genetic
disposition , and progresses under the influence of the social context and environment1 . to perform activities in daily life , motor
process and
motor development is based on actions
that a person enacts when interacting with and moving task objects and themselves around a
task environment2 , 3 . among environmental factors , home and family
parental education , socioeconomic status , family size , and
interaction with siblings are main elements of a child s close environment4 .
fine motor development affects other areas
of development , and in particular , school performance in later childhood . despite their
importance ,
age - appropriate fine motor abilities are seldom questionedor evaluated in
pediatric clinics : often , physicians ask parents or caregivers about the child s language
and gross motor abilities , and observe social and gross motor functions during physical
examination .
developmental screening tests , despite their high reliability and interest
agreement , are used only by 60% of u.s .
physicians , a rate likely to be lower in many other
countries5 , 6 . to interpret any observations or test results
, health professionals
should be familiar with normal development and influencing factors , and recognize the nature
and extent of external influences so that delays due to medical and treatable conditions are
not erroneously attributed to adverse environmental factors .
therefore , the aim of this
study was to investigate the effect of socioeconomic and maternal factors on the fine motor
development of healthy children .
data were obtained from 2,038 healthy children aged 082 months , 999 boys ( 49% ) and 1,039
girls ( 51% ) in four age groups : 024 months ( 57% ) , 2540 months ( 21.1% ) , 4156 months
( 10.4% ) , and 5782 months ( 11.5% ) . children with a history of preterm delivery , birth weight
<
demographic data collected by using a standard questionnaire included the following : mother s age : stratified as 20 , 2125 , 2630 , 3139 , and 40 years ; mother s education : no education , up to 8 years schooling , 812 years schooling , and 12
years ; number of children at home ; area of residence within the district of ankara , indicating three different socioeconomic
groups ( seg ) as identified by the turkish institute of statistics : high , middle , and low
seg7 .
the developmental items commonly used in outpatient evaluation were retrieved from the
denver ii developmental screening test .
the denver ii version standardized for turkey was
applied by trained child development specialists or a pediatric neurologist .
the test
contains total 134 items in four developmental domains : personal - social , fine motor ,
language , and gross motor .
inter tester and intra tester reliability were assessed by testers
watching video recordings of 20 children at 4 weeks interval and scoring separately , and
were > 90% throughout the data collection . only children with normal test results
were
included in this study , and the mean age at which they passed each fine motor item was
calculated .
this study was conducted by ihsan doramaci childrens hospital and the department of
pediatric neurology of hacettepe university , ankara , turkey .
ethical approval was obtained
from the ethics committee of hacettepe university faculty of medicine .
the effect of demographic and maternal factors on fine motor items was assessed for each
age group .
the results of tests were expressed as the number of observations ( n ) , mean ( x )
standard deviation ( sd ) .
homogeneity ( levene s ) and normality ( shapiro wilk ) tests were used
to choose statistical methods .
groups with normal distribution and homogeneous variances
were assessed by using pearson s correlation coefficient . as parametric test assumptions
were not available for some variables , these were assessed by using spearman rho correlation
coefficient .
the demographic characteristics of children are shown in table 1table 1.demographic characteristics of childrenn%age ( months)0241,13657.0254042021.1415620810.4578222911.5gendergirl1,03951.0boy99949.0number of children at home199948.8271334.8320510.04556.4minmaxxsdage ( months)0.38224.920.5height ( cm)5013584.120.5weight ( kg)1.630.811.95.5head circumference ( cm)345846.44.3 , and those of mothers in table
2table 2.demographic characteristics of mothersn%age ( years)<201075.3212549624.6263068333.8313964632.04086 4.3educationno education371.818 years72236.0812 years76438.1>12 years48324.1socioeconomic grouplow51925.9middle80640.2high65132.5minmaxxsdage ( years)165328.85.5 . the number of boys and girls were similar .
most children were from middle seg
and most mothers educational level was high school ( 812 years ) .
the factors affecting fine motor items were gender , mother s age and education , seg , and
number of siblings .
girls acted at earlier ages in grasping a rattle ( table 3table 3.factors affecting fine motor skills at 024 months of agefollows past midlinegrasps a rattlefollows 180reaches for objectslooks for ayarntransfers blocks from hand to handtakes two blocksbangs two blocks togetherplaces cube in a cupscribbles spontaneouslydumps raisin from bottle demonstrateddumps raisin from bottle spontaneousgenderr0.090 * 0.0020.0040.0010.0290.0200.1220.0400.0020.0500.0390.036mother s ager0.0490.0660.0800.0290.0690.0230.225 * 0.134 * 0.090 * 0.151 * 0.092 * 0.071mother s educationr0.0370.0870.0480.0490.0810.0180.0240.0820.0150.0680.0030.094*socioeconomic groupr0.217 * 0.187 * 0.153 * 0.181 * 0.093 * 0.117 * 0.1550.0700.139 * 0.0250.153 * 0.176*number of children at homer0.0010.0270.0080.0070.0580.0310.0580.0440.0170.0020.0370.017significant p values are in bold .
* p<0.05 ) , copying a circle ( table
4table 4.factors affecting fine motor skills at 2540 monthsoldcopies a circledraws a man of three partschild s genderr0.209 * 0.027mother s ager0.156 * 0.123*mother s educationr0.179 * 0.123*socioeconomic statusr0.137 * 0.070number of children at homer0.0560.120*significant p values are in bold . *
p<0.05 ) , copying a square ( table
5table 5.factors affecting fine motor skills at 4156 months oldcopies a circlecopies a crosscopies a squarecopies a square demonstrateddraws a man of six partschild s genderr0.1310.1210.140 * 0.1220.240*mother s ager0.0430.0730.0680.0200.081mother s educationr0.0630.184 * 0.172 * 0.1330.105socioeconomic statusr0.206 * 0.226 * 0.1340.147 * 0.206*number of children at homer0.1360.0510.152 * 0.0840.102significant p values are in bold . * p<0.05table 6.factors affecting fine motor skills at 5782 months oldcopies circlecopies crosscopies squarecopies demonstrated squaredraws man and partschild s genderr0.0220.0100.0720.0190.231*mother s ager0.235 * 0.217 * 0.233 * 0.165 * 0.117mother s educationr0.200 * 0.334 * 0.350 * 0.309 * 0.309socioeconomic statusr0.0570.1260.0850.0380.232*number of children at homer0.1250.0340.0080.0120.054significant p values are in bold . * p<0.05 ) , and drawing a man of six parts ( tables
5 and 6 ) .
. * p<0.05 significant p values are in bold . * p<0.05 significant p values are in bold . * p<0.05 significant p values are in bold . * p<0.05 the mother s age was influential on several items in all age groups , most markedly in older
children ( > 57 months ) ( tables 36 ) . as the mother s age increased , the fine motor
skills of the children were acquired earlier . the mother s educational level was associated
with earlier acquisition of fine motor items , mostly in children older than 24 months ( tables 36 ) .
seg was positively correlated with fine motor skills before 56 months , most
markedly in the first 6 months of life ( tables
36 ) .
the number of children at home
was not effective ; however , it showed a negative correlation with one fine motor skill
between 41 and 56 months : copying a square ( table
5 ) .
fine motor functions carry great biological importance for humans , as reflected by the
large cortical representation of the hands in the cerebral cortex .
fine motor skills
correlate with cognitive test results , partly because of their part in psychometric testing
and partly because they allow the child to experiment and learn about the environment9 , 10 .
on the other hand , they are less well recognized by parents who usually are more aware of
gross motor milestones and more often concerned with delays in gross motor skills11 .
factors likely to affect fine motor
skills must be known to plan interventions in children at a risk for delayed development .
the present study analyzed fine motor development with respect to environmental factors in
the population , namely , mother s age and education , socioeconomic status , and number of
children in the household . the overall effect of gender was modest , with girls starting earlier in certain fine motor
skills of various ages .
similarly , nordberg et al.12 found that girls had higher scores in eye - hand coordination on
griffiths development scales at 4 years of age .
flatters et al.13 reported that girls were more likely to have superior
manual control in aiming and tracing tasks at school age .
other studies also showed girls
out performing boys on manual dexterity , especially in pencil- and paper - based skills14,15,16 .
it is plausible that fine motor
maturationis completed at a later age in boys .
the quality of the family environment has been associated with the intellectual and motor
development of the family members16 .
seg
affects the home environment , opportunities for educational and play activities , and
therefore gross and fine motor performance8 .
certain studies observed the influence of social class on a child s
development after 1 year17 and at 3 and 5
years of age18 , while others demonstrated
the effect of cultural factors , home environment , and seg on fine motor development in
9-month - old children and during the first 18 months of life10 , 19 .
children of low seg tend to show delays on
several motor development assessment batteries , although certain reports point to earlier
achievement of gross motor milestones than in children from higher seg20,21,22 .
perceptual - motor problems of children with lower
environmental resources may be related to poor nutrition , poor health care , or lack of
stimulation and opportunities for experience .
the effect of maternal education may involve higher intellectual level , positive
psychology , or higher income resulting in increased opportunities for the child .
jackson et
al.23 observed fewer behavioral
problems and improved preschool motor development in children of single - parent families with
higher maternal education .
higher social class and maternal education was found to be
related to psychomotor performance in children > 1 year of age17 , 23 and low
maternal education , after the age of 2 or 3 years24 ,
25 .
our findings are consistent with
these studies : the positive effect of the mother s education was observed mostly in children
> 24 months of age .
the mother s age had a modest effect from late infancy through
childhood , which is less marked than the mother s education .
older siblings may serve as models for fine motor tasks and provide encouragement to their
younger siblings .
our
study did not show a considerable influence of the number of children at home : if at all ,
the correlation with fine motor skills was negative .
dilution of parental resources or fewer
opportunities for the young child s fine motor experience26 . alvik27 also
demonstrated the presence of an older sibling to be associated with reduced scores in the
ages and stages questionnaire , a parent - completed screening instrument for children < 5.5
years old .
our study is based on items used in clinics for developmental screening because our aim was
to offer recommendations for pediatric outpatient and well - baby clinics caring for children
on a day - to - day basis .
fine motor problems are an important part of developmental
coordination disorder ( dcd ) , a term defining a neuromotor disability where motor
difficulties ( lower speed , lower accuracy ) interfere with daily life or school activities .
motor control and muscle strength impairments are the primary reasons for motor behavior
disorders28 .
dcd affects about 5% of
school - age children29 . whether the
diagnosis of dcd can be predicted by screening for early fine motor skills , and whether the
severity of dcd may be reduced by means of intervention on influencing factors constitute
interesting areas to explore30.in
addition
, attention - deficit hyperactivity disorder ( adhd ) is a common neurodevelopmental
disorder that affects 37% of preschool and school - aged children .
it has been suggested that
the deficits of adhd children in memory performance , and the inability to allocate
sufficient attention to postural control may contribute to the trend of further
deteriorating fine motor skills with postural balance31 , 32 .
lee et al.33suggested that complex interactions between
multiple risk factors such as physical fitness levels of children are responsible for
adhd . in conclusion ,
sex and environmental and maternal factors appear influential in the
development of fine motor skills in early life .
these first years are a period of intense
biological maturation likely to shape the architecture of the central nervous system .
negative environmental factors increase the developmental risk brought by adverse medical
conditions such as prematurity34 . on the
other hand
, those children at risk may benefit from reinforcement of positive factors :
interventions may overcome the effect of adverse perinatal events35 , 36 .
the findings
of our study may help the planning of interventions , such as providing additional preschool
education for children from disadvantaged economic and maternal education groups , and can
also contribute to the planning of research projects with matching intervention and control
groups .
Output:
| [ purpose ] the aim of this study was to investigate the influence of gender and family
factors on performance in the fine motor domain of the denver ii developmental screening
test . [ subjects and methods ] data were obtained from 2038 healthy children , 999 boys ( 49% )
and 1039 girls ( 51% ) in four age groups : 024 months ( 57% ) , 2540 months ( 21.1% ) , 4156
months ( 10.4% ) , and 5782 months ( 11.5% ) .
[ results ] female gender , higher maternal age ,
especially in children older than 24 months , and higher maternal education were associated
with earlier accomplishment of fine motor items .
higher socioeconomic status was
correlated with fine motor skills more noticeably at young ages .
[ conclusion ] the results
of this study support the role of environmental factors in the interpretation of fine
motor test results and point to target groups for intervention , such as infants in the low
socioeconomic group and preschool children of less educated mothers .
studies in different
populations may reveal particular patterns that affect child development . |
PubmedSumm8845 | ***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 behet 's disease , coronary ostial stenosis following a bentall procedure is rarely reported but can be fatal.1 ) among chronic total occlusion ( cto ) lesions , the ostial location is especially difficult to treat with percutaneous coronary intervention ( pci ) due to the inability to engage the guiding catheter into the coronary artery .
however a retrograde approach , has been recently introduced , which may increase the rate of success of pci.2 ) here we report a case of retrograde recanalization of a chronically occluded right coronary artery ( rca ) ostium after a repeated bentall procedure in a patient with behet 's disease .
a 41-year - old man with behet 's disease was referred to our outpatient clinic for treatment of cto of the rca ostium .
he did not have any risk factors such as hypertension , diabetes , hyperlipidemia , and smoking .
he had undergone a bentall procedure for severe aortic regurgitation 10 years ago , and required reoperation on the aortic root replacement with prima plus 23 mm ( edwards lifesciences , irvine , ca , usa ) and an ascending aortic graft insertion with intergard 24 mm ( maquet , wayne , nj , usa ) due to infective endocarditis 7 months prior .
two months earlier , he experienced rapidly worsening exertional angina and was evaluated at another hospital .
emergent coronary angiography showed a significant tubular lesion of the left main coronary artery ( lmca ) ostium ( fig .
stent implantation in the lmca was successfully performed , but catheter engagement into the rca failed due to cto of the rca ostium . on admission , electrocardiography revealed abnormal q waves over the inferior leads ( fig .
coronary angiography showed a patent lmca stent and no disease in the left sided vasculature ; however , the rca ostium was totally occluded and collateral flow ( grade 3 ) was supplied by the left coronary artery ( fig .
we first attempted to use a 6 fr jr 4 guiding catheter ( cordis , miami , fl , usa ) for an antegrade approach , but were unable to penetrate into the rca ostium .
subsequently , a 5 fr xb 3.5 guiding catheter ( cordis , miami , fl , usa ) was used in a retrograde approach via the right radial artery .
a superselective tip injection of contrast using a finecross microcatheter ( terumo , tokyo , japan ) was performed , and a channel from the lcx to the posterolateral branch of the rca was confirmed .
a runthrough ns ( terumo , tokyo , japan ) with a microcatheter was retrogradely advanced into the distal rca , and further advanced into the distal end of the occlusion ( fig .
we then exchanged the runthrough ns guidewire for a fielder - fc 300 cm guidewire ( asahi intecc , aichi , japan ) , which was subsequently snared into the ascending aorta ( fig .
3d ) and pulled out of the sheath placed in the right femoral artery using a multi - snare ( pfm medical , ca , usa ) ( fig .
the lesion was pre - dilated using a 2.020 mm lacrosse balloon ( goodman , nagoya , japan ) at 18 atmospheres . a 3.028 mm nobori stent ( terumo , tokyo , japan )
the medications of the previous hospital were maintained including colchicine 0.6 mg qd , azathioprine 50 mg qd , aspirin 100 mg qd , clopidogrel 75 mg qd , ramipril 5 mg qd , bisoprolol 5 mg qd , and atorvastatin 80 mg qd .
aneurysmal dilatations of the sinus of valsalva and ascending aorta are more frequent in patients with behet 's disease than in healthy subjects.3 ) the bentall procedure for aortic root and valve replacement with coronary reimplantation is considered the gold standard for treatment of combined valve and ascending aortic pathology,4 ) with coronary ostial stenosis following this procedure occurring in less than 2% of patients.5 ) this complication may be related to an imperfect suture technique , or to the direct instrumentation of the coronary ostium itself . in these cases ,
signs of ischemia typically present early on during hospitalization.6 ) in recent reports , delayed ostial coronary stenosis occurring within months of the operation might be due to inflammatory and/or proliferative responses of the coronary wall to tissue adhesives used during the operation.7)8 ) coronary artery stenosis in aortitis syndrome with the stenosis occurred two years after the operation has been reported.9 ) in our case , signs and symptoms of stenosis were observed 5 months after surgery .
thus , the time lapse between the procedure and the presentation of ostial occlusion implies a mechanism that is related to the tissue adhesion rather than the suture technique or behet 's disease itself .
our patient presented with acute myocardial infarction and underwent successful pci of the lmca ostium .
it was not possible to perform this procedure using an antegrade approach to the cto in the rca ostium .
it has been reported that successful revascularization of cto leads to significantly reduced mortality rates and long term risk of adverse cardiac events.10)11 ) retrograde cto recanalization has recently become an essential alternative to the classical antegrade approach . when performed by an experienced clinician , the retrograde technique has a high success rate with a low complication profile , despite frequent utilization in the most anatomically and clinically complex patients.2 ) in retrograde cto recanalization , analysis of all potential collateral channels is critical .
the epicardial collaterals are preferred less than septal collaterals , because rupture could lead to tamponade and procedural ischemia or infarction may occur.2 ) however , we used the epicardial collateral because no septal collaterals are suitable .
in addition , because the occlusion was located at the ostium of the coronary artery , there was no space to engage the antegrade guiding catheter .
in such situation , a pure retrograde wire crossing is the only way to transverse the occlusion .
the retrograde wire was able to advance to the false lumen and advancing more caused the dissection .
if available for antegrade approach , the use of intravascular ultrasound through the antegrade system may prevent the engagement to the false lumen.12 ) however , if not available for antegrade wiring , we have no choice but to advance the retrograde wire carefully by an experienced operator .
after crossing cto lesion , either pushing the retrograde guidewire into the guiding catheter or trapping it at the contralateral sheet may be used for wire externalization.13 ) through this retrograde approach , we were able to snare the 300 cm guidewire into the ascending aorta , and then ultimately pull it out of the proximal end of the femoral sheath . in summary , we propose that a retrograde approach for pci can be useful in the treatment of cto of the coronary ostium as a consequence of the bentall procedure in patients with behet 's disease .
Output:
| we describe a case of chronic total occlusion of the right coronary artery ostium 5 months after a repeated bentall procedure in a patient with behet 's disease . in this patient ,
an antegrade approach to delivering the guidewire during percutaneous coronary intervention was not successful .
coronary angiography revealed the existence of collateral blood supply from the left coronary artery . using a retrograde approach ,
a guidewire was successfully advanced from the distal left circumflex artery through the collateral vessel and into the posterolateral branch of the right coronary artery . after the guidewire crossed over the occluded right coronary artery ostium and was snared into the ascending aorta , antegrade access for balloon and stent delivery succeeded . |
PubmedSumm8846 | ***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 71-year - old woman presented with a swelling on her left upper eyelid in 2009
. she also had a small mass on her right upper eyelid that been present for the previous 3 years .
she had a history of breast cancer occurring in 1991 , which was treated successfully without recurrence for 18 years .
there was a significant family history of cancer ; two of her brothers had also been diagnosed with cancers . surgical excision and
skin biopsy identified a sebaceous carcinoma in her right eyelid and a morphea - like basal cell carcinoma of her left eyelid ( fig .
immunohistochemical analysis was done using anti - mutl homolog ( mlh ) 1 ( mouse monoclonal ; 1:50 ; bd pharmingen , san diego , ca , usa ) and anti - msh2 ( mouse monoclonal ; 1:40 ; calbiochem , san diego , ca , usa ) .
a mlh1 gene product was present in both tumors , but no msh2 genes were found in either tumor ( fig .
colon cancer tissue obtained from another patient was used as a positive control specimen , with the patient 's permission .
mts is a rare autosomal dominant genodermatosis with variable expressivity , and is regarded as a variant of lynch syndrome .
inherited colorectal cancer syndromes such as familial adenomatous polyposis , muty human homologue ( myh)-associated polyposis , and lynch syndrome / hereditary nonpolyposis colon cancer are less common but account for as much as 5% of colorectal cancer cases .
a diagnosis is made based on the presence of at least one sebaceous neoplasm associated with visceral malignancy , or alternatively , multiple keratoacanthomas with visceral malignancies and a family history of mts .
fifty - six percent of the skin lesions in mts develop after diagnosis of the first internal malignant disease , 6% appear concomitantly , and 22% occur as the first tumor of the syndrome .
. other types of cancer , such as breast cancer , are uncommon ( 4% ) .
the present case had a history of breast cancer , and it was possible that her eyelid neoplasms resulted from breast cancer metastasis .
however , this is unlikely because the patient 's breast cancer did not recur for a period of 18 years and 2 different types of neoplasms were found in the eyelids .
more importantly , immunohistochemical staining for hmsh2 and hmlh1 was consistent with a diagnosis of mts , in addition to clinical findings that met the clinical criteria for mts .
considering these results , it would be safe to speculate that the case belonged to a spectrum of mts conditions .
sebaceous gland tumors are much more common in asians than in caucasians , with a reported frequency of 10.2% to 32.7% of malignant tumors in eastern asians in comparison to 0% to 3.2% in the us and europe
. indeed , sebaceous gland tumors in caucasians are so rare that their presence is considered a marker for mts , and lead to a search for an occult malignancy .
the incidence of mts in the asian population is not clear , but it is likely to be underestimated . because sebaceous gland neoplasms of the eyelid are so common in asia , and most of them are successfully treated by local excision , their presence is not regarded as a specific event .
even if another visceral malignancy occurred in the same patient after a long interval , it would often be diagnosed as a coincidence of independent tumors .
in fact , the diagnosis would not have been easy without the help of immunohistochemical analysis for mlh1 and msh2 , which were used in the present case .
many mts patients demonstrate germ - line mutations in genes encoding dna mmr proteins such as mlh1 or msh2 and , less commonly , msh6 .
these proteins function to detect and repair errors in base pairing that occur during dna replication , especially in regions of dna characterized by repetitive mono- or dinucleotide repeats , termed microsatellites .
mmr protein mutations , when paired with a second somatic mutational hit of the remaining functional allele , leads to increased susceptibility to tumor formation .
immunohistochemistry assessing msh2 , mlh1 , and msh6 activity , and microsatellite instability ( msi ) analysis are currently the two main screening tests for mts .
mmr genes encode proteins that recognize and remove improper genomic insertions and deletions and nucleotide mismatches that arise during dna replication and recombination .
collectively , these genes maintain the integrity of the genome and prevent mutations from accumulating . in mts ,
individuals are born with one defective copy of an mmr gene and acquire a second somatic mutation in the other allele during their lifetimes .
the first mutations identified in mts involved the mmr genes msh2 and mlh1 , the same genes known to cause lynch syndrome .
recent advances in immunohistochemistry and msi analysis have made the diagnosis of mts much easier and more reliable .
msi analyses and reviews of family history should guide cancer surveillance options for patients and their extended families after immunohistochemistry .
patients with visceral malignant disease as part of mts tend to survive longer than those with visceral malignant diseases outside of the syndrome , and even metastatic disease can respond to aggressive surgical treatment
. the role of ophthalmologists is much larger than before because 22% of skin lesions in mts develop prior to the diagnosis of the first internal malignant disease .
generally , sebaceous skin tumors characteristic of mts can be regarded as premonitory physical characteristics for an underlying cancer predisposition . at present ,
screening studies for msh1 and mlh2 on eyelid tumors would give us important information about future treatment and follow - up programs for patients .
Output:
| we report a case of muir - torre syndrome ( mts ) with a very rare combination of cancers , involving bilateral eyelid cancers and breast cancer .
a 71-year - old female with a history of breast cancer from 18 years prior presented with bilateral eyelid tumors .
one of her siblings had lung cancer , and another had pancreatic cancer .
she underwent excisional biopsy of the eyelid tumors and histopathology revealed sebaceous carcinoma of the right eyelid and basal cell carcinoma of the left .
she was diagnosed with mts : a skin cancer associated with visceral malignancy .
immunohistochemical tests for muts homolog 2 showed a lack of expression in both eyelid carcinomas . |
PubmedSumm8847 | ***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 4-year - old male neutered domestic shorthair cat was referred for investigation of jaundice .
sequential serum biochemistry demonstrated increasing plasma bilirubin concentrations ; abdominal ultrasonography revealed ongoing pancreatitis and apparent extrahepatic obstruction of the common bile duct .
exploratory laparotomy identified constriction of the common bile duct with foreign material ( cat hair ) .
postsurgical quality of life is excellent with chronic treatment of tylosin , omeprazole and ursodeoxycholic acid .
to our knowledge , this is the first reported case of extrahepatic biliary duct obstruction resulting from the intra - abdominal migration of a foreign body , in this case , hair shafts .
the mechanism by which this occurred was likely a combination of physical constriction by the hair shafts and subsequent foreign body reaction surrounding this .
a 4-year - old male neutered domestic shorthair cat , weighing 5.7 kg was referred for investigation and management of jaundice .
one week prior to presentation at eastside veterinary emergency and specialists , the cat presented to the referring veterinarian when the owner discovered a 23 cm skin laceration adjacent to the xyphoid process of the sternum ( cause unknown ) .
the cat was allowed to roam freely outdoors ; it had been involved in territorial aggression in the past .
the laceration was closed and the cat treated with amoxicillin - clavulanate ( amoxyclav ; apex laboratories ) 17.5 mg / kg , po , q12h for 1 week .
the cat s mucous membranes were jaundiced and there was abdominal discomfort noted on palpation .
marked bruising was identified on the right abdominal wall at the level of the caudal rib margins .
immune - mediated haemolysis ( secondary to tissue damage or medications ) and traumatic pancreatitis leading to extrahepatic biliary duct obstruction ( ehbdo ) were considered the most likely differential diagnoses .
serum biochemistry , haematology and an abdominal ultrasound were undertaken to help differentiate between these causes .
the results of serum biochemistry analysis ( idexx catalyst dx chemistry analyser ) are presented in table 1 .
abnormalities included a marked elevation in alanine transaminase ( alt ) , a moderate hyperbilirubinaemia and mild elevations in alkaline phosphatase and -glutamyl transpeptidase ( ggt ) .
haematology results were within the reference intervals ( ri ; idexx procyte dx haematology analyser ) ; specifically , the haematocrit was 32.1% ( ri 30.352.3% ) .
citrated prothrombin time was 18 s ( coag dx analyzer ) and within the ri ( 1222 s ) .
feline immunodeficiency virus and feline leukaemia virus serology was negative ( idexx snap fiv and felv combo test ) .
urine concentration was adequate ( > 1.050 ) and bilirubin crystalluria the only abnormality noted on urine sediment examination .
serial serum biochemistry observations ri = reference interval ; alp = alkaline phosphatase ; alt = alanine transaminase ; ggt = -glutamyl transpeptidase abdominal ultrasound identified a hypoechoic pancreas surrounded by hyperechoic mesentery . the gall bladder was moderately distended , as was the proximal common bile duct ( figure 1 ) .
ultrasound image of the liver , gall bladder and common bile duct ( 4.3 mm ) .
sonographically , a diagnosis of extrahepatic biliary duct obstruction can be made in cats when the bile duct diameter exceeds 5 mm supportive treatment included intravenous fluids ( 5 ml / kg / h , hartmann s compound sodium lactate ; baxter viaflex ) , maropitant citrate ( 1.0 mg / kg sc q24h , cerenia ; zoetis ) , buprenorphine ( 10 g / kg sc q8h , temgesic ; rackitt benckiser ) , mirtazapine ( 0.7 mg / kg po q3d , axit ; alphapharm ) and amoxicillin clavulanate ( 17.5 mg / kg po q12h ) was continued .
initial improvement in demeanour in the first 24 h was attributed to correction of dehydration , as anorexia , vomiting and abdominal pain persisted .
clavulanate was substituted for a combination of clindamycin ( 8.7 mg / kg po q12h , clinacin ; intervet ) and marbofloxacin ( 4.4 mg / kg po q24h , zeniquin ; zoetis ) .
a lincosamide and fluoroquinolone were chosen based on the high frequency of escherichia coli and/or streptococcus species ( 35% ) identified using fluorescence in situ hybridisation from pancreatic sections of confirmed cases of pancreatitis in one report .
prednisolone ( 0.4 mg / kg , po , q24h , microlone ; mavlab ) was administered to reduce pancreatic inflammation . by the following day , there was marked improvement , the cat was eating well and appeared comfortable .
it did well for 7 days at which time its appetite reduced rapidly and the owner noticed that it was icteric .
repeat abdominal ultrasound revealed marked dilation of the gall bladder and distension of the entire common bile duct ( figure 2 ) .
a small amount of free fluid was present around the common bile duct ( figure 3 ) .
distension of the common bile duct through to the duodenum ultrasound image shows free fluid around the common bile duct .
free fluid in this region raised a concern of biliary rupture the dilation of the common bile duct suggested biliary obstruction .
owing to the cat s rapidly deteriorating clinical state , an exploratory laparotomy was performed . during surgical exploration of the abdomen
an omental adhesion was identified that surrounded the common bile duct at the level of the duodenal papilla and right pancreatic lobe .
this material was a mass of what appeared to be the cat s own fur .
the hair ( a solid 3 mm wide band of individual hair shafts ) that wrapped around the common bile duct was also removed until the common bile duct could be completely visualised .
in - house microscopy of the peritoneal fluid showed a scant number of non - degenerative neutrophils .
no bacteria were identified ( diff - quik ) . comparative glucose concentration between the free peritoneal fluid and peripheral venous blood ( 9.0 mmol / l and 6.0 mmol / l , respectively ) made septic peritonitis unlikely .
therefore , the non - septic peritoneal effusion was most likely the result of acute and ongoing pancreatic inflammation and/or inflammation secondary to a foreign body .
this was consistent with the gross findings at exploratory laparotomy specifically , no gastrointestinal perforation was identified .
neoplasm such as teratoma was considered unlikely to be the origin of these hair shafts given that the hair shafts did not appear to germinate from the bile duct itself .
patency of the common bile duct was evaluated by making a 2.5 cm anti - mesenteric incision opposite the duodenal papilla .
a 22 g intravenous catheter was introduced into the duodenal papilla but could not be fed more than 2 cm .
a 5 mm incision into the gall bladder was made and a 5 fr catheter was passed from the gall bladder into the common bile duct but would not pass the obstructed area . to establish biliary patency a cholecystoduodenostomy was performed .
the gall bladder was loosened from the hepatic fossa with blunt dissection . a 2.5 cm incision in the distal end of the gall bladder corresponding to the incision in the duodenum opposite the duodenal papilla was made .
the two mucosal surfaces were approximated and sutured in the form of a stoma with continuous 4/0 polydioxanone ( pds ; ethicon johnson & johnson ) .
the linea alba , subcutaneous tissue and skin was closed in a routine manner . a 14 fr oesophagostomy feeding tube ( canine esophagostomy feeding tube ; mila international )
a diagnosis of ehbdo secondary to migration and entrapment of the common bile duct by autologous hair shafts was made .
it was thought that the hair shafts induced adhesions ( secondary to a foreign body reaction ) , which contributed to biliary duct obstruction .
it was presumed that hair shafts were introduced into the abdomen via the penetrating wound present at the time of presentation to the referring veterinarian .
postsurgical recovery was rapid ; serum bilirubin had normalised and alt concentration had decreased significantly by day 10 ( table 1 ) .
resting energy requirement was calculated at 258 kcal per 24 h , and this was achieved by gradually increasing tube feeding volumes over a 4 day period to reach 290 kcal of hill s a / d .
the cat was discharged 5 days postsurgery on clindamycin ( 8.7 mg / kg po q12h ) , marbofloxacin ( 2.2 mg / kg po q24h ) , transdermal fentanyl ( 12.5 g , duragesic ; janssen - cilag ) , mirtazapine ( 0.7 mg / kg po every 3 days as required ) , ondansetron ( 0.2 mg / kg , po , q12h for 10 days , zofran wafer ; aspen pharmacare ) , omeprazole ( 1.8 mg / kg po q24h , losec ; astrazeneca ) indefinitely and metoclopramide ( 0.4 mg / kg po q68h for 7 days , metomide ; ceva ) .
tylosin ( 13.2 mg / kg , po , q12h , bova compounding ) was introduced to the cat s treatment regimen .
tylosin s beneficial mechanism of action in enteric disease remains unknown . despite this , the rationale of its use in this case is that , anecdotally , tylosin may help modify enteric bacterial populations favourably to reduce the likelihood of ascending bacterial cholangitis , a common complication of cholecystoduodenostomy in cats .
two months following initial presentation the patient was eating well and had gained weight but was having frequent episodes of vomiting .
bilirubin was within ri and alt and ggt were only slightly elevated ( table 1 ) .
ursodeoxycholic acid ( 8.7 mg / kg po q24h ) was added to the treatment regimen ( omeprazole and tylosin ) to improve bile flow and reduce cholesterol saturation of bile . following this ,
two years following initial presentation ( time of writing ) the owners reported occasional vomiting ( every 12 weeks ) ; however , this was roughly the frequency of vomiting prior to initial presentation .
to our knowledge , this is the first suspected case of ehbdo as a result of migration and entrapment of the common bile duct by a foreign body in a cat .
other reported causes of ehbdo in cats include inflammatory disease , specifically cholecystitis , cholangiohepatitis , pancreatitis , cholelithiasis , hepatic lipidosis and inflammatory bowel disease .
neoplastic causes of ehbdo are also reported , specifically carcinoma of the biliary tract , pancreatic carcinoma , unclassified biliary tract carcinoma , squamous cell carcinoma involving the duodenal papilla , and duodenal lymphoma . finally , a duodenal foreign body , biliary foreign body and platynosomum concinnum are also reported causes of ehbdo in cats . a teratoma arising from the common bile duct has rarely been documented in humans . in humans ,
lesions have been described as a lobulated polypoid mass , which was not evident in this case ; hence , we feel that this differential is unlikely .
another suggestion is that this could represent a form of feline eosinophilic gastrointestinal sclerosing fibroplasia ( fgesf ) due to the foreign body leading to an overzealous fibrous tissue reaction causing biliary duct obstruction .
cases of fgesf often have hyperglobulinaemia or hypereosinophilia , which was not documented at any stage in this case .
it is our opinion that the obstruction was due to a combination of physical constriction from the hair shafts and obstructive adhesions ( induced by a foreign body reaction to the hair shafts )
. we can not exclude concurrent extra and intraluminal inflammation such as cholangitis as a cause of biliary obstruction as cholecystocentesis or hepatic , pancreatic or gastrointestinal biopsies were not collected for culture and susceptibility and histopathological evaluation .
we speculate that this was because inflammation of the surrounding pancreatic and omental tissue made it difficult to delineate these structures .
given the history of recent trauma resulting in a deep laceration , it is likely the abdominal cavity was penetrated and this was not appreciated during the initial surgical exploration .
foreign body migration distant from the original penetration site is well recognised in dogs and cats .
unusual locations of migration are reported , for example in one case report , a grass awn migrated from the neck to the heart in cat leading to fatal endocarditis and myocarditis .
it is therefore not unreasonable to suggest that hair shafts could have migrated from the original laceration site to the common bile duct in this case .
another consideration is that hair was ingested and perforated the gastrointestinal tract ; however , there was no evidence of gastrointestinal damage at exploratory laparotomy .
six month survival in cats after biliary diversion is reportedly poor , ranging from 2767% .
only three cases had biliary diversion surgery performed in the study where 67% ( 2/3 cases ) long - term survival was reported .
long - term complications include reflux of bile into the stomach ( alkaline gastritis ) , cholangitis and stricture or leakage of the anastomosis .
alkaline reactive gastritis is a clinical entity that has been linked to duodenogastric reflux of bile constituents after cholecystectomy in humans . in humans
it is managed with proton pump inhibitors ; hence , omeprazole was used indefinitely in this case .
it is thought that this may be related to stricture at the anastomosis site , resulting in inadequate drainage of the biliary system .
based on previous recommendations to prevent stricture formation , a large ( 2.5 cm ) biliary intestinal anastomosis was made at the time of surgery and mucosal surfaces were carefully approximated and sutured in the form of a stoma . additionally ,
because recurrent biliary tract infection secondary to enterobiliary reflux has been reported as a complication of biliary diversion surgery , tylosin was administered indefinitely in the hope of favouring the growth of a desirable microflora in the gastrointestinal tract .
to our knowledge , this is the first reported case of intra - abdominal migration of foreign matter ( specifically hair shafts ) contributing to ehbdo through physical constriction and a secondary foreign body reaction causing adhesions surrounding this .
this should be included in the differential diagnosis of a cat with jaundice , particularly following abdominal trauma .
in addition , lacerations over the abdominal cavity need to be explored carefully for evidence of penetration . if present , the abdomen should be explored and flushed thoroughly to prevent complications .
Output:
| case summarya 4-year - old male neutered domestic shorthair cat was referred for investigation of jaundice .
the cat had a recent history of a skin laceration repair following trauma .
sequential serum biochemistry demonstrated increasing plasma bilirubin concentrations ; abdominal ultrasonography revealed ongoing pancreatitis and apparent extrahepatic obstruction of the common bile duct .
exploratory laparotomy identified constriction of the common bile duct with foreign material ( cat hair ) .
the constricting band of hair was removed surgically ; cholecystoduodenostomy was performed .
postsurgical quality of life is excellent with chronic treatment of tylosin , omeprazole and ursodeoxycholic acid.relevance and novel informationto our knowledge , this is the first reported case of extrahepatic biliary duct obstruction resulting from the intra - abdominal migration of a foreign body , in this case , hair shafts .
the mechanism by which this occurred was likely a combination of physical constriction by the hair shafts and subsequent foreign body reaction surrounding this .
this should be included in the differential diagnosis of a cat with jaundice . |
PubmedSumm8848 | ***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: posterior teeth , particularly maxillary premolars , have an anatomic shape that makes them more likely to fracture the cusps under occlusal load14 .
additionally , these teeth when treated endodontically can be easily fractured because of pulp chamber roof removal19,20 , mainly when the marginal ridge is thin or totally removed28 .
several studies have emphasized the importance of maintaining dental structure to preserve the strength of remaining tooth .
generally , the wider the involvement by caries or cavity preparation , the weaker the tooth19,20 .
other authors have suggested an alternative cusp coverage with amalgam to restore the weakened teeth , with satisfactory long - term results20 .
this alternative therapy is economically more accessible , easy to perform and has no cement line as conventional cast restorations , which are more costly and time consuming .
it has been stated that remaining tooth structure restored with adhesive technology presents higher fracture resistance29 . however , the hypothesis that direct cusp coverage is still necessary even when adhesive procedures are used in large cavities must be confirmed .
this study compared the fracture resistance of weakened human premolars restored with direct condensable resin composite with and without cusp coverage .
the freshly extracted teeth were cleaned , stored in tymol solution at 0.1% and used within 1 month after extraction .
every tooth was examined under a 10x magnification and those presenting visible enamel cracks or fractures were rejected .
the selected teeth were embedded in cold - cure plastic resin in metal rings1 , with the resin limit at 1.0 mm below the cementoenamel junction .
the specimens were divided into three groups with 10 teeth each : group a ( control ) included sound teeth , group b included restored teeth without cusp reduction and group c had teeth restored with cusp coverage .
cavity preparation was initiated by occlusal approach with a spherical diamond bur towards the pulp chamber .
removal of the pulp chamber roof and reduction of the mesial and distal walls were done with a cylindrical diamond bur , creating a 4-mm - deep slit cavity design .
the buccolingual isthmus was approximately half the intercuspal distance , as well as the mesial and distal boxes .
teeth of group c received a further 2.0-mm - high reduction of both buccal and palatal cusps ( figure 1 ) . in those teeth , before cavity preparation and cusp reduction , a silicone matrix was prepared by taking an impression of the original cusp height and inclined planes .
the matrix was sectioned into mesial and distal parts and used as a guide to facilitate posterior restoration with resin to the original shape ( figure 2 ) .
the floor of the exposed pulp chambers received a layer of glass ionomer cement ( vitrebond , 3 m espe ) . in group
b , the cavity was etched with 37% phosphoric acid for 30 seconds enamel and 15 seconds dentin , rinsed , and dried ( moist technique ) with an absorbing paper . the adhesive ( prime & bond nt , dentsply ) was applied and light - cured by 20s .
circumferential metal matrix was adapted to the cervical margins with low fusion impression material ( aquasil , dentsply ) .
surefil resin composite ( surefil , dentsply ) was inserted in 2.0 mm thick , oblique increments and light - cured for 40 s each at 600 mw / cm ( gnatus , ribeiro preto , so paulo , brazil ) . in group c , tooth restoration was performed in the same way as in group b , with the aid of the matrix to reconstruct the cusp height and slopes ( figure 3 ) .
after 24 hours , all surfaces of the restorations were polished with rubber points and were stored again in distilled water at 37c until testing . after 48 hours of storage , the specimens were mounted in an universal testing machine ( emic dl500 ; so jos dos pinhais , pr , brazil ) and subjected to an axial compression load applied parallel to the long axis of the tooth and to the slopes of the cusps by means of a round - end steel device ( 8.0 mm in diameter ) running at a crosshead speed of 0.5mm / minute ( figure 4 ) .
a flame - shaped bur was used to create small contact points on the buccal and lingual cusps for preventing lateral deflection of the sphere . the load required to cause fracture of the specimens
the results were analyzed by oneway anova and tukey 's test at 5% significance level .
the freshly extracted teeth were cleaned , stored in tymol solution at 0.1% and used within 1 month after extraction .
every tooth was examined under a 10x magnification and those presenting visible enamel cracks or fractures were rejected .
the selected teeth were embedded in cold - cure plastic resin in metal rings1 , with the resin limit at 1.0 mm below the cementoenamel junction .
the specimens were divided into three groups with 10 teeth each : group a ( control ) included sound teeth , group b included restored teeth without cusp reduction and group c had teeth restored with cusp coverage .
cavity preparation was initiated by occlusal approach with a spherical diamond bur towards the pulp chamber .
removal of the pulp chamber roof and reduction of the mesial and distal walls were done with a cylindrical diamond bur , creating a 4-mm - deep slit cavity design .
the buccolingual isthmus was approximately half the intercuspal distance , as well as the mesial and distal boxes .
teeth of group c received a further 2.0-mm - high reduction of both buccal and palatal cusps ( figure 1 ) . in those teeth , before cavity preparation and cusp reduction , a silicone matrix was prepared by taking an impression of the original cusp height and inclined planes .
the matrix was sectioned into mesial and distal parts and used as a guide to facilitate posterior restoration with resin to the original shape ( figure 2 ) .
the floor of the exposed pulp chambers received a layer of glass ionomer cement ( vitrebond , 3 m espe ) . in group
b , the cavity was etched with 37% phosphoric acid for 30 seconds enamel and 15 seconds dentin , rinsed , and dried ( moist technique ) with an absorbing paper . the adhesive ( prime & bond nt , dentsply ) was applied and light - cured by 20s .
circumferential metal matrix was adapted to the cervical margins with low fusion impression material ( aquasil , dentsply ) .
surefil resin composite ( surefil , dentsply ) was inserted in 2.0 mm thick , oblique increments and light - cured for 40 s each at 600 mw / cm ( gnatus , ribeiro preto , so paulo , brazil ) . in group c
, tooth restoration was performed in the same way as in group b , with the aid of the matrix to reconstruct the cusp height and slopes ( figure 3 ) .
after 24 hours , all surfaces of the restorations were polished with rubber points and were stored again in distilled water at 37c until testing .
after 48 hours of storage , the specimens were mounted in an universal testing machine ( emic dl500 ; so jos dos pinhais , pr , brazil ) and subjected to an axial compression load applied parallel to the long axis of the tooth and to the slopes of the cusps by means of a round - end steel device ( 8.0 mm in diameter ) running at a crosshead speed of 0.5mm / minute ( figure 4 ) .
a flame - shaped bur was used to create small contact points on the buccal and lingual cusps for preventing lateral deflection of the sphere . the load required to cause fracture of the specimens
the results were analyzed by oneway anova and tukey 's test at 5% significance level .
teeth restored with condensable resin composite without cusp coverage presented a significant decrease in strength as compared to sound teeth .
restorations with cusp coverage recovered the strength of the teeth to values similar to the sound teeth ( p<0.05 ) .
different letters indicate statistically significant difference all teeth of group c showed fractures that occurred only within condensable resin , without fracture of the remaining structure .
teeth of group b presented cusp fracture mostly at cusps base level , starting in the adhesive interface towards the apical third .
the natural and drastic consequence of dental weakness is cusp fracture , and the study of this pathology is relevant because it is considered a common occurrence in clinics3 - 5,7,15 . some authors have investigated the incidence of these dental fractures in oral cavity and found that is more concentrated in upper premolars5,7,15 .
sedgley and messer26 studied the biomechanical properties of non - vital teeth in tests of tenacity , microhardness and shear and fracture resistance .
they concluded that these properties do not change , suggesting that cumulative loss of dental structure by caries , trauma , restorative and endodontic procedures lead susceptibility to fracture .
it has been suggested that cusp elongation due to cavity preparation may be the major factor in fracture susceptibility , mainly in endodontically treated upper premolars whose anatomy tends to separate the buccal and palatal cusps under occlusal load7,19 .
some authors have emphasized that endodontically treated premolars with class ii mod cavity designs have a drastic decrease in fracture resistance . after receiving an indirect metallic restoration with cusp protection , these teeth
placement of amalgam restorations in weakened premolars with cusp coverage significantly increased the fracture resistance of the teeth ( 63% ) as compared to teeth restored without cusp coverage20 .
although metallic restorations with cusp coverage are a reference in the rehabilitation of weakened teeth and cracked tooth syndrome10 .
some authors12,13,16,23,24,32 have confirmed that resin composite could be an viable alternative to amalgam , with better results in posterior endodontically treated teeth with mod preparations2 .
however , in larger cavities , cusp reduction and posterior restoration with direct or indirect procedures seems to be a more secure option8 , 25 .
although cusp reduction promotes more dental tissue reduction27 , this procedure leads the restoration margins to buccal and palatal surfaces , protecting the adhesive interface from early marginal discrepancies30 . in a previous finite element analysis
, it was stated that stress value in the restorative material and remaining tooth structure was mainly influenced by the restorative material itself ( 95.49% ) and cavity design ( > 80% ) .
when cuspal - coverage treatment is considered , the cuspal height should be reduced in at least 1,5 mm to significant reduce the stress values17 .
the present study confirm these results showing that 2.0-mm cusp reduction and posterior restoration with direct resin composite can restore the fracture resistance of weakened teeth .
these results seems to be also confirmed clinically6 . as seen in table 1 , the results of the present study do not agree with those of previous investigations2,9,13,18,21,23 that found fracture resistance of weakened teeth restored with resin composite without cusp coverage been similar of sound teeth .
this probably occurred because the cavity size used in the present study was larger than those of other studies .
the anchorage promoted by resin composite , protecting the buccal and lingual cusps of group c specimens , recovered the fracture resistance in similar values of sound teeth .
the adhesive procedure was clearly not the only responsible for this resistance , but also cusp protection that avoided the separation in consequence of the wedge effect caused by cusp elongation14,19,20 .
no cusp fracture was seen in group c. however , group b presented some fractures indicating that only the adhesive interface may be insufficient to avoid these fractures . despite failures mentioned by different authors , resin composites improved and are now indicated for posterior teeth as an alternative to amalgam , especially condensable resins , which have higher wear resistance31 .
the results of the present study showed that cusp coverage with condensable resin might be an option for restoring weakened endodontically treated teeth because cusp coverage resulted in similar fracture resistance to that sound teeth .
cusp coverage with condensable resin might be a safe option for restoring weakened endodontically treated teeth .
Output:
| objectives : this in vitro study evaluated the fracture resistance of weakened human premolars ( mod cavity preparation and pulp chamber roof removal ) restored with condensable resin composite with and without cusp coverage.material and methods : thirty human maxillary premolars were divided into three groups : group a ( control ) , sound teeth ; group b , wide mod cavities prepared and the pulp chamber roof removed and restored with resin composite without cusp coverage ; group c , same as group b with 2.0 mm of buccal and palatal cusps reduced and restored with the same resin .
the teeth were included in metal rings with self - curing acrylic resin , stored in water for 24 h and thereafter subjected to a compressive axial load in a universal testing machine at 0.5 mm / min.results : the mean fracture resistance values standart deviation ( kgf ) were : group a : 151.40 55.32 , group b : 60.54 12.61 , group c : 141.90 30.82 .
statistically significant differences were found only between group b and the other groups ( p<0.05 ) .
the condensable resin restoration of weakened human premolars with cusp coverage significantly increased the fracture resistance of the teeth as compared to teeth restored without cusp coverage.conclusion:the results showed that cusp coverage with condensable resin might be a safe option for restoring weakened endodontically treated teeth . |
PubmedSumm8849 | ***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: it is associated with peptic ulcer disease ( pud ) , gastric / duodenal erosions , gastric adenocarcinoma , and gastric lymphoma both in healthy population and patients with uremia .
studies have shown that pud is more prevalent in h.pylori positive hemodialysis patients than the general population .
furthermore , these patients are more prone to gastrointestinal bleeding , partially because of the fragility of gastric mucosa and inevitable use of anticoagulant therapy during hemodialysis .
therefore , h.pylori treatment is an important issue in this group of patients .
on the other hand , patients with uremia , especially those with end - stage renal disease ( esrd ) have some degrees of immune system dysfunction .
consequently , the eradication of h.pylori may be more difficult in such patients , because antibiotic resistance is the most common cause of failure to eradicate h.pylori .
hybrid regimen is a novel treatment including a proton pump inhibitor ( ppi ) + amoxicillin during the first 7 days , followed by quadruple regimen of a ppi + amoxicillin + clarithromycin + metronidazole / tinidazole for the second 7 days .
also , a recent review article considering h.pylori eradication regimens in west asia has reported hybrid regimen as an ideal regimen for first line h.pylori therapy in this geographic region . however , to the best of our knowledge , no study has assessed the effects of hybrid regimen for h.pylori eradication in patients with uremia .
therefore , we designed a study to compare the effects of hybrid therapy with standard triple therapy in hemodialysis patients .
from december 2013 to january 2014 , forty hemodialysis patients with nave h.pylori infection entered the study .
h.pylori infection had been confirmed by both rapid urease test ( rut , shim anzy , tehran , iran ) and fecal h.pylori antigen test ( dahelwit 93 , germany ) .
the reasons for gastrointestinal evaluation were long - standing dyspepsia , iron deficiency anemia , or being candidate for renal transplantation . before starting the protocol ,
the exclusion criteria were age less than 18 years or above 85 years , any chronic disease that would hinder follow - up ( such as liver failure , heart failure , chronic pulmonary disease , or history of malignancy ) , history of allergic reactions to any of the medications used in this study , history of gastric or esophageal surgery , using antibiotics during the previous week , pregnancy , or breastfeeding .
twenty patients received hybrid regimen including : pantoprazole 40 mg + amoxicillin 500 mg both twice a day during the first 7 days , followed by pantoprazole 40 mg + amoxicillin 500 mg + clarithromycin 500 mg + tinidazole 500 mg , all twice a day , for the second 7 days .
the remaining 20 patients received standard triple therapy including : pantoprazole 40 mg , clarithromycin 500 mg , and amoxicillin 500 mg , all twice a day for 14 days .
the patients were advised to call the doctor in case of any severe side effects .
after treatment , all patients were visited and were asked about the number of remained medications ( if any ) .
compliance to treatment was considered excellent if the patient took more than 90% of the medications , good in case of taking 70 - 90% of the drugs and poor , if the patient used less than 70% of the prescribed medications .
h.pylori eradication was assessed by fecal h.pylori antigen test ( dahelwit 93 , germany ) 8 weeks after the treatment . in order to calculate intention to treat eradication rates , all the patients who entered the study
but in order to calculate per - protocol eradication rates , only data of those who completed the entire protocol with more than 90% compliance to treatment were analyzed .
demographic data including age , sex , history of gastrointestinal bleeding , endoscopic findings , the reasons for gastrointestinal evaluation , and the need for h.pylori eradication did not show statistically significant difference between the two groups ( table 1 ) .
the indications for h.pylori eradication were : being candidate for renal transplantation , dyspepsia , or gastroduodenal ulcer or erosions .
gib : gastrointestinal bleeding
six patients in the triple therapy group ( 30% ) reported mild adverse effects ( four cases of metallic taste and two cases of malaise ) .
also , two patients who received hybrid regimen ( 10% ) complained of mild metallic taste ( p<0.05 ) .
however , compliance to treatment was excellent in all patients and no one interrupted treatment because of adverse effects of the treatment .
according to both intention to treat and per - protocol analyses , h.pylori eradication rates were 100% ( 95% ci : 100 ) in those who received hybrid regimen and 70% ( 95% ci : 69.41 70.89 ) in those who were treated by standard triple therapy ( p=0.02 , figure 1 )
method of follow - up & treatment efficacy
our study showed that hybrid regimen could eradicate h.pylori in 100% of patients , but the eradication rate achieved by standard triple therapy was disappointing .
furthermore , the rates of side - effects of treatment were significantly lower in those who received hybrid regimen . however , both regimens were well tolerated and no one interrupted the treatment because of the adverse effects of the prescribed drugs .
if we consider h.pylori as an infectious disease , the ideal regimen would be the one that can eradicate h.pylori in more than 95% of the cases .
most of previous studies could not achieve optimal eradication rates in hemodialysis patients .
comparing the results of our study with previous reports ,
this is in concordance with most previous studies . according to a recent study performed by makhlough and colleagues ,
49 hemodialysis patients were randomized to receive either 14-day clarithromycin - containing triple therapy or sequential regimen .
h.pylori eradication rates were 76.2% and 87.5% by per - protocol analysis , respectively . according to another study by wang and co - workers on 40 hemodialysis patients , 7-day omeprazole - amoxicillin - clarithromycin(oac ) regimen
in addition , tsukada and colleagues reported 82.1% eradication rate using the same regimen for 39 hemodialysis patients .
sezer and others showed a high eradication rate ( 94.1% ) in 17 hemodialysis dependent patients using 14-day oac regimen .
however , itatsu and colleagues reported low eradication rate ( 72.7% ) among 11 hemodialysis patients who had received 7-day lansoprazole - amoxicillin - clarithromycin . on the other hand
, chang studied the effects of low - dose oac on 33 hemodialysis patients and reported an eradication rate of 83.4% by per - protocol analysis .
on the other hand
however , to the best of our knowledge , all related studies have been performed on patients without uremia and no study has been performed on patients with uremia . according to a study performed by de francesco and coleagues on patients without uremia , hybrid therapy could achieve 82.7% eradication rate by intention to treat analysis . also , oh and co - workers reported 81.1% and 85.9% eradication rates by hybrid therapy according to intention to treat and per - protocol analyses , respectively .
zullo and others evaluated the effects of concomitant , sequential and hybrid therapies on 270 patients with non - ulcer dyspepsia .
the eradication rates achieved by hybrid therapy were 80% and 85.7% according to intention to treat and per - protocol analyses , respectively .
sardarian and colleagues also performed a study to compare the effects of hybrid therapy versus sequential therapy for h.pylori eradication .
the eradication rates achieved by hybrid therapy were 89.5% and 92.9% by intention to treat and per - protocol analyses , respectively . in the mentioned study ,
it has been shown that chronic renal failure , either prior to renal transplantation or in patients on hemodialysis , is a predisposing factor for gastroduodenal mucosal lesions .
also patients with uremia are more prone to complications of pud than the general population .
furthermore , some studies have reported higher resistance rates to antibiotics in patients with uremia than the general population . therefore , introducing an h.pylori eradication regimen with ideal eradication rates seems to be important in this group of patients and our study reported excellent h.pylori eradication rate by hybrid regimen .
one of the main limitations was small number of patients that is because of evaluating a special group of patients ( hemodialysis patients ) .
however , the strong point of the present study was to evaluate the effects of hybrid regimen in patients with uremia , because to the best of our knowledge , no study has been performed to evaluate the effects of hybrid therapy in hemodialysis patients
in conclusion , hybrid regimen could achieve ideal h.pylori eradication rate with low rate of side - effects and excellent compliance to treatment .
Output:
| background
the prevalence of peptic ulcer disease in hemodialysis patients is more than the general population .
they are also more prone to complications including upper gastrointestinal bleeding .
the aim of this study was to compare the efficacy of 14 days hybrid regimen with 14 days triple therapy for helicobacter pylori ( h. pylori ) eradication in hemodialysis patients .
methods
forty hemodialysis patients with nave h.pylori infection were randomized to receive either hybrid regimen ( pantoprazole 40 mg + amoxicillin 500 mg , both twice a day during the first 7 days , followed by pantoprazole 40 mg + amoxicillin 500 mg + clarithromycin 500 mg + tinidazole 500 mg , all twice a day , for the second 7 days , or standard triple therapy including pantoprazole 40 mg , clarithromycin 500 mg , and amoxicillin 500 mg , all twice a day for 14 days .
h.pylori eradication was assessed by fecal h.pylori antigen test 8 weeks after the treatment .
results
all the patients completed the study . according to both intention to treat and per - protocol analyses , h.pylori eradication rates were 100% ( 95% confidence interval ( ci ) : 100 ) in those who received hybrid therapy and 70% ( 95% ci : 69.4 70.8 ) in those who were treated by standard triple therapy ( p=0.02 ) .
severe adverse effects were not reported by any patient ; however , mild adverse effects were more frequent in those who received standard triple therapy ( p<0.05 ) .
conclusion
hybrid regimen could achieve ideal h.pylori eradication rates with low rates of adverse effects . |
PubmedSumm8850 | ***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 a service to our authors and readers , this journal provides supporting information supplied by the authors .
such materials are peer reviewed and may be reorganized for online delivery , but are not copyedited or typeset .
technical support issues arising from supporting information ( other than missing files ) should be addressed to the authors .
Output:
| abstractdeubiquitinating enzymes ( dubs ) are proteases that fulfill crucial roles in the ubiquitin ( ub ) system , by deconjugation of ub from its targets and disassembly of polyub chains .
the specificity of a dub towards one of the polyub chain linkages largely determines the ultimate signaling function .
we present a novel set of diubiquitin fret probes , comprising all seven isopeptide linkages , for the absolute quantification of chain cleavage specificity of dubs by means of michaelis menten kinetics .
each probe is equipped with a fret pair consisting of rhodamine110 and tetramethylrhodamine to allow the fully synthetic preparation of the probes by spps and ncl .
our synthetic strategy includes the introduction of n , nbocprotected 5carboxyrhodamine as a convenient building block in peptide chemistry .
we demonstrate the value of our probes by quantifying the linkage specificities of a panel of nine dubs in a highthroughput manner . |
PubmedSumm8851 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: patients are often asymptomatic and the anomaly is discovered during imaging studies carried out for other reasons . however ,
when symptoms are present , they are related to hydro - nephrosis , infection , or calculus formation .
the incidence of renal tumor in a horseshoe kidney is higher than in normal population . we present a case of renal cell carcinoma ( rcc ) in a horseshoe kidney .
presence of the kidney malformation can change the surgery plan for preserving the organ without removing any functional tissue .
a 62-year - old male patient presented to our institute , as a referral case from another hospital , with an abdominal mass .
computed tomography ( ct ) scan of abdomen and pelvis was performed utilizing routine ct renal mass protocol .
the scan revealed presence of a horseshoe kidney anomaly with a well - enhanced isthmus [ figure 1a ] . by using a power injector
, we administered 150 ml of intravenous contrast material at a minimum rate of 3 ml / s . using , a multi - detector row ct scanner , contrast material - enhanced imaging was performed during the corticomedullary and nephrographic phases of enhancement using scanning delays of 40 s and 100 s , respectively .
large lobulated mass was identified in the left side of the horseshoe kidney associated with an area of central cystic necrosis .
the mass measured about 12 cm 13 cm 15 cm in anterior - posterior , width , and crainio - caudal maximum dimensions , respectively [ figure 1b and c ] .
the renal vein and intravenous vena cava were patent and there was no evidence of significant enlarged intra - abdominal lymph nodes .
the diagnosis made was rcc with a horseshoe kidney and patient was sent for urology consultation and surgical resection .
( a - c ) ct scan images of the abdomen obtained at the level of inferior mesenteric artery .
( a ) before administration of the contrast material shows a horseshoe kidney anomaly ( arrow ) .
post - contrast images in b ) axial and c ) coronal planes show a large mass arising from the left part of the horseshoe kidney ( arrow ) .
the mass is multi - lobulated and heterogeneous in attenuation with a central area of cystic necrosis hemi - nephrectomy was performed at our institute .
follow - up ct scan of the abdomen and pelvis obtained in the post - operative period revealed resection of the previously described large mass within the left part of the horseshoe kidney .
single selected axial computed tomography scan image of the abdomen performed in the post - operative period shows resection of the large mass in the left part of the horseshoe kidney with organ preserving surgery .
the surgically removed gross specimen was a large mass , which had replaced more than 2/3 of the left side of the horseshoe kidney .
the mass was lobulated and variegated , ranging from tan and yellow to dark brown .
pathology specimen shows a large multi - lobulated mass associated with an area of hemorrhage and cystic necrosis .
hematoxylin - eosin ( h and e ) stained histology slides of the above described mass revealed clear cell rcc with prominent borders and profuse network of small , thin - walled sinusoid - like blood vessels [ figure 4a and b ] .
hematoxylin and eosin stained slides of the clear cell renal cell carcinoma ( rcc ) mass in a horseshoe kidney .
( a ) at 6 magnification shows the tumor margin ( arrow ) in relation to the reminder of the kidney , ( b ) at 300 shows clear cells with prominent cell borders ( black arrow ) and vascularity ( yellow arrow )
no genetic determinant is known , although , it has been reported in identical twins and in siblings within the same family .
horseshoe kidney consists of two distinct functioning kidneys on each side of the mid - line , connected at the lower poles by an isthmus of functioning renal parenchyma or fibrous tissue that crosses the mid - line of the body .
nearly , one - third of all patients with a horseshoe kidney remain asymptomatic and the pathology is discovered incidentally during physical examination or ct and ultrasound scans .
when symptoms are present , they are related to hydro - nephrosis , infection , or calculus formation .
the incidence of renal tumor in a horseshoe kidney is approximately 3 to 4 times greater than in normal population , and is possibly the result of chronic obstruction , lithiasis , and infection .
the tumor can localized at any part of the kidney but it mostly found within the isthmus .
ct utilizing routine renal mass protocol is the primary imaging modality of choice for localization and staging of any renal tumor .
however , in case of rcc and horseshoe kidney , ct angiography is highly recommended to check the renal vascularity , which generally varies and is essential for pre - operative planning .
if ct scanning is performed specifically to evaluate a known renal mass , the study must include an unenhanced examination prior to the administration of intravenous contrast material .
after administration of contrast , scans are taken at intervals of 40 s and 100 s during the enhancement phase .
the dataset can be manipulated by using a 3d workstation to produce volume - rendered and 3d images when necessary .
it is becoming increasingly important for radiologists to produce 3d reconstructed images as more laparoscopic surgery is being performed for the treatment of renal cancer , and these images are helpful in such procedures .
thus , pre - operative surveillance is highly recommended for early identification of metastatic activity and positive surgical margin .
surgical approach is through the mid - line in order to have better exposure of the isthmus for isthmectomy .
clear cell rcc , the pathology subtype , as found in our case , is typically a solitary tumor and the tumor commonly presents as bosselated , well - circumscribed mass with fibrosis and with a capsule or pseudo - capsule .
lipid - rich cells in clear rcc impart the classical golden yellow color seen on gross pathology analysis .
clear cell rcc may exhibit a variety of histo - architectural patterns including , solid , alveolar , and acinar forms .
horseshoe kidney is the most common renal fusion anomaly and is more predominate in males and it is detected mostly as incidental finding on ct or us examination .
rcc is one of the malignancies associated with this malformation , as was seen in our case .
Output:
| renal cell carcinoma ( rcc ) is encountered in about 3% of all adult neoplasms .
presence of any kidney malformation can change the plan for surgical treatment of rcc with organ preserving surgery .
we report a case of clear cell rcc in a horseshoe kidney .
computed tomography scan revealed a horseshoe kidney anomaly with a large mass in the left side .
the diagnosis of rcc was confirmed by pathology and histology findings . |
PubmedSumm8852 | ***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 von meyenburg complex ( vmc ) was first described in 1918 and is characterized by multiple bile duct hamartomas .
these are benign developmental malformations composed of dilated intrahepatic bile ductules embedded in fibrous stroma .
, the majority are discovered incidentally , but may present a diagnostic dilemma when the patient is undergoing staging imaging for known primary malignancy .
we describe a case of vmc with ultrasound , contrast enhanced ultrasound ( ceus ) , computed tomography ( ct ) , and magnetic resonance ( mr ) imaging correlation .
an 81-year - old man was admitted with a one - week history of abdominal pain and constipation . on clinical examination
contrast - enhanced ct images ( siemens sensation 16 slice ) were acquired in the portal venous phase ( 60 s following administration of contrast ) , demonstrating a focal sigmoid stricture and proximal large bowel obstruction .
multiple low - density lesions of varying sizes were identified within the liver , which were non - enhancing in the portal venous phase [ figure 1 ] .
a sigmoid malignancy was likely , but the majority of liver lesions were near fluid density ( 3 - 20hu ) and not entirely typical for metastases .
an 81-year - old man with adenocarcinoma of the colon and hepatic lesions later diagnosed as von meyenburg complex .
axial enhanced ct image of the abdomen , at the level of the porta , demonstrate multiple fluid density lesions ( arrows ) of varying sizes within the liver .
b - mode ultrasound demonstrated multiple hyperechoic lesions [ figure 2 ] of varying sizes throughout the liver , none of which displayed signal with color doppler ultrasound .
the hepatic lesions were further interrogated with ceus , using sonovue ( bracco spa milan ) as the microbubble contrast agent , on a siemens s2000 ( siemens ag , erlangen ) , with a 4 mhz transducer and imaged using a low mechanical index technique ( cps , siemens ag , erlangen ) .
no appreciable vascularity was seen within the hepatic lesions in all three phases of the study ( arterial , early portal venous , and late portal venous phase ) with imaging performed for 3 min [ figure 3 ] .
the patient proceeded to laparotomy where a hartmann 's procedure was performed and multiple liver biopsies were obtained .
b - mode ultrasound image of the liver shows several hyperechoic focal lesions ( arrows ) .
an 81-year - old man with adenocarcinoma of the colon and hepatic lesions later diagnosed as von meyenburg complex .
contrast enhanced ultrasound of the liver in the late portal venous phase ( 1 min 30 sec following injection of contrast ) demonstrates non - enhancing lesions ( arrow ) .
histology of the resected colon confirmed moderately differentiated adenocarcinoma invading through the muscularis propria , but not penetrating the serosal surface .
histology of the focal lesions demonstrated expanded portal tracts with dense stroma , containing dilated bile ducts ; a few of which contained inspissated bile [ figure 4 ] .
a dilated congested blood vessel within the specimens was presumed to be responsible for the hepatic nodularity .
an 81-year - old man with adenocarcinoma of the colon and hepatic lesions later diagnosed as von meyenburg complex .
hemotoxylin and eosin stained biopsy specimen shows dilated ducts with inspissated bile ( arrow ) in an expanded and fibrotic portal tract .
mr imaging was performed to further evaluate the liver and to identify any lesions characteristic of metastases .
multiple hepatic lesions were again visualized and displayed moderate to high t2 ( tr : 2410 ; te : 103 ) signal intensity [ figure 5 ] and t1 hypointensity with no contrast enhancement [ figure 6 ] .
the multiple liver lesions displayed decreasing signal intensity [ figure 7 ] with increasing b - values on diffusion - weighted imaging , indicating free diffusion .
the imaging findings were in keeping with vmc in addition to simple cysts ; metastases being less likely .
an 81-year - old man with adenocarcinoma of the colon and hepatic lesions later diagnosed as von meyenburg complex . in t2-weighted mr sequence of the liver
an 81-year - old man with colon cancer and lesions in the liver diagnosed as von meyenburg complex .
post - contrast t1-weighted sequence demonstrate multiple non - enhancing lesions ( arrow ) throughout the liver .
an 81-year - old man with adenocarcinoma of the colon and hepatic lesions later diagnosed as von meyenburg complex .
diffusion weighted images of the liver at different b - values reveal negative correlation between the signal intensity of the focal liver lesions ( arrow ) compared to the b - value , in keeping with free diffusion , which favors benign disease .
surveillance imaging 3 years post - surgery demonstrated identical appearances of the liver , with no new abnormalities present and no disease recurrence .
von meyenburg complex ( vmc ) is an uncommon abnormality and affected patients are usually asymptomatic , although jaundice and portal hypertension may arise as a result of mass effect .
the imaging findings of vmc have been documented through case reports and a single case series .
the biliary hamartomas of vmc may be single or multiple , ranging in size from 1 to 15 mm ; not all lesions are identifiable on imaging and given the small size of the lesions , definitive characterization may be difficult . in
the presence of multiple low - density lesions within the liver , differentiation from metastases remains the key clinical question , particularly in the presence of a known primary .
sonographic appearances of vmc are varied , being described as multiple hypoechoic lesions , hyperechoic lesions and also a mixture of both hypo- and hyper - echoic lesions .
it has been postulated that lesional reflectivity may be dependent on the size and number of the dilated bile ducts and degree of fibrosis .
other features of vmc include the presence of a comet tail artifact and association with liver cysts .
contrast enhanced ultrasound ( ceus ) allows a true assessment of lesional vascularity , with no escape of contrast through the interstitium .
this enables dynamic visualization of the lesion of interest through arterial , venous , and delayed phases .
berry et al . , reported a case of multiple vmcs that did not demonstrate contrast enhancement in all phases ; exclusion of hypovascular metastases was not possible .
hohmann et al . , highlighted the presence of enhancement in a biliary hamartoma on ceus with
washout in the delayed phase . however , this was a single biliary hamartoma , measuring 5 mm , which may have affected interpretation .
, has suggested that all metastases invariably display arterial vascularity on ceus albeit transiently , despite hypovascular appearances on ct and mr imaging .
this particular phenomenon is only evident through continuous dynamic observation unique to ceus examination . in the present case , none of the lesions demonstrated contrast enhancement throughout all phases of the study , confirming the avascular nature of the abnormality .
on contrast enhanced ct , biliary hamartomas are predominantly of low attenuation , and may demonstrate an irregular border .
the majority of cases reported suggest that vmc does not exhibit contrast enhancement , although one case of homogeneous enhancement has been reported .
evaluation of lesional contrast enhancement on ct is not truly dynamic , unlike the evaluation of lesional enhancement on contrast ultrasound , and so ct scanning can not definitively differentiate vmc from metastatic disease .
all agree that vmcs appear hypointense on t1-weighted imaging and are hyperintense on heavily t2-weighted sequences with similar signal intensity to the spleen , but less than liver cysts ; our observations corroborate these findings . however , mr enhancement characteristics are difficult to establish with contradicting reports showing both enhancement and no enhancement on gadolinium - enhanced t1-weighted sequences .
more recently , diffusion - weighted imaging ( dwi ) has gained recognition for its potential to differentiate metastatic lesions , showing restricted diffusion , from benign lesions , demonstrating free diffusion .
although there are no published reports on dwi for vmc , our findings of free diffusion support a benign diagnosis .
multiple cysts typically appear as anechoic areas with posterior acoustic shadowing on ultrasound and display very high t2 signal characteristics , with no enhancement with contrast . in abscess formation , peripheral enhancement ,
while vmc has been described as a benign condition , there have been isolated reports of hepatic malignancies on a background of vmc , including hepatocellular carcinoma and cholangiocarcinoma , but given the paucity of reports , a clear association with vmc has not yet been established .
we report a case of von meyenburg 's complex that has been investigated with us , ceus , ct , and mri .
b - mode ultrasound and ct do not help to differentiate hepatic metastases from vmc . however , lack of enhancement on ceus , increased signal intensity on heavily t2-weighted mr sequences and free diffusion on dwi all favor benign disease , but currently biopsy must remain the gold standard for diagnosis .
Output:
| the von meyenburg complex ( vmc ) is an uncommon congenital malformation and is characterized by benign bile duct hamartomas .
these are usually discovered incidentally and may represent a diagnostic dilemma when liver metastases are suspected .
mri of vmc shows distinct imaging characteristics , but reporting of lesional contrast enhancement has been inconsistent , whilst microbubble contrast enhanced ultrasound provides real - time evaluation of soft tissue vascularity .
given the diagnostic uncertainty over imaging in vmc , biopsy is often recommended as the definitive diagnosis .
we report a biopsy proven case of vmc on a background of primary colonic malignancy investigated with ultrasound , contrast enhanced ultrasound , computed tomography ct , and magnetic resonance imaging mri , and review the key imaging features . |
PubmedSumm8853 | ***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 2010 , approximately 15 million babies were born preterm worldwide , and more than one million died due to complications from preterm births ( ptb ) .
however , a pathogen is identified in only one third of the cases , despite evidence of infection .
obligate intracellular bacteria , which do not grow on media used routinely to isolate human pathogens from clinical samples , might represent possible agents of ptb .
chlamydia trachomatis , an obligate intracellular bacterium , is considered the world 's most common sexually transmitted bacterial pathogen .
waddlia chondrophila is another member of the chlamydiales order that has been shown to cause abortions in bovines .
both of these intracellular bacteria have also been implicated in human adverse pregnancy outcomes [ 47 ] .
in addition , c. trachomatis is known to cause premature rupture of the membranes and premature uterine activity , and growing evidence suggests a role for c. trachomatis in ptb . in this study
we studied 407 women with ptbs or uneventful term pregnancies attending the university hospital of lausanne , lausanne , switzerland .
in addition to serology , we also performed pcr to detect waddlia and chlamydia in the placenta and vaginal samples taken from these women , as well as histology on the placenta . from 2006 to 2009 , 407 women were enrolled into this study at the obstetrical ward of the university hospital of lausanne .
the ptb group ( n = 146 ) included women who spontaneously delivered before 37 weeks ' gestation . the control group ( n = 261 ) included women attending a labour ward with uneventful term pregnancies and no history of miscarriages , stillbirths or preterm labour .
we compared demographic data and risk factors of patients with and without ptb or c. trachomatis infection by the pearson test ( or the fisher exact test when indicated ) for categorical variables . for continuous variables ,
statistical analyses were performed using the stata software , version 13.0 ( statacorp , college station , tx , usa ) . only positive urine cultures , gestational and maternal age were significantly different between control and ptb groups ( table 1 ) .
other infectious causes were investigated in the ptb group , showing that a positive culture was found in the vagina , maternal or fetal side of the placenta in 32% , 37% and 17% of the ptb patients , respectively ( supplementary table 1 ) . among all these bacterial species , genital mycoplasma and gardnerella vaginalis , which have been previously associated with ptb ,
were recovered in some subjects from the vagina only ( n = 25 and 3 , respectively ) , never from the placenta .
sera were tested for antibodies directed against c. trachomatis and w. chondrophila , respectively , by using the momp - r , ct pelisa ( r - biopharm , darmstadt , germany ) and waddlia - specific immunofluorescence as described elsewhere .
isolated igg mainly reflects past or chronic infection , whereas igm and/or iga reflect acute infection .
briefly , w. chondrophila strain atcc vr-1470 was used as antigen , whereas fluoline g or m ( biomrieux , marcy l'toile , france ) were used as secondary antibodies .
an antibody titre of 1/64 for igg and 1/32 for igm were considered as positive , respectively .
there was no difference between control and ptb groups in terms of anti - chlamydia igg and iga and anti - waddlia igg and igm titres ( table 1 ) .
a total of 54 patients tested positive only for waddlia igg and 26 only for chlamydia igg , indicating the absence of serologic cross - reaction between both pathogens .
only six patients tested positive for both waddlia and chlamydia igg ( p 0.446 ) . c. trachomatis igg seropositivity (
table 2 ) was associated with civil status ( divorced vs. married , odds ratio ( or ) 7.85 ; 95% confidence interval ( ci ) 2.6123.62 ) , education ( or 0.28 ; 95% ci 0.100.81 ) and number of previous sexual partners ( > 6 vs. 1 : or 13.12 , 95% ci 1.53112.32 ; not answered vs. 1 : or 13.55 , 95% ci 1.76104.09 ) .
patients who used condoms as a previous contraceptive method show less c. trachomatis positive serologies , although this was not statistically significant . of note , only six ( 55% ) and one ( 9% ) of the 11 patients positive for c. trachomatis dna were also positive for c. trachomatis igg and iga , respectively . however , c. trachomatis igg - positive patients exhibited significantly more histologic chorioamnionitis ( 50% ) than c. trachomatis igg - negative patients ( 28.3% , p 0.015 ) .
waddlia seropositivity was not associated with age , number of lifelong sexual partners , place of residence ( rural vs. urban ) , smoking , pet ownership or meat consumption ( data not shown ) .
interestingly , 4.9% of women of european heritage vs. 14.3% of those of non - european heritage had positive waddlia igg serologies of 1/256 ( p 0.008 ) .
this correlation was also observed for waddlia igm of 1/32 ( 3.6% of european vs. 10.4% of non - european , p 0.034 ) . among non - european women ,
the highest waddlia igg titres ( 1/128 or 1/256 ) were more frequent for black ethnicity ( 20% and 14.3% , respectively ) . when total immunoglobulin ( ig 1/64 ) against waddlia was considered , condoms as a previous contraceptive method protected against waddlia infection ( 12.1% condom users vs. 21.4% of the noncondom users exhibited anti - waddlia ig reactivity , p 0.041 ) .
after dna extraction with qiaamp dna mini kit ( qiagen , hilden , germany ) , all vaginal swabs and placenta samples were screened for c. trachomatis dna by a taqman real - time pcr targeting the cryptic plasmid of c. trachomatis , as described earlier .
samples were also tested by a 16s rrna waddlia - specific real - time pcr , as described previously .
vaginal and placental samples from the ptb group were significantly more often c. trachomatis dna positive than the control group ( p 0.002 , unadjusted or 8.51 ; 95% ci 1.8139.93 ) .
this association reminded significant even after adjustment for maternal age , origin , civil status , education , number of sexual partners and positive urine cultures ( or 7.93 ; 95% ci 1.3446.76 ) .
stepwise logistic regression allowed us to confirm that the presence of c. trachomatis dna is an independent factor associated with ptb ( fig . 1 ) .
thirty - four patients were positive only for w. chondrophila , whereas ten other subjects were positive only for c. trachomatis by pcr .
only one patient was positive for both , demonstrating the absence of cross - amplification of these two obligate intracellular bacteria .
presence of waddlia dna was demonstrated in the genital tract or placenta of 13 ptb subjects ( table 3 ) .
of these 13 patients , four exhibited both a positive waddlia serology and presence of waddlia dna .
two had presence of waddlia in multiple samples , including vaginal swab , urine and placenta .
only two of these 13 patients had either a positive c. trachomatis serology or pcr .
both c. trachomatis and w. chondrophila have been implicated in adverse pregnancy outcomes .
however , there have been contradictory findings pertaining to the role of c. trachomatis infection in ptb .
a few small studies have failed to demonstrate a risk of ptb associated with c. trachomatis infections , although several large , well - conducted studies have supported a role for c. trachomatis in ptb [ 1517 ] .
thus , in a large study including 4055 subjects , about 15% of ptb was attributed to c. trachomatis
.
we have previously confirmed an association between waddlia antibodies and human miscarriage and have demonstrated its presence in placenta and/or genital tract [ 47 ] . in the present study ,
w. chondrophila was not associated with ptb despite inflammation , and abnormal histology of the placenta was observed among patients infected by waddlia ( positive pcr ) .
in contrast to waddlia , presence of chlamydia dna in the genital tract and/or in the placenta was strongly associated with ptb . however , c. trachomatis seropositivity did not correlate with ptb , suggesting that acute rather than chronic c. trachomatis infection is associated with ptb .
interestingly , these results are opposite to our previous findings , in which we demonstrated that both chronic and acute c. trachomatis infections correlate with miscarriages .
our results confirm those of a population - based prospective study recently published in the generation r cohort in the netherlands . in this large study ( > 4000 pregnant women ) ,
conflicting data between chlamydia dna , serology and pregnancy outcomes may reflect different pathophysiologic mechanisms , in which chlamydia - induced miscarriages are the result of an immunologic process , whereas the direct impact of the bacteria results in chlamydia - induced ptb .
a limitation of our study was the absence of investigation of other infectious etiology of ptb in all patients ( ptb and control subjects ) .
some pathogens can reach the placenta by hematogenous spread or by an ascending route from the cervix . among bacterial infections ,
ureaplasma urealyticum , mycoplasma hominis and bacterial vaginosis have been associated with ptb , but controversies regarding their true role during pregnancy persist .
overall , these results strongly suggest a role of acute c. trachomatis infection in ptb , and we strongly recommend systematically testing for c. trachomatis in any woman at risk for or after preterm delivery .
Output:
| waddlia chondrophila and chlamydia trachomatis are intracellular bacteria associated with human miscarriage .
we investigated their role in human preterm birth . whereas presence of chlamydia trachomatis dna in genital tract was associated with human preterm birth , waddlia was not , despite being present in women 's genital tracts . |
PubmedSumm8854 | ***TASK***
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***INPUT***
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Input: its impact on the quality of life is similar to that of hypertension and diabetes and is more serious than that of depression . for these reasons
although oab patients show many variable symptoms , the central symptom of oab is urgency , which is closely related to detrusor overactivity ( do ) during the filling phase in cystometry [ 5 - 7 ] .
it was reported that 83% of patients with do showed urgency , and 64% of patient with urgency showed do .
thus , it is important to observe do objectively in clinical and research studies of oab .
recently , we investigated nonvoiding contractions in awake animal models by simultaneous registrations of intravesical pressure ( ivp ) and intraabdominal pressure ( iap ) .
anticholinergic therapy is the first - line treatment option for patients with oab , owing to the parasympathetic activation of the detrusor contractions .
anticholinergic drugs suppress the involuntary detrusor contractions through competition with acetylcholine for the muscarinic receptors during both the storage and the voiding phase .
however , it is known experimentally that these drugs have no effects on voiding contraction and residual volume , because the amount of acetylcholine released during the voiding phase is much more than those of anticholinergic drugs . however , in clinical studies , some patients complained of straining voiding , increased residual volume , and sometimes acute urinary retention .
this suggests that anticholinergics may have an influence on detrusor contractions during the voiding phase . up to now
, there has been no experimental evaluation of the effect of anticholinergics during the voiding phase in awake rats by simultaneous registrations of ivp and iap .
the objective of this study was therefore to perform simultaneous registrations of ivp and iap to evaluate the effects of propiverine 1 and 3 mg / kg on do during the filling phase and on abdominal straining during the voiding phase in awake rats with intravesical prostaglandin e2(pge2 ) instillation .
a total of 22 sprague - dawley ( sd ) female rats weighing between 200 and 250 g were used in this study .
all procedures were performed in accordance with the guide for the care and use of laboratory animals of the national institutes of health and were approved by the inha - university animal ethics committee .
the rats were maintained under standard laboratory conditions with a 12:12 h light : dark cycle and with free access to food pellets and tap water .
simultaneous ivp and iap were continuously recorded during bladder filing and emptying as described previously . in brief , sd rats were anesthetized with ketamine ( ketamine ; yuhan corp , seoul , korea ; 75 mg / kg intraperitoneally ) and xylazine ( rompun ; bayer korea corp , korea ; 15 mg / kg intraperitoneally ) . through a low abdominal incision , a polyethylene catheter ( pe-50 ; becton dickinson , parsippany , usa ) with a cuff was inserted into the dome of the bladder and was held in place with a purse - string suture . to record iap , an abdominal balloon ( latex ; daewoo medical , incheon , korea ) around the cuff of a catheter tip
was placed 1 cm proximal to the bladder along the catheter to the bladder and was attached with a silk tie to the catheter . a catheter ( pe-10 ; becton dickinson )
these catheters were tunneled subcutaneously and anchored to the skin of the back with a silk ligature .
cystometry was performed 3 days after implantation of the catheters in unanesthetized , unrestrained rats in metabolic cages .
the indwelling catheter to the bladder was connected to a two - way valve that was connected via a t - tube to a pressure transducer ( research grade blood pressure transducer ; harvard apparatus , holliston , usa ) and a microinjection pump ( phd22/2,000 pump ; harvard apparatus ) .
another catheter connected to an air - free abdominal balloon was connected to another pressure transducer to record the iap .
micturition volumes were recorded by means of a fluid collector connected to a force displacement transducer ( research grade isometric transducer ; harvard apparatus ) .
room - temperature saline was infused into the bladder continuously at a rate of 10 ml / h .
ivp , iap , and micturition volumes were recorded continuously with acq knowledge 3.8.1 software and an mp150 data acquisition system ( biopac systems , goleta , usa ) at a sampling rate of 100 hz .
iap was defined as the recorded balloon pressure corrected by subtracting the lowest balloon pressure in each voiding cycle , which is comparable to zeroing in human cystometry .
the ivp rises during the filling phase ( ivprs ) were defined as increments of ivp that exceeded 2 cmh2o from baseline , which was interpreted as abdominal straining if occurring with simultaneous similar changes in iap , or as do if occurring without simultaneous similar changes in iap .
the following conventional urodynamic pressure - volume parameters were investigated : micturition pressure ( mp , maximum bladder pressure during micturition ) , basal pressure ( bp , the lowest bladder pressure during filling ) , threshold pressure ( tp , bladder pressure immediately before micturition ) , bladder capacity ( bc , residual volume at the most recent previous micturition plus the volume of infused saline at micturition ) , micturition volume ( mv , volume of expelled urine ) , residual volume ( rv , bladder capacity minus micturition volume ) , and micturition interval ( mi , time between micturition events ) .
the following do - related parameters during the filling phase were observed : time of filling phase ( interval between the end of a micturition and the point immediately before the next micturition ) , total number of do , frequency of do per minute , and increased amplitude of do as ivp . in all groups , a period of about 30 - 60-min micturition cycles was observed and the values from reproducible micturition cycles were used for evaluation .
stock solutions ( 0.01 m ) of pge2 ( sigma chemical co. , st louis , usa ) were made in absolute ethanol and were then diluted to 50 m in saline just before use .
propiverine 1 or 3 mg / kg was infused into the femoral artery after the baseline cystometry .
the rats were randomly allocated to the following four treatment groups after control cystometries with saline : 1 ) intraarterial propiverine 1 mg / kg only ( n=6 ) , 2 ) intravesical pge2 only ( n=6 ) , 3 ) intravesical pge2 and intraarterial propiverine 1 mg / kg ( n=4 ) , or 4 ) intravesical pge2 and intraarterial propiverine 3 mg / kg ( n=6 ) .
normal distributions were confirmed by use of sigmastat 2.0 ( spss inc , chicago , usa ) .
a total of 22 sprague - dawley ( sd ) female rats weighing between 200 and 250 g were used in this study .
all procedures were performed in accordance with the guide for the care and use of laboratory animals of the national institutes of health and were approved by the inha - university animal ethics committee .
the rats were maintained under standard laboratory conditions with a 12:12 h light : dark cycle and with free access to food pellets and tap water .
simultaneous ivp and iap were continuously recorded during bladder filing and emptying as described previously .
in brief , sd rats were anesthetized with ketamine ( ketamine ; yuhan corp , seoul , korea ; 75 mg / kg intraperitoneally ) and xylazine ( rompun ; bayer korea corp , korea ; 15 mg / kg intraperitoneally ) . through a low abdominal incision ,
a polyethylene catheter ( pe-50 ; becton dickinson , parsippany , usa ) with a cuff was inserted into the dome of the bladder and was held in place with a purse - string suture .
to record iap , an abdominal balloon ( latex ; daewoo medical , incheon , korea ) around the cuff of a catheter tip was placed 1 cm proximal to the bladder along the catheter to the bladder and was attached with a silk tie to the catheter .
these catheters were tunneled subcutaneously and anchored to the skin of the back with a silk ligature .
cystometry was performed 3 days after implantation of the catheters in unanesthetized , unrestrained rats in metabolic cages .
the indwelling catheter to the bladder was connected to a two - way valve that was connected via a t - tube to a pressure transducer ( research grade blood pressure transducer ; harvard apparatus , holliston , usa ) and a microinjection pump ( phd22/2,000 pump ; harvard apparatus ) .
another catheter connected to an air - free abdominal balloon was connected to another pressure transducer to record the iap .
micturition volumes were recorded by means of a fluid collector connected to a force displacement transducer ( research grade isometric transducer ; harvard apparatus ) .
room - temperature saline was infused into the bladder continuously at a rate of 10 ml / h .
ivp , iap , and micturition volumes were recorded continuously with acq knowledge 3.8.1 software and an mp150 data acquisition system ( biopac systems , goleta , usa ) at a sampling rate of 100 hz .
iap was defined as the recorded balloon pressure corrected by subtracting the lowest balloon pressure in each voiding cycle , which is comparable to zeroing in human cystometry .
the ivp rises during the filling phase ( ivprs ) were defined as increments of ivp that exceeded 2 cmh2o from baseline , which was interpreted as abdominal straining if occurring with simultaneous similar changes in iap , or as do if occurring without simultaneous similar changes in iap .
the following conventional urodynamic pressure - volume parameters were investigated : micturition pressure ( mp , maximum bladder pressure during micturition ) , basal pressure ( bp , the lowest bladder pressure during filling ) , threshold pressure ( tp , bladder pressure immediately before micturition ) , bladder capacity ( bc , residual volume at the most recent previous micturition plus the volume of infused saline at micturition ) , micturition volume ( mv , volume of expelled urine ) , residual volume ( rv , bladder capacity minus micturition volume ) , and micturition interval ( mi , time between micturition events ) .
the following do - related parameters during the filling phase were observed : time of filling phase ( interval between the end of a micturition and the point immediately before the next micturition ) , total number of do , frequency of do per minute , and increased amplitude of do as ivp . in all groups , a period of about 30 - 60-min micturition cycles was observed and the values from reproducible micturition cycles were used for evaluation .
stock solutions ( 0.01 m ) of pge2 ( sigma chemical co. , st louis , usa ) were made in absolute ethanol and were then diluted to 50 m in saline just before use .
propiverine 1 or 3 mg / kg was infused into the femoral artery after the baseline cystometry .
the rats were randomly allocated to the following four treatment groups after control cystometries with saline : 1 ) intraarterial propiverine 1 mg / kg only ( n=6 ) , 2 ) intravesical pge2 only ( n=6 ) , 3 ) intravesical pge2 and intraarterial propiverine 1 mg / kg ( n=4 ) , or 4 ) intravesical pge2 and intraarterial propiverine 3 mg / kg ( n=6 ) .
normal distributions were confirmed by use of sigmastat 2.0 ( spss inc , chicago , usa ) .
there were no significance differences in pressure- or volume - related parameters before and after the administration of propiverine 1 mg / kg in normal rats .
thus , we showed that propiverine 1 mg / kg had no effect on pressure - volume parameters in normal rats ( table 1 ) .
the rats showed no changes in iap recorded at the point of bp , tp , or mp after intravesical instillation of pge2 50 m compared with baseline cystometries .
the rats administered intravesical pge2 50 m and simultaneous intraarterial propiverine 1 mg / kg also showed no changes in iap at those three points compared with baseline and pge2-instilled cystometries . the rats administered intravesical pge2
50 m and simultaneous intraarterial propiverine 3 mg / kg showed increased iap at mp ( p<0.05 ) only compared with baseline cystometries ( table 2 ) .
recorded as ivp or dp , oab was successfully induced in rats by intravesical instillation of pge2 , which resulted in increases in bp , tp , and mp compared with baseline cystometries ( p<0.01 , p<0.05 , and p<0.01 , respectively ) .
the rats administered pge2 and propiverine 1 mg / kg showed decreased bp by ivp ( p<0.01 ) , compared with pge2-instilled cystometries , and decreased mp by ivp and dp ( p<0.01 , p<0.01 ) , compared with baseline cystometries .
the rats administered pge2 and propiverine 3 mg / kg showed decreased bp by ivp and dp ( p<0.01 and p<0.01 , respectively ) , compared with pge2-instilled cystometries , and decreased mp by ivp and dp ( p<0.01 and p<0.01 , respectively ) , compared with baseline cystometries ( table 3 ) .
oab was successfully induced in rats by intravesical instillation of pge2 , which resulted in decreases in bc , vv , and mi without changes in rv , compared with baseline cystometries ( p<0.05 , p<0.05 , and p<0.05 , respectively ) .
the rats administered pge2 and propiverine 1 or 3 mg / kg showed no change in volume - related parameters compared with baseline or pge2-instilled cystometries ( table 4 ) .
after intravesical instillations of pge2 , do of 2.00.42 /min was observed ( p<0.01 ) compared with baseline cystometries .
however , do was not significantly decreased after propiverine injection in rats with intravesical pge2 instillation ( table 5 ) .
there were no significance differences in pressure- or volume - related parameters before and after the administration of propiverine 1 mg / kg in normal rats .
thus , we showed that propiverine 1 mg / kg had no effect on pressure - volume parameters in normal rats ( table 1 ) .
the rats showed no changes in iap recorded at the point of bp , tp , or mp after intravesical instillation of pge2 50 m compared with baseline cystometries .
the rats administered intravesical pge2 50 m and simultaneous intraarterial propiverine 1 mg / kg also showed no changes in iap at those three points compared with baseline and pge2-instilled cystometries . the rats administered intravesical pge2
50 m and simultaneous intraarterial propiverine 3 mg / kg showed increased iap at mp ( p<0.05 ) only compared with baseline cystometries ( table 2 ) .
recorded as ivp or dp , oab was successfully induced in rats by intravesical instillation of pge2 , which resulted in increases in bp , tp , and mp compared with baseline cystometries ( p<0.01 , p<0.05 , and p<0.01 , respectively ) .
the rats administered pge2 and propiverine 1 mg / kg showed decreased bp by ivp ( p<0.01 ) , compared with pge2-instilled cystometries , and decreased mp by ivp and dp ( p<0.01 , p<0.01 ) , compared with baseline cystometries .
the rats administered pge2 and propiverine 3 mg / kg showed decreased bp by ivp and dp ( p<0.01 and p<0.01 , respectively ) , compared with pge2-instilled cystometries , and decreased mp by ivp and dp ( p<0.01 and p<0.01 , respectively ) , compared with baseline cystometries ( table 3 ) .
oab was successfully induced in rats by intravesical instillation of pge2 , which resulted in decreases in bc , vv , and mi without changes in rv , compared with baseline cystometries ( p<0.05 , p<0.05 , and p<0.05 , respectively ) .
the rats administered pge2 and propiverine 1 or 3 mg / kg showed no change in volume - related parameters compared with baseline or pge2-instilled cystometries ( table 4 ) .
after intravesical instillations of pge2 , do of 2.00.42 /min was observed ( p<0.01 ) compared with baseline cystometries .
however , do was not significantly decreased after propiverine injection in rats with intravesical pge2 instillation ( table 5 ) .
oab is known to include various different pathophysiologic mechanisms . recently , among those mechanisms , special attention has been given to the sensory and afferent mechanisms .
research on the new generation of oab drugs is focused on the inhibition of afferent firing before the generation of a detrusor contraction during the filling phase , whereas the present anticholinergic drugs suppress the afferent firing after the generation of do .
the intravesical pge2 instillation method , one of the oab models , induces do by the indirect activation of afferent nerves in the bladder as well as the direct activation of detrusor muscle .
when the bladder is injured or stimulated , the prostanoids activate capsaicin - sensitive afferents .
then , tachykinins are released from the afferents , which lower the threshold for afferent firing , and , finally , stimulate the detrusor to induce overactivity [ 15 - 17 ] .
experimentally , the tachykinins initiate a micturition reflex by stimulating nk1,nk2 receptors , and intravesical prostanoids can induce do in cystometry in vivo . in our study ,
the cystometric features of oab patients were successfully generated by intravesical prostanoids in rats , which showed increased bp , tp , and mp and decreased bc , mv , and mi . the detrusor contraction is mainly caused by stimulating muscarinic receptors , and the m3 subtype in particular is believed to have the most major action for detrusor contraction . in general , anticholinergic drugs inhibit involuntary detrusor contraction during the storage phase , but they do not significantly affect contractions during the voiding phase , because the quantity of acetylcholine is several dozen times higher than that during the storage phase . in the present study , propiverine significantly decreased bp only , the basal tension of the bladder , in the intravesical pge2 group and showed no effect on mp , bc , vv , or mi .
this might be partly related to the accumulation of continuously infused intravesical prostanoids in this rat model .
however , we know that there were some effects of the propiverine , because this group showed no differences in pressure or volume parameters compared with the control group , unlike the intravesical pge2 only instillation group .
if we look at the effects by different concentrations of propiverine on the pge2-instilled state of rat bladder , propiverine 3 mg / kg decreased bp by dp but not by ivp , whereas propiverine 1 mg / kg showed no decrease in bp by either ivp or dp .
this suggests that the higher dose of propiverine decreased the basal tension of the detrusor .
this is not in accordance with previously reported studies , in which the investigators did not observe any difference in bp , but only in mp .
our study is the first observation of propiverine effects in the animal model of prostanoid - induced oab .
the volume parameters were significantly decreased after pge2 instillation and increased to the levels of control rats after propiverine injection .
this suggests that propiverine inhibits the effects of pge2 , regardless of concentrations of propiverine .
also , do was not seen in control rats , but was shown in pge2-instilled animals .
the propiverine showed no effects on the frequency or pressure of do , which is in contrast with the conventional concept for anticholinergic drugs .
we conclude that the propiverine did not have any effect on the do in animal models of prostanoid - induced oab .
this is supported by the fact that some anticholinergic drugs for oab show no effects in some patients .
the side effects of anticholinergic drugs are well known and described through clinical and basic research . however , straining voiding , which is a complaint from some people taking anticholinergic medication , has not been well investigated in previous reports .
this symptom is a straining of the abdomen to void because of feeling difficulty in voiding or a sense of residual urine and could be related to urinary retention . in the present study , we checked the grade of straining during the voiding phase by using our models .
there were no differences in abdominal straining on mp between the control rats and the pge2-induced oab model .
straining was not increased after infusion of propiverine 1 mg / kg but was significantly increased after infusion of propiverine 3 mg / kg .
this suggests that in the oab model , taking a higher dose of anticholinergic drugs showed more straining during voiding .
this finding may be associated with acute urinary retention and dysuria , which are among the complications of anticholinergic drugs .
according to the study by elisa et al , which was based on patient information collected by general practitioners in the united kingdom , increased risk of voiding difficulty and acute urinary retention were observed in patients administered anticholinergic drugs , and these patients should be closely monitored during the first 30 days of treatment for signs or symptoms of urinary retention .
therefore , the presence and significance of these symptoms need to be taken into consideration when elucidating the side effects of anticholinergic drugs in future research .
propiverine improved pressure and volume - related parameters in an oab model induced by intravesical pge2 , showing that propiverine can inhibit the activation of bladder contractions and possibly providing experimental evidence for decreased urgency symptoms after administration of propiverine in patients . furthermore , propiverine also decreased the do frequency .
however , a higher concentration of propiverine induced straining voiding , suggesting the need for clinical studies of the side effects of anticholinergic drugs , which are still unknown .
Output:
| purposewe investigated the effect of propiverine on cystometric parameters based on intraabdominal pressure ( iap ) in awake rats in an overactive bladder ( oab ) model induced by intravesical instillation of prostaglandin e2 ( pge2).materials and methodstwenty - two female sprague - dawley rats were used .
polyethylene catheters were implanted into the bladder to record the intravesical pressure ( ivp ) and into the femoral artery to administer medication .
a balloon - fitted catheter was positioned in the abdominal cavity to record the iap .
awake cystometries were performed before and after intraarterial administration of propiverine 1 mg / kg ( n=6 ) , intravesical administration of 50 m pge2 only ( n=6 ) , or intravesical pge2 plus 1 mg / kg ( n=4 ) or 3 mg / kg ( n=6 ) of intraarterial propiverine .
cystometric pressure and volume parameters and variables related to detrusor overactivity ( do ) were investigated.resultsrats administered intravesical pge2 showed increased pressure parameters and decreased volume parameters comparable to the do model , which was effectively prevented by propiverine ( 1 or 3 mg / kg ) .
typical do shown during the filling phase was decreased by intraarterial propiverine ( 3 mg / kg ) injection .
after propiverine ( 3 mg / kg ) injection , iap was increased at the time of micturition pressure with or without threshold pressure ( p<0.05 , p<0.01 ) depending on the dose administered.conclusionspropiverine improved pressure- and volume - related parameters in an oab model .
furthermore , it also decreased the frequency of do .
however , higher concentrations of propiverine induced straining voiding . |
PubmedSumm8855 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
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the output is the summary of an input biomedical literature in six sentences
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Input: invasion is a most important and characteristic step in the complicated process of cancer cells .
the blockage of these biological events by drugs or factors from food and natural resources will prolong the life span of an affected host .
our previous research showed that green , oolong , and black tea extracts , the sera from rats orally given these teas , and related components inhibited the proliferation and invasion of a rat ascites hepatoma cell line of ah109a through induction of apoptosis and cell cycle arrest and antioxidative activity .
lignans also suppressed both the proliferation and invasion of ah109a hepatoma cells in vitro , and hence solid tumor growth and metastasis of ah109a cells in vivo .
resveratrol ( 3,5,4-trihydroxy - trans - stilbene ) is known to possess cancer chemopreventive activity and strong antioxidative activity .
hsieh et al . reported that resveratrol showed a greater antiproliferative effect on highly invasive breast carcinoma cells ( mda - mb-435 ) than on minimally invasive cells ( mcf-7 ) .
however , our previous study showed that , in the hepatoma cells , resveratrol as such showed a weaker suppressive effect on the proliferation than on the invasion , and the sera from rats orally given resveratrol completely lost the antiproliferative activity in culture , although its anti - invasive activity was maintained [ 8 , 9 ] .
these findings suggest that the effect of resveratrol on the proliferation may be dependent on cancer cell properties .
piceatannol ( 3,4,3,5-tetrahydroxy - trans - stilbene ) , an analogue of resveratrol , has been reported to induce apoptosis and cell cycle arrest in human melanoma cell ( sk - mel-28 ) . in the present study
, we examined whether piceatannol or its in vivo metabolite(s ) would have antiproliferative and anti - invasive effects against ah109a and their modes of actions .
, osaka , japan ) and the piceatannol solution was added to the medium at a final ethanol concentration of 0.2% .
the animal experiments in this article were conducted in accordance with guidelines established by the animal care and use committee of tokyo university of agriculture and technology and were approved by this committee .
male donryu rats ( 4 weeks of age ) were purchased from nrc haruna ( gunma , japan ) .
ah109a cells were generously provided by the cell resource center for biomedical research , tohoku university , sendai , japan .
ah109a cells were maintained in peritoneal cavity of male donryu rats and isolated from accumulated ascites and then cultured in eagle 's minimum essential medium ( mem ) ( nissui pharmaceutical co. , tokyo , japan ) containing 10% calf serum ( cs , jrh biosciences , lenaxa , ks , usa ) ( 10% cs / mem ) .
these cells were cultured for at least 2 weeks after isolation to eliminate contaminated macrophages and neutrophils and used for the assays described hereinafter .
effect of piceatannol on ah109a proliferation was examined by measuring the incorporation of [ methyl - h]thymidine ( 0.15 ci / well , specific radioactivity ; 20 ci / mmol , perkinelmer life and analytical sciences , boston , ma , usa ) into dna as described previously [ 8 , 11 ] .
effect of piceatannol on ah109a invasion was estimated by coculturing ah109a cells with rat mesentery - derived mesothelial cell ( m - cell ) monolayers , which were isolated and cultured from donryu rats as described previously with slight modifications .
briefly , mesothelial cells ( m - cells ) were isolated from mesentery of male donryu rats ( 68 weeks of age ) .
after digestion by trypsin , 1.32.0 10 m - cells were plated in a 60 mm culture dish with 2 mm grids ( corning incorporated , corning , ny , usa ) and cultured for 57 days to attain a confluent state in 10% cs / mem .
then , ah109a cells ( 2.4 10 cells per dish ) were applied on the monolayer of m - cells in 10% cs / mem with piceatannol for 24 h. invaded cells and colonies underneath m - cells were counted with a phase - contrast microscope .
the invasive activity of ah109a cells was expressed as the number of invaded cells and colonies / cm .
piceatannol was suspended in a 0.3% carboxymethyl cellulose sodium salt ( cmc , wako pure chemical industries , osaka , japan ) aqueous solution at concentrations of 0.25 , 0.5 , and 1 mg / ml , unless otherwise noted .
piceatannol suspension or 0.3% cmc alone ( vehicle control ) ( 1 ml/100 g body weight ) was intubated to male donryu rats ( 5 weeks old ) which had been fasted overnight , and blood was collected 2 h after oral administration as described previously [ 8 , 13 ] .
the sera were prepared by centrifugation , sterilized by filtration , and added to the culture medium at a concentration of 10% instead of cs . for cell cycle analysis , 3.0 10 cells of ah109a per
well were seeded in a 6-well plate in the medium containing various concentrations of piceatannol and cultured for 24 h. cells were collected and washed twice with sterilized , ca- and mg - free , phosphate - buffered saline [ pbs( ) ] .
thereafter , 500 l of propidium iodide ( pi ) solution containing 1 mg of pi ( sigma chemical co. , st .
louis , mo , usa ) in 20 ml of 1% triton x-100 ( sigma ) and 0.1% of sodium citrate ( wako pure chemical industries ltd .
, osaka , japan ) was added and cells were incubated for 30 min on ice .
cells at different cell cycle phases were then analyzed with a flow cytometer ( epics elite eps , beckman - coulter , hialeah , fl , usa ) as previously described .
the effect of piceatannol on apoptosis in ah109a cells was assessed using annexin - v - fitc kit ( immunotech , marseille , france ) according to the manufacturer 's instructions .
phosphatidylserine ( ps ) , which can specifically bind to annexin - v , is one of the phospholipids in the cell membrane and exists predominantly in inner leaflet of the cell membrane of normal cells .
when apoptosis occurs , ps in the cell membrane immediately appears on the outer leaflet of the cell membrane .
the cells with ps on their surface can thus be thought to be early apoptotic cells .
briefly , 5 10 cells of ah109a per well were seeded in a 6-well plate and cultured in the medium containing 0 , 50 , and 100 m piceatannol for 3 h. at the end of culture , cells were labeled with annexin - v - fitc and analyzed with a flow cytometer as described previously .
ah109a cells were cultured for 4 h in the absence or presence of 10 m piceatannol with or without 25 m hydrogen peroxide ( h2o2 , wako pure chemical industries ) .
ah109a cells were then washed once with 10% cs / mem and seeded on the m - cell monolayer in 10% cs / mem without piceatannol and ros . after cultured for 24 h , invaded cells and colonies underneath m - cells
intracellular peroxide levels in ah109a cells were assessed by flow cytometric analysis using a fluorometric probe ( 2,7-dichlorofluorescin diacetate ; dcfh - da , molecular probes , eugene , or ) with a flow cytometer as described previously .
male donryu rats ( 3 weeks of age ) were maintained on a stock pellet diet ( ce-2 , clea japan , tokyo , japan ) for 10 days .
starting 4 days prior to ah109a cell injections , the rats were fed ain-93 g basal diet containing 20% casein ( oriental yeast co. , ltd . , tokyo , japan ) , 39.75% -corn starch ( nihon nosan kogyo co. ltd . , yokohama , japan ) , 13.2% -corn starch ( nihon nosan kogyo co. ltd . ) , 10% sucrose ( nihon nosan kogyo co. ltd . ) , 7% corn oil ( miyazawa yakuhin co. ltd . ,
tokyo , japan ) , 5% cellulose powder ( oriental yeast co. , ltd . ) , 3.5% mineral mixture ( ain-93 g composition , nihon nosan kogyo co. ltd . ) , 1% vitamin mixture ( ain-93 composition , nihon nosan kogyo co. ltd . ) , 0.3% l - cystine ( wako pure chemical industries , ltd . ) , and 0.25% choline bitartrate ( wako pure chemical industries , ltd . ) .
piceatannnol was given to rats by adding 0.001% and 0.005% to the basal diet at the expense of -corn starch .
each rat was implanted subcutaneously on one site in the dorsal region with 110 ah109a cells suspended in pbs( ) ( 0.5 ml / rat ) to produce a solid tumor , as described previously .
the tumor size is expressed as the sum of three measured dimensions , that is , height , length , and width . on day 20
, the rats were deprived of their diets at 9:00 but allowed free access to water until they were sacrificed at 13:00 .
metastatic tumor foci in lung and inguinal and axillary lymphatic nodes were macroscopically examined and excised , and the number of metastatic foci was recorded .
multiple comparison was performed by one - way analysis of variance ( anova ) followed by tukey - kramer multiple comparisons test , and p < 0.05 was considered statistically significant .
when added to medium , piceatannol dose - dependently and significantly reduced the proliferation of ah109a hepatoma cells .
it commenced to decrease at 12.5 m and continued to decrease up to 200 m ( figure 1(a(a ) ) ) .
of sera obtained from rats 1 , 2 , 3 , and 6 hours after oral administration of piceatannol at a dose of 10 mg / kg body weight , serum obtained 2 hours after administration was found to show most prominent inhibitory effect against both the proliferation and invasion of ah109a hepatoma cells ( data not shown ) .
thus , we prepared sera obtained from rats 2 hours after oral administration of piceatannol at doses 0 , 2.5 , 5 , and 10 mg / kg body weight .
these sera also reduced dose - dependently and significantly the proliferation of ah109a cells as seen in figure 1(a(b ) ) .
when added to medium , piceatannol was demonstrated to induce cell cycle arrest at g2/m phase in ah109a cells at lower concentrations of 25 and 50 m ( figures 1(b(b ) ) and 1(b(c ) ) ) as compared with the control ( 0 m ) ( figure 1(b(a ) ) ) .
in contrast to the effect on cell cycle , piceatannol failed to induce apoptosis at lower concentration of 50 m as compared with the control ( figures 1(c(a ) ) and 1(c(b ) ) ) .
however , it induced strong apoptosis at higher concentration of 100 m ( figure 1(c(c ) ) ) . when added to medium , piceatannol dose - dependently and
it commenced to decrease at 12.5 m and continued to decrease up to 200 m ( figure 2(a(a ) ) ) .
sera obtained from rats 2 hours after oral administration of piceatannol at doses 0 , 2.5 , 5 , and 10 mg / kg body weight also reduced dose - dependently and significantly the invasion of ah109a cells as shown in figure 2(a(b ) ) . to examine whether or not piceatannol would inhibit the invasion of tumor cells by its antioxidative activity , the invasion assay was performed with ah109a cells precultured in hydrogen peroxide- ( ros- ) containing medium for 4 hours . as shown in figure 2(b(a ) ) , the invasive activity of ah109a cells precultured in ros ( 25 m hydrogen peroxide ) was significantly higher than that of ah109a cells with no treatment .
piceatannol suppressed the ros - potentiated invasive activity of the precultured cells when added to the medium at a concentration of 10 m on preculturing the hepatoma cells with ros . in our preliminary experiment , 12.5 m of piceatannol exposure for 4 hours to ah109a cells exerted no influence on the following ah109a proliferation during 24 hours ( data not shown )
thus , the concentration of 10 m of piceatannol was adopted in this experiment to avoid an influence of the piceatannol - mediated proliferation inhibition on the ah109a invasion . as illustrated in figure 2(b(b ) ) , ah109a cells treated with 100 m hydrogen peroxide for 4 hours contained more intracellular peroxides than did control cells when analyzed with a flow cytometer using dcfh - da as an indicator ( control versus h2o2 ) .
piceatannol ( 10 m ) suppressed the rise in the intracellular peroxide levels of ah109a cells ( h2o2 versus h2o2 and piceatannol ) .
dietary piceatannol ( 0.001% and 0.005% ) tended to suppress the ah109a tumor size dose - dependently , although significant differences were not seen ( figure 3(a ) ) .
accordingly , at the end of the 20-day treatment period , the weights of solid tumors were lower in the piceatannol - treated groups than in the control group ( figure 3(b ) ) .
the solid tumor weight of the 0.005% piceatannol group was significantly reduced from 20.5 4.4 ( control ) to 9.4 2.5 ( 0.005% piceatannol group ) g / rat , indicating that ca .
numbers of metastatic foci were 0.22 , 0.2 , and 0 ( number / rat ) in the control , 0.001% , and 0.005% piceatannol groups , respectively .
in the present study , piceatannol was demonstrated to inhibit both the proliferation and invasion of ah109a hepatoma cells in vitro .
sera obtained from donryu rats orally given piceatannol also inhibited both the proliferation and invasion of ah109a hepatoma cells ex vivo . in our previous experiment ,
the sera obtained from donryu rats orally given resveratrol completely lost the antiproliferative activity ex vivo , although its anti - invasive activity was preserved [ 8 , 9 ] .
these previous and present findings suggest that metabolism of resveratrol by intestinal flora , intestine itself , or in the liver may be different from that of piceatannol .
precise reasons for the difference between two stilbenoids , however , are unclear at present . to elucidate the mechanisms for the inhibition of hepatoma cell proliferation by piceatannol ,
the effect of piceatannol treatment on cell cycle and on the rate of apoptosis was examined by using flow cytometry .
piceatannol was found to suppress the proliferation from lower concentrations ( ~25 m ) by arresting cell cycle of ah109a cells at g2/m phase ( figure 1(b ) ) .
furthermore , piceatannol increased the rate of apoptosis at higher concentrations ( ~100 m ) ( figure 1(c ) ) .
dependencies of cell cycle arrest and apoptosis induction on piceatannol concentrations are similar to those on -gingerol .
although the doses of piceatannol which induced apoptosis were higher than those which induced cell cycle arrest in ah109a hepatoma cells , these results suggest that piceatannol affects both cell proliferation and cell death which at least in part account for the inhibitory effect of piceatannol on the proliferation of ah109a cells .
our previous studies have demonstrated that the invasion of ah109a cells is accelerated by ros [ 16 , 17 ] . in the present study ,
we therefore examined the effect of piceatannol on the ros - potentiated invasive activity using h2o2 .
piceatannol was demonstrated to suppress the ros - induced elevation of the ah109a invasion ( figure 2(b(a ) ) ) .
we have found that ros can induce gene expression of hepatocyte growth factor ( hgf ) , which is known as a cell motility factor , in m - cells as well as ah109a cells [ 9 , 16 ] .
thus , hgf produced by ah109a and m - cells may potentiate the motility of ah109a cells , leading to acceleration of the invasion of ah109a cells .
if piceatannol , like resveratrol , suppresses the production of hgf through antioxidative activity , piceatannol may reduce the motility of ah109a invasion , this leading to the reduction of the ah109a invasion . although preliminarily , we have measured hgf secretion from ah109a cells by elisa .
piceatannol was found to dose - dependently suppress the hgf secretion after exposure of ah109a to piceatannol for 1 hour or 24 hours at the concentration ranges of 25100 m ( data not shown ) , suggesting an involvement of decreased hgf secretion in anti - invasive activity of piceatannol against ah109a hepatoma cells .
although not significant , piceatannol dose - dependently suppressed solid tumor size in hepatoma - bearing rats ( figure 3(a ) ) . however , solid tumor weights , a most simple but reliable index for tumor growth , were significantly reduced by feeding the 0.005% diet ( figure 3(b ) ) .
in addition to in vitro efficacy , piceatannol is demonstrated to be effective in vivo in suppressing tumor growth .
antimetastatic effect of piceatannol was not clear in vivo in the present study , this being probably due to weak metastatic activity in the control group .
selection and use of highly metastatic ah109a cell clone will clarify the in vivo antimetastatic effect of piceatannol . in summary ,
piceatannol was clearly demonstrated to suppress both the proliferation and invasion of ah109a hepatoma cells in vitro and ex vivo .
antiproliferative effect might be due to induction of cell cycle arrest and apoptosis in ah109a , while anti - invasive effect might be due to anti - oxidative property of piceatannol .
as was expected , piceatannol is shown to significantly suppress the solid tumor growth in vivo .
these functions of piceatannol may be of significance from the aspects of both nutritional and pharmacological control of cancers .
Output:
| piceatannol is a stilbenoid , a metabolite of resveratrol found in red wine .
piceatannol and sera from rats orally given piceatannol were found to dose - dependently suppress both the proliferation and invasion of ah109a hepatoma cells in culture .
its antiproliferative effect was based on cell cycle arrest at lower concentration ( 25~50 m ) and on apoptosis induction at higher concentration ( 100 m ) .
piceatannol suppressed reactive oxygen species - potentiated invasive capacity by scavenging the intracellular reactive oxygen species .
these results suggest that piceatannol , unlike resveratrol , has a potential to suppress the hepatoma proliferation by inducing cell cycle arrest and apoptosis induction .
they also suggest that the antioxidative property of piceatannol , like resveratrol , may be involved in its anti - invasive action .
subsequently , piceatannol was found to suppress the growth of solid tumor and metastasis in hepatoma - bearing rats .
thus , piceatannol may be a useful anticancer natural product . |
PubmedSumm8856 | ***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 mellitus is a heterogeneous metabolic disorder characterized by altered carbohydrate , lipid and protein metabolism .
the chronic hyperglycemia of diabetes is associated with long term damage , dysfunction and failure of various organs . in diabetic rats ,
however , complete cure of the disease has been eluding physicians for centuries and the quest for the development of more effective anti - diabetic agents is pursued relentlessly .
many herbal products , including several metals and minerals have been described for the cure of diabetes mellitus in ancient literature .
ruellia tuberosa l. is a tropical plant and widely distributed in southeast asia . in folk medicine
, it has been used as anti - diabetic , antipyretic , analgesic , anti hypertensive , thirst- quenching , and antidotal agent .
dipteracanthus patulus ( jacq . ) belongs to the family acanthaceae , it is used for curing eyesore by introducing the extract into the eyelid .
the leaves were ground into paste and used to treat fresh wounds , itches , insect bites , venereal diseases , sores , tumors and rheumatic complaints .
the fresh leaves of ruellia tuberosa l. and dipteracanthus patulus ( jacq . ) were collected from abs ( altogether botanical species ) medicinal plants garden , karipatti , salem , tamil nadu , india .
the plant was identified by the herbarium of botanical survey of india ( bsi ) southern circle , tamil nadu agricultural university ( tnau ) ( no : bsi / sc/5/23/08 - 09/tech- 118 , 229 ) .
the fresh leaves of ruellia tuberosa l. and dipteracanthus patulus ( jacq . ) collected ( 6 kg ) , were shade dried for five days and crushed to coarse powder ( 3 kg ) .
the coarse powder thus obtained was cold macerated with 1.5 liters of 50% ethanol ( ethanol : water in 1:1 ratio ) and kept for 3 days at room temperature , with occasional stirring .
the suspension was filtered through a fine muslin cloth and was evaporated to dryness at a low temperature ( at 40c ) under reduced pressure in a rotary evaporator .
healthy swiss albino rats of six to eight weeks old weighing about 110 - 120 g were obtained from the animal facility of psg institute of medical science and research ( no : 158/1999/cpcsea ) , coimbatore , india . the rats were grouped and housed in polyacrylic cages and maintained under standard conditions ( 25 2c ) with 12 1 h dark / light cycle .
all procedures described were reviewed and approved by the animal ethical committee ( aec ) .
animals were allowed to fast for 18 h and were injected intraperitoneally with freshly prepared alloxan monohydrate in sterile normal saline at a dose of 120 mg / kg body weight .
the animals were divided into seven groups of six animals in each group , after two week acclimatization period .
group i ( normal control + normal saline 5 ml / kg body weight ) , group ii ( diabetic control ) , group iii ( drug control - glibenclamide 600 g / kg body weight ) , group iv ( diabetes + 250 mg / kg body weight 50% hert ) , group v ( diabetes + 500 mg / kg body weight 50% hert ) , group vi ( diabetes + 250 mg / kg body weight 50% hedp ) , group vii ( diabetes + 500 mg / kg body weight 50% hedp ) .
( 50% hedp / hert hydroethanolic leaf extract of ruellia tuberosa l./dipteracanthus patulus ( jacq . ) ) .
after the end of experimental period ( 30 days ) , the rats were fasted overnight and sacrificed by cervical decapitation .
serum was separated from the blood collected , by centrifugation and the serum was stored at 4c for biochemical analysis .
estimation of serum cholesterol was done by richmond ( 1973 ) , hdl - cholesterol was determined by castelli et al .
triglyceride and phospholipid was estimated by philip and mayne ( 1994 ) , raheja , et al . vldl ( very low density lipoprotein ) - cholesterol was calculated by ; triglyceride/5 ; ldl ( low density lipoprotein ) cholesterol .
data was reported as mean sd by using the statistical package of social sciences ( spss ) .
the data for all the parameters was analyzed by using analysis of variance ( anova ) and the group means were compared by duncan 's multiple range test ( dmrt ) .
the fresh leaves of ruellia tuberosa l. and dipteracanthus patulus ( jacq . ) were collected from abs ( altogether botanical species ) medicinal plants garden , karipatti , salem , tamil nadu , india .
the plant was identified by the herbarium of botanical survey of india ( bsi ) southern circle , tamil nadu agricultural university ( tnau ) ( no : bsi / sc/5/23/08 - 09/tech- 118 , 229 ) .
the fresh leaves of ruellia tuberosa l. and dipteracanthus patulus ( jacq . ) collected ( 6 kg ) , were shade dried for five days and crushed to coarse powder ( 3 kg ) .
the coarse powder thus obtained was cold macerated with 1.5 liters of 50% ethanol ( ethanol : water in 1:1 ratio ) and kept for 3 days at room temperature , with occasional stirring .
the suspension was filtered through a fine muslin cloth and was evaporated to dryness at a low temperature ( at 40c ) under reduced pressure in a rotary evaporator .
healthy swiss albino rats of six to eight weeks old weighing about 110 - 120 g were obtained from the animal facility of psg institute of medical science and research ( no : 158/1999/cpcsea ) , coimbatore , india .
the rats were grouped and housed in polyacrylic cages and maintained under standard conditions ( 25 2c ) with 12 1 h dark / light cycle .
all procedures described were reviewed and approved by the animal ethical committee ( aec ) .
animals were allowed to fast for 18 h and were injected intraperitoneally with freshly prepared alloxan monohydrate in sterile normal saline at a dose of 120 mg / kg body weight .
the animals were divided into seven groups of six animals in each group , after two week acclimatization period .
group i ( normal control + normal saline 5 ml / kg body weight ) , group ii ( diabetic control ) , group iii ( drug control - glibenclamide 600 g / kg body weight ) , group iv ( diabetes + 250 mg / kg body weight 50% hert ) , group v ( diabetes + 500 mg / kg body weight 50% hert ) , group vi ( diabetes + 250 mg / kg body weight 50% hedp ) , group vii ( diabetes + 500 mg / kg body weight 50% hedp ) .
( 50% hedp / hert hydroethanolic leaf extract of ruellia tuberosa l./dipteracanthus patulus ( jacq . ) ) . after the end of experimental period ( 30 days )
serum was separated from the blood collected , by centrifugation and the serum was stored at 4c for biochemical analysis .
estimation of serum cholesterol was done by richmond ( 1973 ) , hdl - cholesterol was determined by castelli et al .
triglyceride and phospholipid was estimated by philip and mayne ( 1994 ) , raheja , et al . vldl
( very low density lipoprotein ) - cholesterol was calculated by ; triglyceride/5 ; ldl ( low density lipoprotein ) cholesterol .
data was reported as mean sd by using the statistical package of social sciences ( spss ) .
the data for all the parameters was analyzed by using analysis of variance ( anova ) and the group means were compared by duncan 's multiple range test ( dmrt ) .
the results of the serum lipid profile [ figures 1 and 2 ] shows that in alloxan induced diabetic rats ( group ii ) there was not onlyhyperglycemia but also hyperlipidemia in which serum triglycerides , total cholesterol and phospholipids levels were increased significantly when compared to the control group ( group i ) .
treatment of diabetic rats with 50% hydro - ethanolic leaf extracts of ruellia tuberosa l. and dipteracanthus patulus ( jacq . )
( group iv to vii ) for 4 weeks resulted in a significant decrease in serum phospholipids , triglycerides , ldl - c and vldl - c and increase in hdl - c level was found as compared to diabetic control .
total cholesterol level was found to be significantly decreased in the administration of 500 mg / kg body weight of 50% hydro - ethanolic leaf extracts of ruellia tuberosa l. and dipteracanthus patulus ( jacq . ) .
group treated with glibenclamide 600 g / kg body weight was found to be effective in lowering the lipid profile level as compared to plant extracts treatment groups .
effect of 50% hydroethanolic leaf extracts of ruellia tuberosa l. and dipteracanthus patulus ( jacq . ) on cholesterol , triglycerides , and phospholipid levels in the serum of alloxan induced diabetic rats effect of 50% hydroethanolic leaf extracts of ruellia tuberosa l. and dipteracanthus patulus ( jacq . ) on hdl , ldl , and vldl - cholesterol levels in serum of alloxan induced diabetic rats
it has been established that diabetes mellitus causes change in the normal metabolism of lipids in diabetic rats .
it is seen that cholesterol and triglyceride were elevated in diabetic condition such an elevation represented the risk factor for coronary heart disease .
there was a reduction in the cholesterol and triglyceride level of diabetic rats after 50% hydro - ethanolic leaf extracts of ruellia tuberosa l. and dipteracanthus patulus ( jacq . )
it is well known that ldl plays an important role in arteriosclerosis and that hypercholesterolemia , which is associated with a defect relating to the lack of ldl receptors . in diabetes mellitus
, have reported that vldl and ldl level was found to be decreased and hdl level was increased during plant extracts treatment .
this study has shown that , oral administration of 50% hydro - ethanolic leaf extracts of ruellia tuberosa l. and dipteracanthus patulus ( jacq . ) was not effective in reducing the serum lipid levels associated with diabetes mellitus when compared to that of the drug ( glibenclamide 600 g / kg body weight ) administered .
we suggest that the lowering of lipids to certain level by 50% hydro - ethanolic leaf extracts of ruellia tuberosa l. and dipteracanthus patulus ( jacq . ) may be due to the presence of phytochemicals , which has been reported already
. however , further pharmacological investigations are needed to find out the mechanism of action of the active components involved .
Output:
| background : the study was undertaken to investigate the effect of 50% hydro -ethanolic leaf extracts of ruellia tuberosa l. and dipteracanthus patulus ( jacq . ) on lipid profile in alloxan induced diabetic rats.method:in lipid profile the parameters studied were serum total cholesterol , phospholipids , triglycerides , hdl - c , ldl - c and vldl - c level .
extracts were orally administered daily for 30 days at a dosage of 250 and 500 mg / kg bodyweight to alloxan induced diabetic rats.results:the levels of phospholipids , triglycerides , ldl - c and vldl - c were significantly ( p < 0.05 ) reduced .
the hdl - c level was found to be increased in the treatment groups .
total cholesterol level was found to be significantly ( p < 0.05 ) decreased at 500 mg / kg bodyweight of both the plant extracts treated groups.conclusion:the results further suggests that the effect of plant extract treated groups was found to be lower in reducing the lipid levels in serum when compared to the drug ( glibenclamide 600 g / kg body weight ) treated group . |
PubmedSumm8857 | ***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 recent decades participation in long - distance endurance exercise events ( e.g. , ironman triathlons , ultra - marathons , and ultra - distance cycling events ) , has increased substantially among recreational exercisers and competitive athletes ( 7 , 17 , 34 ) .
many of these events occur in extreme environmental conditions including high altitude or low or high ambient temperature .
such extreme environmental conditions provide substantial additional physiological stress beyond that induced by the long - distance exercise alone and thus can provide additional perturbations to homeostasis . high intensity endurance exercise and environmental stress independently can affect immune system function , but the combination of multiple stressors likely has a more drastic effect on the immune system ( 23 ) .
long - distance exercise alone affects populations of circulating immune cells that function in non - specific immunity .
marathon ( 42.195 km ) runners exhibit increases in total leukocytes ( ~4 fold ) , monocytes ( ~2.5 fold ) , neutrophils ( ~5.5 fold ) ( 8 , 14 ) , with only a minor increase ( ~1.25 fold ) ( 8) in lymphocytes from before to immediately after the event .
ultramarathon ( 160 km ) runners display a similar increase in total leukocytes and monocyte / neutrophil subsets , but exhibit a less dramatic increase in circulating lymphocytes compared to traditional marathon runners ( 27 , 37 ) .
similar results of a 12 fold increase in leukocytes , monocytes , neutrophils , has also been observed for 75-km cycling events ( 19 , 27 , 46 ) .
such long - distance exercise events impose a substantial mechanical and systemic physiological demand on the body , even in thermoneutral environments ( 46 ) .
it is likely that micro - trauma to musculature and vascular system , leakage of endotoxins from the gut to the circulation , and glycogen depletion ( 13 , 20 , 39 , 40 , 43 ) occur during ultra - endurance exercise and can instigate activation , differentiation , and demargination of leukocytes and greater systemic inflammation ( 13 ) .
hot and humid environmental conditions magnify the effect of exercise that occurs in thermoneutral environments .
studies of shorter duration running and cycling during hot and cold water immersion ( 40 min ) ( 6 , 33 ) and in temperature controlled laboratory settings ( 40 min to 4 h ) ( 3 , 16 , 21 , 23 , 38 ) demonstrate that exercise in a hot environment ( 3539c ) elicits greater increases in total leukocytes , neutrophils , and lymphocytes than exercising in a cold to moderate temperature environment ( 1823c ) ( 6 , 21 , 33 ) .
one study emphasized the inefficacy of a thermal clamp ( 16 ) in reducing the exercise - induced changes in circulating leukocyte populations .
however , it is interesting to note that the exercise protocol in this study did not elicit core body temperature increases above and beyond the passive heating control in which participants did not exercise .
it is likely that the core temperature increase associated with high intensity exercise alone has a role in instigating immune responses , in addition to the damage associated with long duration , eccentric exercise . despite the growing popularity of recreational long - distance exercise events no field or
controlled laboratory study appears to have investigated the nonspecific immune response to such prolonged endurance events ( > 4 h ) in a thermally stressful hot environment .
long - distance exercise in moderate temperature conditions induces an increase in leukocytes and in laboratory settings a hot environment augments the leukocyte response to shorter - distance exercise .
therefore , the purpose of this observational study was to determine the leukocyte subset response to completing a recreational 164-km road cycle event in an extremely hot and humid environment .
exercise duration and relative exercise intensity ( 42 ) likely have significant effects on the immune response , independent of the extreme environmental conditions .
thus , a secondary purpose of this study was to examine the associations among the time to complete the event , relative intensity ( % vo2max ) and changes in leukocyte subsets .
in order to determine the leukocyte subsets response to completing a recreational 164-km road cycle event in a hot ambient temperature we recruited adults registered for participating in the 2013 hottern hell hundred cycling event ( hhh ) . the procedures of the study were reviewed and approved by the university institutional review board and undertaken in compliance with the helsinki declaration .
on the day of the hhh , participants provided a blood sample in the morning 12 hours prior to the start of the event ( pre ) and immediately upon completion of the event ( post ) .
blood samples were analyzed for total leukocyte as well as leukocyte subsets : neutrophils , monocytes , and lymphocytes . in order to describe the immune response that recreational riders experience when completing the hhh , we aimed to minimize any effect of study involvement on participant behavior before and during the event . therefore , no instructions or restrictions were provided with regard to ride strategies ( e.g. , hydration / diet intake ,
number rest stops , pace of the ride , or length of the rest stops ) .
twenty - eight men and four women volunteered to participate and were enrolled in this study .
participants demographic information and ride characteristics ( e.g. , pace ) are presented in table 1 and 2 , respectively .
core temperature was not measured in the present study but based on findings from a prior year s hhh event ( same course and similar populations , environmental conditions ) it was expected to rise approximately 1.6 c from before to after the ride ( 1 ) .
participants were recruited through the hhh official event registration website , through invitation emails sent to all hhh entrants , and at the official hhh onsite event registration center ( wichita falls , tx ) .
upon review of the medical history , and with follow - up questions as needed , all participants were approved for participation by the on - site medical doctor . to be included in the study ,
volunteers were required to 1 ) be apparently healthy , 2 ) be 1862 years of age , 3 ) have previously completed a 160-km cycle ride , and 4 ) intent to complete the hhh ride within 9 hours .
participants were excluded if they met any of the following criteria : 1 ) tobacco product user ; 2 ) taking cholesterol - lowering , blood pressure , or anticoagulant medications ; 3 ) healing from a musculoskeletal injury ; 4 ) liver , kidney , cardiovacular , gastrointestinal or blood disease or severe metabolic or endocrine disorders ( e.g. , diabetes ) ; 5 ) past history of exertional heatstroke or exercise - heat inotlerance ; 6 ) use of anabolic hormonal substances .
a detailed description of the anthropometrics measurements used in this study has previously been published ( 15 ) .
briefly , anthropometric measurements were obtained on one of the two days preceding the event .
body weight and height was measured using a floor scale and a tape measure attached to the wall , respectively .
percent body fat was estimated using three - site ( men : chest , abdomen , thigh ; women : triceps , suprailiac , thigh ) skinfold thickness equations ( 18 ) using calibrated skinfold calibers ( bodycare harpenden caliper , england ) .
the hhh is among the largest recreational road cycle events ( > 10,000 participant annually ) in the usa and held every late - august in wichita falls , tx .
the 164-km course covers largely flat terrain ( 15 ) and is usually held under hot and humid conditions ( average wichita falls environmental conditions for late - august is 35c and humidity is 59% , with little to no cloud cover ) . on event day ,
dry bulb temperature , relative humidity , and wet bulb globe temperature were recorded at the start / finish line ( 7:31am to 3:24pm ) and at the 97-km aid station ( 8:17am to 12:32pm ) using the kestrel meter 4400 heat meter ( nielson - kellerman co. , boothwyn , pa , usa ) .
the ride began at 0700h and depending on starting position a particular rider might not pass the start line until as late as 0800h . participants without a computer - downloadable heart rate monitoring device were provided one to wear during the ride ( polar electro inc . , lake success , ny ) ; participants having their own computer - downloadable heart rate monitoring device were requested to provide heart rate data files via electronic mail within 7d after the event .
participant total ride time was determined using either the participant s own timer or a timer provided by the research team and was confirmed using official hhh ride electronic chip monitoring system .
participants were instructed to record the number of stops and the duration of each stop .
the rolling time was calculated as the difference between the total event time and the resting time .
heart rate was collected by standard telemetry using either participants own device or one provided by the investigators .
whole blood samples and urine sample were obtained 12 hours prior to the start of the ride ( pre ) and immediately after ( post ) completion of the event without fasting . upon arrival , participants were weighted and then sat for a few minutes after which 30ml of blood were collected from an antecubital vein using venipuncture by a 21 gauge needle with an evacuated tube containing edta , while participants remained in a seated position .
after blood collection , participants provided a small urine sample for determination of urine specific gravity .
participants were instructed to be arrive for the pre time point before performing their event warm - up .
the edta - treated whole blood samples were refrigerated and stored at 4c until biochemical analyses on the following morning .
participants were instructed to remember the food consumption during the ride and if possible , kept the food labels . upon arrival at the medical tent after the ride
, participants recorded the quantity and the type of food that were consumed or participants provided the food labels to investigators for them to record . prior to analysis , blood samples were diluted with an equal volume of phosphate buffered saline and results were adjusted to account for this dilution .
then complete blood count was measured in duplicate using a 20-l sample of diluted edta - whole blood loaded into an automatic hematology analyzer ( bc-3200 ; mindray , mahwah , nj ) . in this automated procedure ,
total ( total leukocytes ) wbc and three - part differentiation ( lymphocytes , monocytes , and neutrophils ) of wbc are measured using electrical impedance .
the analyzer has a precision of 2.5% and a linear range from 0.3~99.9 10cellsl for wbc .
the complete blood count analysis also included determination of hemoglobin ( hb ) concentration ( using a cyanide free method ) and hematocrit ( hct ) .
plasma volume change ( pv ) was determined by the change in hct and hb from pre to post using established methods ( 9 ) ( pv : 7.1 12.6% ) .
the post immune cell ( total leukocytes , lymphocytes , monocytes , and neutrophils ) concentration was adjusted according to individual pv .
the percent of body mass loss ( % bml ) was the fluid loss as percent of pre - body mass , and it was corrected for the weight of food consumed during the ride .
estimated relative exercise intensity during the ride was calculated through the estimation of % vo2max from exercise heart rate using an equation which was validated by franklin et al .
( 11 ) ( i.e. % vo2max = 1.33 x ( % hrmax ) - 37.3 ) .
the percent of maximum heart rate ( % hrmax ) was calculated using the maximum heart rate ( hrmax ) and the average heart rate ( hravg ) recorded during the cycling event . although it is not possible to determine if the recorded hrmax represents the true hrmax , the recorded hrmax ( 167 10 bpm ) was similar to but slightly less than the age predicted hrmax ( i.e. 208 ( 0.7 x age ) ; 174 6 bpm ) ( 44 ) . data were analyzed using spss version 20.0 ( ibm , chicago , il ) .
tests for normality of distribution and homogeneity of variance were performed for all data sets .
data sets that did not meet assumptions of linear statistics were log10 transformed and retested ; after transformation all data sets met these assumptions .
paired t - tests were used to evaluate the mean pre and post differences in total leukocytes , and each leucocyte subset ( neutrophils , monocytes , and lymphocytes ) concentrations . to examine the effect intensity and duration on total leukocytes and each leucocyte subset ,
first , pearson s product - moment correlation coefficients between pre to post changes and ride characteristics ( estimated relative exercise intensity and total rolling time ) were calculated .
then data for the fastest and slowest quartiles were examined using 2 ( time point : pre vs post ) 2 ( rolling time : fastest vs slowest quartile ) anovas with repeated measures on time point .
in order to determine the leukocyte subsets response to completing a recreational 164-km road cycle event in a hot ambient temperature we recruited adults registered for participating in the 2013 hottern hell hundred cycling event ( hhh ) . the procedures of the study were reviewed and approved by the university institutional review board and undertaken in compliance with the helsinki declaration .
on the day of the hhh , participants provided a blood sample in the morning 12 hours prior to the start of the event ( pre ) and immediately upon completion of the event ( post ) .
blood samples were analyzed for total leukocyte as well as leukocyte subsets : neutrophils , monocytes , and lymphocytes . in order to describe the immune response that recreational riders experience when completing the hhh , we aimed to minimize any effect of study involvement on participant behavior before and during the event . therefore , no instructions or restrictions were provided with regard to ride strategies ( e.g. , hydration / diet intake ,
number rest stops , pace of the ride , or length of the rest stops ) .
twenty - eight men and four women volunteered to participate and were enrolled in this study .
participants demographic information and ride characteristics ( e.g. , pace ) are presented in table 1 and 2 , respectively .
core temperature was not measured in the present study but based on findings from a prior year s hhh event ( same course and similar populations , environmental conditions ) it was expected to rise approximately 1.6 c from before to after the ride ( 1 ) .
participants were recruited through the hhh official event registration website , through invitation emails sent to all hhh entrants , and at the official hhh onsite event registration center ( wichita falls , tx ) .
upon review of the medical history , and with follow - up questions as needed , all participants were approved for participation by the on - site medical doctor . to be included in the study ,
volunteers were required to 1 ) be apparently healthy , 2 ) be 1862 years of age , 3 ) have previously completed a 160-km cycle ride , and 4 ) intent to complete the hhh ride within 9 hours .
participants were excluded if they met any of the following criteria : 1 ) tobacco product user ; 2 ) taking cholesterol - lowering , blood pressure , or anticoagulant medications ; 3 ) healing from a musculoskeletal injury ; 4 ) liver , kidney , cardiovacular , gastrointestinal or blood disease or severe metabolic or endocrine disorders ( e.g. , diabetes ) ; 5 ) past history of exertional heatstroke or exercise - heat inotlerance ; 6 ) use of anabolic hormonal substances .
a detailed description of the anthropometrics measurements used in this study has previously been published ( 15 ) .
briefly , anthropometric measurements were obtained on one of the two days preceding the event .
body weight and height was measured using a floor scale and a tape measure attached to the wall , respectively .
percent body fat was estimated using three - site ( men : chest , abdomen , thigh ; women : triceps , suprailiac , thigh ) skinfold thickness equations ( 18 ) using calibrated skinfold calibers ( bodycare harpenden caliper , england ) .
the hhh is among the largest recreational road cycle events ( > 10,000 participant annually ) in the usa and held every late - august in wichita falls , tx .
the 164-km course covers largely flat terrain ( 15 ) and is usually held under hot and humid conditions ( average wichita falls environmental conditions for late - august is 35c and humidity is 59% , with little to no cloud cover ) . on event day ,
dry bulb temperature , relative humidity , and wet bulb globe temperature were recorded at the start / finish line ( 7:31am to 3:24pm ) and at the 97-km aid station ( 8:17am to 12:32pm ) using the kestrel meter 4400 heat meter ( nielson - kellerman co. , boothwyn , pa , usa ) .
the ride began at 0700h and depending on starting position a particular rider might not pass the start line until as late as 0800h .
participants without a computer - downloadable heart rate monitoring device were provided one to wear during the ride ( polar electro inc . , lake success , ny ) ; participants having their own computer - downloadable heart rate monitoring device were requested to provide heart rate data files via electronic mail within 7d after the event .
participant total ride time was determined using either the participant s own timer or a timer provided by the research team and was confirmed using official hhh ride electronic chip monitoring system .
participants were instructed to record the number of stops and the duration of each stop . the rolling time was calculated as the difference between the total event time and the resting time .
heart rate was collected by standard telemetry using either participants own device or one provided by the investigators .
whole blood samples and urine sample were obtained 12 hours prior to the start of the ride ( pre ) and immediately after ( post ) completion of the event without fasting . upon arrival ,
participants were weighted and then sat for a few minutes after which 30ml of blood were collected from an antecubital vein using venipuncture by a 21 gauge needle with an evacuated tube containing edta , while participants remained in a seated position .
after blood collection , participants provided a small urine sample for determination of urine specific gravity .
participants were instructed to be arrive for the pre time point before performing their event warm - up .
the edta - treated whole blood samples were refrigerated and stored at 4c until biochemical analyses on the following morning .
participants were instructed to remember the food consumption during the ride and if possible , kept the food labels . upon arrival at the medical tent after the ride ,
participants recorded the quantity and the type of food that were consumed or participants provided the food labels to investigators for them to record . prior to analysis , blood samples were diluted with an equal volume of phosphate buffered saline and results were adjusted to account for this dilution .
then complete blood count was measured in duplicate using a 20-l sample of diluted edta - whole blood loaded into an automatic hematology analyzer ( bc-3200 ; mindray , mahwah , nj ) . in this automated procedure ,
total ( total leukocytes ) wbc and three - part differentiation ( lymphocytes , monocytes , and neutrophils ) of wbc are measured using electrical impedance .
the analyzer has a precision of 2.5% and a linear range from 0.3~99.9 10cellsl for wbc .
the complete blood count analysis also included determination of hemoglobin ( hb ) concentration ( using a cyanide free method ) and hematocrit ( hct ) .
plasma volume change ( pv ) was determined by the change in hct and hb from pre to post using established methods ( 9 ) ( pv : 7.1 12.6% ) .
the post immune cell ( total leukocytes , lymphocytes , monocytes , and neutrophils ) concentration was adjusted according to individual pv .
the percent of body mass loss ( % bml ) was the fluid loss as percent of pre - body mass , and it was corrected for the weight of food consumed during the ride .
estimated relative exercise intensity during the ride was calculated through the estimation of % vo2max from exercise heart rate using an equation which was validated by franklin et al . ( 11 ) ( i.e. % vo2max = 1.33 x ( % hrmax ) - 37.3 ) .
the percent of maximum heart rate ( % hrmax ) was calculated using the maximum heart rate ( hrmax ) and the average heart rate ( hravg ) recorded during the cycling event .
although it is not possible to determine if the recorded hrmax represents the true hrmax , the recorded hrmax ( 167 10 bpm ) was similar to but slightly less than the age predicted hrmax ( i.e. 208 ( 0.7 x age ) ; 174 6 bpm ) ( 44 ) .
tests for normality of distribution and homogeneity of variance were performed for all data sets .
data sets that did not meet assumptions of linear statistics were log10 transformed and retested ; after transformation all data sets met these assumptions .
paired t - tests were used to evaluate the mean pre and post differences in total leukocytes , and each leucocyte subset ( neutrophils , monocytes , and lymphocytes ) concentrations . to examine the effect intensity and duration on total leukocytes and each leucocyte subset , two different analyses were utilized .
first , pearson s product - moment correlation coefficients between pre to post changes and ride characteristics ( estimated relative exercise intensity and total rolling time ) were calculated .
then data for the fastest and slowest quartiles were examined using 2 ( time point : pre vs post ) 2 ( rolling time : fastest vs slowest quartile ) anovas with repeated measures on time point .
the concentrations of total leukocytes and of each leukocyte subset increased significantly from pre to post .
the data for leukocyte subset is presented in table 4 and individual responses are presented in figures 14 .
both leukocytes and neutrophils increased in concentration uniformly , while monocytes and lymphocytes did not show this pattern .
thirteen of 32 participants had a reduction from pre to post in monocyte concentration ( range : 0.05 to 0.88 10l ) and eight of 32 showed a reduction from pre to post in lymphocyte concentration ( range : 0.11 to 0.83 10l ) .
the cause of these findings is unclear but could represent naturally occurring individual differences or be due to differences in training state , heat acclimation , and/or immune function .
no significant relationship was observed between changes in total leukocytes or leukocyte subset concentrations from pre to post and ride characteristics ( estimated relative exercise intensity and rolling time ) .
circulating total leukocytes and leukocyte subset concentrations were not different between the fastest and slowest quartile of riders .
the primary purpose of this study was to determine the circulating leukocyte response to completing a recreational 164-km road cycle event in a hot ambient temperature .
our data indicated that leukocytes ( 134% ) and the each leukocyte subset ( neutrophils : 319% ; monocytes : 24% ; lymphocytes : 53% ) increased from pre to post , but these increases were not affected by estimated relative exercise intensity .
considering the growing popularity of long - distance cycling , this is important new knowledge since this substantial immune response might affect the acute and long - term health of recreational cyclist who regularly perform long - distance cycling in the heat .
better understanding of the acute physiological effects of such exercise is critical to defining proper recovery and monitoring health following rides and over the course of training . to our knowledge
these results are the first to describe the non - specific immune response to a completion of a self - paced recreational long - distance road cycling in a hot ( > 30 c ) environment .
overall , this study provides unique physiological insight by showing that completing a 164-km cycling event ( 58h ) without instructions or restrictions with regard to pace or food and fluid intake during the exercise induces substantial leukocytosis .
these findings adds to the previous findings of increases in leukocyte subsets concentrations with prolonged endurance exercise in more moderate temperature conditions : including standard marathon running ( 8 , 14 , 46 ) ; 160-km running ( 27 ) ; 24h cycling ( 28 , 35 ) ; and 3h treadmill running ( 26 ) .
long - distance endurance exercise induces leukocytosis ( 8 , 14 , 19 , 2628 , 35 , 37 ) .
although all circulating leukocyte subsets increase with exercise , the largest increase is observed in neutrophils .
neutrophils are involved in phagocytosis of damaged tissue and thus are important to recovery from exercise . despite of its importance to the host defense , neutrophils release reactive oxygen species , which further the process of muscle damage following exercise and contribute to inflammation ( 29 ) .
the exercise - induced increase in neutrophils has been suggested to be the result of demargination of cells from endothelial tissues and bone marrow to the circulation , a response which is mediated by catecholamine and cortisol , respectively ( 30 ) . the absolute resting ( pre ) circulating of total leukocytes and each leukocyte subset observed in the present study were all within the normal reference range for the general population ( 2 ) and for elite , albeit younger , cycle athletes ( 12 ) ; however , the absolute concentration of neutrophil was near the low end of the normal range .
this low - end pre neutrophil concentration likely explain the low relative proportion of neutrophils ( 33% ) and the high relative proportion of lymphocytes ( 60% ) among total circulating leukocytes .
it is uncertain why the neutrophil proportion was low in the study population ; however , it has been suggested that that plasma volume expansion , which is commonly observed among trained endurance athletes ( 5 ) , might cause a selective reduction in neutrophil concentration but not in lymphocytes ( 12 ) . following 164-km of cycling in the heat , post neutrophil concentrations were greater than 4-fold those observed for pre .
the magnitude of the increase in neutrophils is similar to the increase found for 100-km ( 31 ) and 160-km ( 27 ) running in a moderate ( ~23c ) ambient temperature although these events were likely performed at a lower relative intensity ( 10 ) since running induces greater muscle damage than cycling at the same relative intensity ( 41 ) , the similar neutrophil response suggests that a hot environment provides added stress to the immune system during exercise .
this is supported by the previous finding that cycle exercise induced a greater increase in neutrophils during shorter - term heat exposure ( 40 min submersion in 39c water ) than cold exposure ( 1823c water ) ( 6 , 33 ) . a potential mechanism underlying this augmented neutrophil response when exercising in the heat
exercise in the heat induces a greater increase in the concentration of cortisol ( 2 fold ) , epinephrine ( 4 fold ) , and norepinephrine ( 23 fold ) compared to exercise in the cold ( 6 , 33 , 38 ) .
cortisol and catecholamine interact with glucocorticoid receptors ( 22 ) and 2-andrenergic receptors ( 24 ) of neutrophils , respectively , and influence the development , trafficking , and function of immunocytes ( 25 , 36 , 47 ) .
monocytes with inflammatory profiles migrate to damaged tissue and mature into macrophages after entering that tissue .
similar to neutrophils , macrophages are involved in phagocytosis of damaged tissue and thus facilitate muscle remodeling ( 45 ) , but macrophages also serve an important role as a link between the non - specific and specific response by releasing cytokines into the circulation to attract other immune cells .
the increase in monocytes ( 24% ) in the present study is similar to that observed for 4 hours of ergometer cycling at room temperature ( 29%)(35 ) and for 40 min water immersed cycling at 39c ( 15% ) and 18c ( 20%)(33 ) .
the similarity in these monocyte responses to exercise suggests that , unlike neutrophils and lymphocytes , the monocytes response is ambient temperature independent during cycle exercise .
in contrast to the moderate increase in monocytes found with cycling , long distance running across a range of relative intensities , including intensities similar to that of the current study , induces a substantial increase in monocytes : marathon ( 150% ) ( 8) , 3 hour treadmill ( 67% ) ( 26 ) , 100 km ( 148% ) ( 31 ) , and 160 km ( 213% ) ( 27 ) running in moderate temperature ; no study appears to have investigated the monocyte response to long distance running in the heat .
running induces greater muscle damage than cycling at the same intensity ( 41 ) thus , it appears likely that the smaller monocyte increase observed in this and other cycling studies compared to that observed for running is due to the difference in muscle damage from the two exercise modes .
the increase in lymphocytes in response to endurance exercise observed in this and previous studies is less pronounced than that of neutrophils ( 6 , 8 , 26 , 32 , 33 , 38 ) .
the increase in lymphocytes ( 53% ) in the present study following the completion of a 164-km cycling event in the heat ( average temperature 35c ) , is similar to the increase found in studies involving shorter - term exercise under heat exposure : 40 min cycling immersed in 39c water ( 5354%)(6 , 33 ) and 90 min cycling at 70% vo2peak at 35c ( 38 ) .
in contrast , exercise in a cold environment ( 1823c water ) induced only a modest increase in lymphocyte concentration ( 2125% ) ( 6 , 33 ) . using multiple regression , cross et al .
( 6 ) found that cortisol concentration , growth hormone concentration , and rectal temperature accounted for 93% of the variance in lymphocyte concentrations following exercise in the heat and 87% of the variance following exercise in the cold(6 ) .
thus as with neutrophils , the greater lymphocyte response to exercise in the heat than in the cold is likely , at least in part , the result of core temperature mediated stimulation of stress hormone release(6 , 33 ) .
the results of present study showed no significant relationship between the change in leukocyte subsets concentrations and time to complete the event ( rolling time ) or intensity ( % vo2max ) .
it was hypothesized that the slower riders would have a greater leukocyte response since they were exposed to the high temperature for longer .
although there was a large spread in the time to complete the event ( 4.78.2 hours ) even the fastest rider spent more than 4 hours under heat exposure and thus the additional heat exposure for the slower riders appears to have not affected the leukocyte subsets response .
it is possible that any potential effects of prolonged heat exposure on leukocyte subsets concentrations were counteracted by the lower absolute intensity of exercise performed by the slower riders .
in contrast to the large range in time to complete the event , the range of the estimated relative intensity was rather small ( 6185% ) and thus not well suited for investigations of bivariate correlations .
it appears that when completing a 164-km cycling event in the heat , the rolling time and self - determined relative intensity do not affect the leukocyte response .
it should be noted that the age range of participants in the current study was large ( 2561 years ) although most of the participants were between 40 and 58 .
previous studies have found that age can significantly affect neutrophils ( 4 ) , thus the findings might not apply to young adults .
gender can also affect immune cell volume , but since only 4 women volunteered for the current study , it is not possible to examine a potential gender effect on changes in immune cell volume during the 164 km ride in a hot ambient temperature .
although in this observational study , we do not have clear information about the activational state and characterization within each immune cell subpopulation , the increases observed , most notably , in neutrophil and monocyte sub - populations vs. lymphocyte sub - populations , suggest that the exercise in combination with the environmental stress posed a significant stimulus for a circulating immune response . furthermore , the lack of correlation to relative exercise intensity or duration suggests that in this event , the participants might have experienced a dramatic enough environmental stressor or overall exercise stress such that differences on the order of hours for duration time had no apparent effect on circulating concentrations of immune cells .
this secondary finding suggests an intriguing hypothesis that there is a threshold of heat stress exposure beyond which any additional effects of exercise are either non - significant or negligible with regard to the leukocyte subset response .
long - distance endurance events , and the training preceding these events , which often occur in extreme environmental conditions , might affect the acute and long - term health of even in well - trained participants .
considering the growing popularity of these types of events , better understanding the acute effects of such events is critical to defining proper recovery and monitoring health over the course of training and post - ride .
Output:
| the purpose of this observational study was to determine the circulating leukocyte subset response to completing the 2013 hottern hell hundred recreational 164-km road cycle event in a hot and humid environmental condition .
twenty - eight men and four women were included in this study .
whole blood samples were obtained 12 hours before ( pre ) and immediately after ( post ) the event .
electronic sizing / sorting and cytometry were used to determine complete blood counts ( cbc ) including neutrophil , monocyte , and lymphocyte subsets .
the concentration of circulating total leukocytes ( 103l1 ) increased 134% from pre to post with the greatest increase in neutrophils ( 319% , p<0.0001 ) .
circulating monocytes ( including macrophages ) increased 24% ( p=0.004 ) and circulating lymphocytes including b and t cells increased 53% ( p<0.0001 ) .
no association was observed between rolling time or relative intensity and leukocyte subset .
completing the hotter n hell hundred ( hhh ) , a 100 mile recreational cycling race in extreme ( hot and humid ) environmental conditions , induces a substantial increase in total leukocytes in circulation .
the contribution of increases in specific immune cell subsets is not equal , with neutrophils increasing to greater than 4-fold starting values from pre to post race .
it is likely that exercise in stressful environmental conditions affects the complement of circulating immune cells , although activational state and characterization of specific leukocyte subsets remains unclear .
the observed increase in circulating cell sub - populations suggests that the circulating immune surveillance system may be acutely affected by exercise in hot and humid conditions . |
PubmedSumm8858 | ***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: inflammatory bowel diseases ( ibd ) are chronic immune - mediated conditions that are associated with a heavy personal and economic burden for patients and health care systems .
ulcerative colitis ( uc ) and crohn s disease ( cd ) are the two main types of ibd . although their etiologies are unknown , some risk factors have been suggested , including tobacco use ( for cd ) , genetic factors , oral contraceptives , and hormone replacement therapy.1,2 a number of european and us epidemiologic studies indicate a substantial increase in the incidence of ibd since world war ii , with cd now affecting 6/100,000 and uc 1520/100,000 of the general population.2 an italian multicenter study indicated a mean annual incidence of 3.4/100,000 for cd and 7.0/100,000 for uc.3 the prevalence of ibd has probably been underestimated , especially in its milder forms.4 the italian association for ibd patients ( amici ) has calculated that the total number of ibd patients in italy , as at april 2009 , is officially 104,762 , with a prevalence of 177/100,000 in the population but , as reported by rubin et al , the problem is almost certainly underestimated given that most studies rely on hospital records.5,6 diagnosis of ibd is often delayed , and the mean interval between symptom onset and diagnosis is 1.52.0 years .
it is also difficult to distinguish between cd and uc in clinical practice , because the diagnosis changes within the first two years in 10% of patients.78 the fact that these diseases are difficult to diagnose and demand regular monitoring makes the gp s role fundamental both in establishing the primary disease and in dealing with relapses , with a view to reducing hospitalizations , and the related problems and economic costs .
given the generally young age of ibd patients ( median age at diagnosis 30 years ) , the economic costs are not limited to hospital stays , treatments , and tests , but also include the patient s decreased ability to work .
the gp s role should be borne in mind when looking at all the factors ( medical and economic ) involved in these diseases because the gp is the first point of contact for the patient in the health care system.9 rubin et al reported that only 30% of their patients were under the care of a specialist , whereas about 50% were dispensed from specialist followup .
it is noteworthy that 48.2% of uc patients and 60.5% of cd patients in this study were not on treatment for their disease , and about 22% of patients with extensive colitis ( ie , those most in need of cancer screening ) were lost to specialist followup.6
a uk study by stone et al confirmed rubin s findings with regard to the prevalence of ibd and showed that about 32% of patients were under the care of a gp alone,10 reporting that only 65% of patients had been prescribed 5-aminosalicylate in the previous six months , and only 42% of patients adhered to their prescribed therapy . also noteworthy is that only 69% of cd patients were given advice on smoking cessation .
because 30%50% of ibd patients are under the care of gps , who as a group do not seem to be well informed about the importance of continuous treatment with 5-aminosalicylate , screening for colon cancer , and the need to advise their patients ( especially those with cd ) to quit smoking , we conducted a brief investigation among local gps on relevant topics , including timing of appointments , endoscopy , and laboratory followup for ibd patients , and hospitalization rates before a continuing medical education ( cme ) course .
this study was done in a hilly and mountainous area covering 1281.49 square kilometers in the marche region of central italy , inhabited by about 49,100 people ( 38.2 people per km in december 2005 ) , which is a lower density than the average for the marche region ( 147.9 per km ) .
there are 39 gps serving the area , comprising 33 males and six females , with a mean age of 52.8 4.3 years ( median 53 years ; range 4364 years ) .
latest data available for this area identify 95 ibd patients as at 31 december 2004 ( marche regional authority database ) .
the prevalence of about 190/100,000 population is fairly evenly distributed throughout the marche region . in the marche region about 6.2/100,000 population / year are hospitalized for cd ( 95% confidence interval [ ci ] : 6.06.4 ) and 17.7/100,000 for uc ( 95% ci : 17.617.8 ) [ database 20042006 ] . in the camerino - matelica area , 13.3/100,000 population / year ( 95% ci : 12.314.2 ) are admitted to hospital for cd and 23.5/100,000 population / year ( 95% ci : 22.724.7 ) for uc [ database 20042006 ] .
the above reported data are according to statistics from the last istat ( italian statistics institute ) census in 1991 .
the mean age of patients hospitalized for ibd in our area is similar to the average for the marche region ( 45.8 years versus 47.1 years , p > 0.05 ) , as is the gender distribution ( 55.8% of males in our target area versus 53.3% in whole region , p > 0.05 ) , so there is unlikely to be any difference between the type of patient living in our area and those living elsewhere in the marche region . in an attempt to improve and coordinate the management of these patients ,
the department of surgery in camerino and the department of medicine in matelica instituted a cme course for gps on 25 may 2007 . before starting the course , each gp completed an anonymous multiple - choice questionnaire containing 10 items allowing for only one answer to each question ( table 1 ) .
the purpose of this questionnaire was to assess how gps approached treatment of their ibd patients before they attended the course .
following the course , gps were asked to fill out an anonymous questionnaire to assess their satisfaction with the course , using a numerical scale of 05 .
we also verified the rate of hospitalization of ibd patients in both regional ( marche ) and local ( camerino - matelica ) hospitals in the year following the course .
the data were analyzed using the student s t - test for mean comparisons and the chi - square test for gender comparisons . a p value < 0.05 was considered to be statistically significant .
we used 95% ci for the hospitalization rates . the stata statistical program , ( version 10 , statacorps college station , tx ) was used .
twenty - eight gps ( 71.8% of the total canvassed ) answered the questionnaire and attended the cme course .
gps completed the questionnaire in about five minutes and returned their completed questionnaire before starting the course so that the information provided on the course could not influence their subsequent answers .
the gps visited their patients with the following timing : monthly 26% of gps , every three months 33% , every six months 30% , and every year 11% .
laboratory tests were requested each month by 4% of gps , every three months by 22% , every six months by 59% , and every year by 15% ; 74% of gps did not require determination of calprotectin in patients with ibd and only 15% of gps used antibiotics in cd patients . also , the use of probiotics in uc was limited , with only 37% of gps always using them ( table 2 ) . when asked whether they advised female ibd patients of child - bearing age to avoid becoming pregnant , 74% of the gps replied no .
asked when they requested endoscopic followups ( excluding patients with cancer ) , 41% said they did so when the disease relapsed , 29% said every two years , and 26% said once a year ; the other 4% said they did so only rarely .
item 8 in table 1 is basically to double - check of item 7 , because variations in therapy often occurred when the disease relapsed .
results of the satisfaction questionnaire following the course indicated that the course was successful in providing information to gps ( table 3 ) .
for the following year ( 2008 ) we verified that regional hospitals had fairly analogous rates for cd ( 6.3/100,000 population / year ; 95% ci : 5.17.5 ) and for uc ( 18.9/100,000 population / year ; 95% ci : 16.721.1 ) to those in the period 20042006 .
hospitalization rates in the camerino - matelica area were reduced compared with those of previous years but the confidence intervals require confirmation ( for cd 4.1/100,000 population / year with 95% ci : 09.8 and for uc 10.2/100,000 population / year with 95% ci : 1.319.1 ) .
to the best of our knowledge , the present study is the first in italy to focus on how gps approach the problem of ibd , and it probably reflects the situation in other parts of central italy too .
a weakness of our questionnaire is its generic nature , but considering the small numbers of ibd patients followed up by our gps ( 2.4 patients per gp ) , we opted not to request details about specific clinical situations .
our results indicate that gps in our area examine their ibd patients once every 36 months and prescribe laboratory tests every six months on average .
it is important to emphasize that ibd diagnosis and followup must involve not just endoscopy but also several laboratory blood and fecal tests .
our study indicates that fecal calprotectin , a biochemical marker of inflammatory activity , is still not widely used by gps , and nor are probiotics prescribed for uc , or antibiotics prescribed for cd .
in addition to being an excellent noninvasive method for monitoring ibd , calprotectin is also useful in screening for these diseases.11,12 fewer endoscopies are needed if fecal calprotectin or lactoferrin are used to follow up patients , and an endoscopic protocol to screen for cancer risk is not needed until 810 years after the ibd is diagnosed .
another interesting issue emerging from our study is that our group of gps resort to specialists primarily when their patient s disease relapses , and they tend to adjust therapy in consultation with a specialist , probably only when the disease relapses .
the limited use of probiotics in uc and antibiotics in cd by the gps may in part be due to poor attention of specialists to these therapies .
williams et al showed that both patients and gps appreciate having ready access to the advice of a specialist.13 all the gps in the williams study were following up at least five ibd patients ( twice the number that our gps had in their care ) , and both patients and gps wanted to be able to contact a specialist easily .
it is likely that this would apply to our gps and patients too , in the light of responses to items 7 and 8 in table 1 .
casellas et al administered a questionnaire to 393 spanish ibd patients about the services they received and emphasized the importance of patients and their families being adequately informed about their condition.14 the study was limited by the fact that it was conducted in a university environment , but it found that 97.8% of the patients considered the information they received about their disease inadequate .
the authors also emphasized that the best way to give patients information is by talking to them directly .
this is especially important because ibd is often associated with depression and anxiety , in which case personal contact between patients and their health care professionals is essential .
although the number of patient hospitalizations and the number of consultations with their gastroenterologists do not seem to improve patient information flow , we do not know if outpatient contact with gps can improve the level of a patient s knowledge and information about his / her condition.15,16 undoubtedly , the fact that the patients in the present study did not have ready access to a psychologist is a severe handicap , resulting in patients making more use of the health system s resources and having a suboptimal quality of life.17 since any given gp has very few ibd patients , it is important for them to receive information and training periodically from specialists .
we believe that the two most important duties of a gp are to provide their patients with information ( also with a view to improving patient adherence to prescribed treatments ) and to guarantee basic management and rapid access to a specialist in the event of relapse.18 basic management should also include monitoring of any adverse effects of prescribed drugs . in the case of ibd , underestimating such adverse effects puts patients at serious risk , not only of hematologic sequelae , but also of potential renal , hepatic , and pulmonary toxicity.19,20 although often overlooked , the indirect economic costs of a disease are also very important .
stark et al found that the monthly cost of an outpatient with cd in germany is 1425 and for one with uc it is 1015 ; 64% of the cd - related costs are indirect ( eg , sick leave , early retirement ) compared with 54% for uc patients.21 these costs might increase with greater use of biologic therapies , but adequate studies are needed , because increasing the use of these treatments might mean fewer hospital stays and medical appointments , and better quality of life and fewer absences from work .
another point to emphasize is that our gps did not advise their female ibd patients of child - bearing age to avoid becoming pregnant , even though a recent meta - analysis shows that pregnant women with ibd have higher rates of premature births , low - birthweight infants , cesarean sections , and babies with congenital abnormalities than do non - ibd controls.22 although the data available do not permit any correlation of such adverse events with the activity of the disease , there are sporadic reports of women being more likely to have premature and low - birthweight infants if they have conceived in an active phase of their disease .
important messages that a female patient of child - bearing age should receive is that she should conceive her child while the disease is quiescent , and that close cooperation is needed between her gastroenterologist and her obstetrician .
the patient needs to be clearly informed about which therapies to continue and which to stop , and when these should be stopped ( ie , during the period of attempting to conceive , the first trimester , and lactation ) .
perhaps the most interesting finding of this study is that the hospitalization rate for ibd was markedly reduced during 2008 in the camerino - matelica area ( 69% for cd and 57% for uc ) while the regional rates remained about the same .
of course we can not exclude the fact that this lower rate was compensated for by higher rates in other regional hospitals , but we think this improbable , given the information imparted to gps about ibd . in conclusion , although ibd are not as widespread as other chronic diseases , such as hypertension , the fact that the incidence of ibd peak in patients about 30 years of age means that they can be a heavy burden on the health care system due to the patient needing treatment for many years .
we feel that more attention paid to ibd patients by gps would result in cost savings , taking into account the balance between the savings ( fewer hospital stays , fewer days off work ) and the added costs ( more use of sometimes costly medicines , more contact with the specialist ) . in any case
, the changes we advocate would certainly result in a better quality of life for patients , who would then be able to contribute more to their families and communities .
it is therefore necessary to ensure a good understanding of ibd among all health care personnel in order to provide efficient service to patients , avoid wasting resources , and improve patient quality of life .
Output:
| background : inflammatory bowel diseases ( ibd ) are a serious burden for both patients and health care providers because of the young age at which they occur and their chronic course.aim:the purpose of this study was to assess how general practitioners ( gps ) in the area of camerino - matelica , marche ( central italy ) manage their patients with ibd.materials and methods : before providing an educational course about ibd to gps , we administered a simple questionnaire containing 10 multiple - choice questions , allowing for only one possible answer , to gps in the target area .
after the educational course we administered a satisfaction questionnaire and evaluated the hospitalization rates for ibd in the catchment area in the year following the course.results:in our gp sample , 71.8% indicated that they needed better instruction regarding ibd to enable them to diagnose the conditions given the difficulties posed by nonspecific symptoms and the need to use invasive diagnostic methods such as colonoscopy .
early results after the educational course for gps indicate a reduced rate of hospitalization for ibd but these data must be confirmed by future research.conclusions:if specialists and gps managed ibd patients more carefully , their patients would probably suffer from fewer relapses and would have a better quality of life , which would be likely to mean considerable cost savings for the public health care system and society in general . |
PubmedSumm8859 | ***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: osteoporosis is primarily a disease of older people and advancing age is one of the main determinants of osteoporosis and fragility fractures .
the estimated lifetime risk of hip , spine , or distal forearm fracture for caucasian man at the age of 50 years is 20% and approximately 30% of all hip fractures occur in men .
heredity is now generally accepted as playing an important part in the pathogenesis of osteoporosis in both men and women .
indeed , after excluding secondary risk factors and age then the other main causal factor for osteoporosis in men is genetic .
this view is supported by genetic epidemiological studies on bmd , an important surrogate of fracture risk , which show that peak bone density has a substantial heritable component .
variation in bmd is determined by multiple genes ; objective evidence for this is provided by candidate gene snp studies , as well as quantitative trait locus ( qtl ) studies in inbred animals and humans .
qtl studies have identified multiple chromosomal regions which influence bone mass and are linked to osteoporosis - related phenotypes .
studies of classical and novel candidate genes have only been able to account for a small proportion of the variance in bone mass .
candidate gene contributions to bone mass also show gender , geographic , and ethnic variability .
therefore , studies aimed at identifying the contribution of specific genes towards bmd and the heritable component to osteoporosis should ideally be gender and ethnic specific .
one such candidate gene is bone morphogenetic protein 2 ( bmp2 ) , located on chromosome 20p12.3 .
it is a growth factor that possesses osteoinductive properties and promotes osteoblast differentiation and bone formation [ 49 ] .
linkage analysis in extended families with osteoporosis in iceland , using a phenotype that combines osteoporotic fractures and bmd measurements , showed linkage to chromosome 20p12.3 .
three variants in the bmp2 gene , a missense polymorphism , and two anonymous single nucleotide polymorphisms and the resultant haplotypes have been associated with an osteoporotic phenotype , including osteoporotic fractures as well as low bmd , both before and after the menopause .
a number of follow - up studies however have yielded inconsistent results [ 59 ] .
to date no investigation has been performed in an exclusively male cohort and no follow - up study has investigated the association with risk of osteoporosis in men and rate of bone loss . in view of the inconclusive nature of the earlier study and to determine possible gender and geography - related variability , we therefore investigated the association of ser37ala and arg190ser genotypes / haplotypes with bmd , rate of bone loss , and fracture risk in men from the uk .
participants comprised 342 male subjects , 224 controls , and 118 subjects with osteoporosis , who were all caucasian men from england , uk [ 1012 ] .
the men with osteoporosis comprised men who had a bmd t score below 2.5 at either the femoral neck or lumbar spine or had a low trauma fracture and a t score below 1.0 at either the femoral neck or lumbar spine . of the patients
89 also had a history of fractures ( 46 had distal forearm fracture , 33 symptomatic vertebral , 6 hip , and 4 other fractures ) .
their fractures had all occurred at least six months prior to their inclusion in the study , and all blood samples were taken before the initiation of therapy .
underlying secondary causes of osteoporosis were excluded by medical history , physical examination , and laboratory investigations .
the laboratory investigations included full blood count , esr , biochemical profile , thyroid function tests , serum testosterone , sex - hormone - binding globulin , gonadotrophins , and serum and urine electrophoresis . in a subset of 145 control subjects , there was a follow - up bmd estimation and annual change in bmd was determined , in order to test the association between bmp2 genotypes and change in bmd .
a similar analysis of the annual change in the bmd measurement was not performed in the men with osteoporosis , because of the confounding effect of antiresorptive treatment .
serum testosterone , sex - hormone - binding globulins , follicular stimulating hormone , and luteinizing hormone were measured by commercially available radioimmunoassay ( sas laboratory , royal victoria infirmary , newcastle upon tyne ) .
all bone density measurements , for both the osteoporotic and control subjects , were performed by dxa using a hologic qdr 2000 bone densitometer ( hologic , waltham , mass ) . in vivo precision for measurement with this system
is 1.0% at the lumbar spine ( l1l4 ) and 1.5% for the femoral neck .
bmd results were obtained as an areal density in g / cm , but were also given as t and z scores .
the t score is the number of standard deviation units above or below the mean for normal young men , whilst the z score is the number of standard deviation units above or below the age - related normal men ( calculated using the manufacturer 's standard normal reference database ) .
individual pcr standardisation reactions were set up prior to setting up multiplex pcr for the three bmp2 snps .
the three bmp2 snp polymorphisms ( snp1 , ser37ala ; snp2 , ala94ser and snp3 , arg190ser ) studied are shown in the schematic diagram ( figure 1 ) .
the multiplex reactions were transferred into 384 well plates and treated with shrimp alkaline phosphatase to remove the excess dntps in the reaction mixture .
extension primers designed to detect the three bmp2 snps were added to the samples and incubated as a pcr reaction for 2 h. salt ions were removed from the reaction mixture using a desalting resin and finally resuspended with 16 l ddh2o .
15 nl of each sample was spotted onto the chip and analysed on the sequenom ( maldi - tof mass spectrometer ) .
the results were collected by spectroanalyser software and the snp information , represented by chromatogram peaks at g , t , a , gt , or at , was sorted by the typeranalyser software .
the snp information was then exported along with the sample details into ms - excel file(s ) for further statistical analysis .
data were analyzed using appropriate statistical packages ( microsoft excel xl , spss ) ; the significance of differences in genotype and allele frequency between control subjects and men with vertebral fractures was determined using odds ratio and tests .
anova and student 's unpaired t - test were used to determine significant differences in bmd and anthropometric measurements between different bmp2 genotypes and between control subjects and osteoporotic men , respectively .
genetic association analyses were carried out using an online hwe calculator ( http://ihg.gsf.de/cgi-bin/hw/hwa1.pl ) and snpstats programme ( http://bioinfo.iconcologia.net/snpstats ) which also worked out the hardy - weinberg equilibrium statistics .
the binary logistic regression analyses were performed ( spss , version 13.0 ) with disease or fracture outcome as the dependent variables .
the genotypes as categorical variables were used as specific genotypes ; the other variables included in the regression analysis were age , height , weight , bmi , and key relevant biochemical parameters .
the age , anthropometric , and bmd measurements for the men with osteoporosis and the control subjects are given in table 1 .
the men with osteoporosis , who had age range of 30 to 86 yr , were on average 6 years younger than controls with the age range of 41 to 79 yr .
for this reason when comparing bone density comparisons , to compensate for age - related decline in bmd , comparison with z score was performed .
the osteoporotic patients were also significantly shorter and lighter than the male control subjects , as well as having significantly lower bmd at the lumbar spine , total femoral and femoral neck ( p < 0.0001 ) . in both men with osteoporosis and control subjects
the bmp2 gene snp1 gg genotype was absent , and in the combined cohort only eight subjects were found to be heterozygotes , thus making this locus uninformative .
snp1 genotype , due to ser37ala variants that change a conserved amino acid , has been previously shown to have significant association with osteoporosis in both danish and icelandic cohorts . however , in our cohorts the frequency of snp1-related g allele was low in both the patients ( 0.004 ) and controls ( 0.015 ) .
snp2 , which gives rise to ala to ser change at 94th position , was rare , uninformative , and monomorphic , and of the three genotypes gg , gt , and tt , only gg was observed .
snp3 ( arg190ser ) was polymorphic , and distribution of genotypes and allele frequencies in both male controls and men with osteoporosis is shown in table 2 . in both cohorts
genotype aa was slightly higher in controls ( 14.3% versus 10.2% , p = 0.36 ) while susceptibility genotype tt was higher in patients ( 38.1% versus 31.7% , p = 0.28 ) .
the odds ratio for bmp2 snp3 genotypes and alleles * a and * t showed no statistically significant evidence of association with the risk of osteoporosis , although a trend towards carriers of the * t allele may be worth exploring . linkage disequilibrium ( ld )
the d prime is 0.989 ( p value = 0.0264 ) , suggesting that there is a significant linkage disequilibrium between snp1 and snp3 , but caution is warranted in view of the relatively small numbers and low allele frequencies especially at snp1 locus which led to a low r value ( 0.02 ) .
haplotype analysis based on two snps ( snp1 and snp3 ) showed that two common haplotypes ( ta and tt ) accounted for > 99% of the alleles at these bmp2 loci ( table 3 ) .
haplotype - based association analysis indicated higher odds ratio for t - t haplotype ; however , it was nonsignificant ( or = 1.43 , ci 0.962.15 , p = 0.08 ) .
the effect of bmp2 gene snp3 genotypes on weight , height , and bmd at lumbar spine , femoral neck , and total femoral was analysed by anova in both the male controls and men with osteoporosis , and genotype was found to lack any significant association ( table 4 ) .
the analysis of the pooled data , comprising controls and patients , also failed to demonstrate any significant association of snp3 genotype with the bmd or anthropometric indices ( data not shown ) .
the association of the snp3 genotype was also determined by employing a binary logistic regression model , which accounted for between 44.5% and 62.6% of the variance in disease status and the overall model successfully predicted 72% of osteoporotic cases correctly ( table 5 ) .
an analysis of fracture incidence with reference to genotypes and age , age at fracture , and biochemical parameters was performed .
age at fracture , weight , biochemical parameters , and genotypes did not show any interaction or independent effect in the fracture prediction .
the addition of covariates to the model resulted in very sparse data categories and led to wide confidence intervals .
this investigation is the only one from the uk that has sought an association between bmp2 gene polymorphisms and bmd and susceptibility to osteoporosis .
as far as we know this is the first such investigation carried out exclusively in men with idiopathic osteoporosis .
however , the power of this study is low ; therefore any conclusions drawn should be treated with caution .
post hoc power analysis , calculated using a quanto programme and based on observed allele frequencies , sample size , and odds ratios , showed that the study had 67% power to detect an odds ratio of 1.50 ( moderate level ) and above . in order to achieve an odds ratio of 1.25 one would require a case - control sample size of 507 individuals in each group . in the original icelandic study a significant effect of bmp2 gene snp1 polymorphism , ser37ala ,
was demonstrated in a cohort of 201 subjects , comprising 153 controls and 58 subjects with fracture . just like the earlier observation we too found it to be a rare variant in our cohort with an allele frequency of 1.25% for ala37 . in previous reports ,
the allele frequency for ala37 in the icelandic cohort was 0.8% in controls and 3% to 4.9% in osteoporotic patients and 2.5% in the rotterdam study .
however , unlike the icelandic study , we did not see a significant association or increase in the relative risk ( rr ) with the snp1 genotype . in our cohort
we did not see any gt or tt genotypes of the rare variant of the snp2 genotype that arises from ala94ser .
the gene frequency for snp3 polymorphism , due to arg190ser variants , constituting three genotypes , tt ( arg190arg ) , at ( arg190ser ) , and aa ( ser190ser ) , was akin to earlier reports in european populations . in both male controls and men with osteoporosis
in addition to studying the association of the bmp2 to risk of fracture and bmd , in a subset of subjects we also investigated the association of the genotype with annual bone loss at the lumbar spine , total femoral , and femoral neck . both initial bmd as well as
this could be partly due to allele frequency differences in different geographical and gender cohorts . in our study
we observed a higher frequency of susceptible t ( ser ) allele ( 64% in patients and 59% in controls ) which is comparable to hapmap frequencies ( 58%73% in european populations ) , but other populations like turkish , korean , and african populations show a lower frequency [ 1315 ] .
the desirability of having a large cohort for snp studies investigating polygenic disease association with putative candidate genes with phenotype or disease state is well established .
this is due to the fact that in a polygenic disorder like osteoporosis many genes make a small , but significant contribution towards the attainment and maintenance of bmd .
therefore , many genes may be involved in the pathogenesis of osteoporosis and risk of osteoporotic fractures . in view of this small contribution of a large number of genes ,
the contribution of the genotypic influence is likely to be more clearly demonstrated in a sufficiently large cohort with the required level of statistical power .
it is , however , becoming increasingly evident that the association of a large number of candidate gene snps with bmd and osteoporosis risk shows race- , geography- and gender - related differences [ 3 , 16 , 17 ] .
we would also contend that , if a given genotype does make a substantial contribution to the attainment and maintenance of bmd and pathophysiology of disease then it should be possible to demonstrate such effects even in smaller homogenous cohorts .
indeed , in the original study on bmp2 the genotype association with osteoporosis was established in a small cohort . we have been able to demonstrate associations of some novel genotypes in smaller cohorts and which were subsequently verified in much larger studies [ 5 , 18 , 19 ] .
there have been only a handful of studies following the first report of bone morphogenetic protein 2 ( bmp2 ) as a susceptibility gene for osteoporotic fractures and low bmd in icelandic and danish populations .
even these relatively few studies of polymorphisms , within the bmp2 gene in relation to bone mineral density ( bmd ) and fracture , have produced inconsistent findings [ 49 ] .
neither a rotterdam study of a large population - based cohort of dutch whites nor a study in healthy american whites could find any contribution to bmd by variations in bmp2 genotypes [ 7 , 8 ] .
on the other hand , a snp- and haplotype - based us family study showed highly suggestive associations with bmp2 . in another analysis on a european cohort , variation in bmp2
genotype showed no association with bmd ; it did , however , find a role in aspects of bone quality , which may be age and site dependent .
the 3 region of the gene was significantly associated with the ultrasound parameters speed of sound and stiffness .
similarly in turkish women study bmp2 polymorphisms did not substantially contribute to lumbar spine bone mineral density .
overall , association studies have shown that arg190ser snp is not associated with bmd in different populations and the initial study may have been a false positive association .
alternatively , it is entirely possible that the association may show gender - related variation , as the initial study had shown association in females and our study was carried out in an exclusively male population . in conclusion ,
in a bmp2 candidate gene polymorphism study in the uk , comprising osteoporotic men and male control subjects , there were no genotypic or haplotypic effects on phenotype and fracture risk identified .
Output:
| introduction .
the association of bone morphogenetic protein 2 ( bmp2 ) with bmd and risk of fracture was suggested by a recent linkage study , but subsequent studies have been contradictory .
we report the results of a study of the relationship between bmp2 genotypes and bmd , annual change in bmd , and risk of fracture in male subjects .
materials and methods .
we tested three single - nucleotide polymorphisms ( snps ) across the bmp2 gene , including ser37ala snp , in 342 caucasian englishmen , comprising 224 control and 118 osteoporotic subjects .
results .
bmp2 snp1 ( ser37ala ) genotypes were found to have similar low frequency in control subjects and men with osteoporosis .
the major informative polymorphism , bmp2 snp3 ( arg190ser ) , showed no statistically significant association with weight , height , bmd , change in bmd at hip or lumbar spine , and risk of fracture .
conclusion .
there were no genotypic or haplotypic effects of the bmp2 candidate gene on bmd , change in bmd , or fracture risk identified in this cohort . |
PubmedSumm8860 | ***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: research on stroke mechanisms reveals secondary injury develops through the inflammatory reaction induced by the leukocytes that adhere to the micro vessels during cerebral ischemia - reperfusion.9 ) this mechanism was verified in animal experiments using middle cerebral artery occlusion and reperfusion ( mcao - r ) models.5)12 ) experiments using the mcao - r model , found reduced leukocyte infiltration and enhanced neurologic functions in mice that were injected with adhesion - molecule - specific monoclonal antibodies ( mabs ) , or in mice whose adhesion molecules were removed through genetic manipulation , compared with wild - type mice.13)21)25 ) studies on adiponectin are active , and many favorable effects of adiponectin on the vascular system reported .
adiponectin activates angiogenesis in ischemic damages,19 ) and inhibits atherosclerosis.15 ) in addition , a negative association between the initial infarction volume and the adiponectin level in ischemic stroke was confirmed.6 ) in serial measurement of adiponectin level in ischemic cerebrovascular disease patients , a gradual decrease was observed.24 ) in this study , the effects of adiponectin on the interaction between leukocytes and endothelia were investigated through experiments based on the hypothesis that adiponectin might inhibit the secondary inflammatory reaction in cerebral ischemia .
all experiments were conducted according to the guidelines issued by the institutional animal care and use committee and complied with the national institutes of health ( nih ) guide for the care and use of laboratory animals . for the experiments of this study , 10 to 12-week - old adiponectin - deficient mice ( apn - ko ) ( n = 8) and wild - type mice ( wt ) ( n = 8) were prepared .
each group was sub - divided into 2 groups by reperfusion time ; 6h apn - ko , 12h apn - ko , 6h wt and 12h wt .
general anesthesia was given to mice using 2% isoflurane and 70% nitrous oxide , and 30% oxygen was supplied during the experiments via a face mask .
the mice 's body temperatures were maintained at 36.5 - 37.5 during the experiments , as measured by a rectal thermometer .
focal cerebral ischemia was induced using the intraluminal filament technique.11 ) after the left common carotid artery was dissected and completely exposed , the external carotid artery was tied by 4 - 0 silk . thereafter ,
silicon - coated 8 - 0 monofilament was headed to the middle cerebral artery through the common carotid artery .
the inserted monofilament was tightened with a 6 - 0 silk suture to prevent bleeding while advancing the monofilament and removing the monofilament during reperfusion .
the mice were placed on a stereotactic frame to perform 46 mm - sized craniotomy in the left parietal area using a dental drill .
extreme caution was required to avoid damage to the dura mater and the tissues beneath it .
after the craniotomy , the dura mater was opened using 26-gauge needles to expose the brain cortex of the mca territory and the artificial cerebrospinal fluid was arranged to flow over the surface of the brain ( fig .
a straight pial venule ( 100 m long and 30 - 40 m in diameter ) was selected . to observe the microcirculation ,
a fluorescence intravital microscope was used at 780 specimen - to - monitor magnification . using 1 ml fluorescein isothiocyanate - albumin that was intravenously injected shortly before data collection ,
a bright contrast was obtained , and the length and diameter of the microvessel were measured . using 1 ml of the 0.1% rhodamine that was intravenously injected 10 minutes before data collection , the leukocytes and platelets were selectively stained .
data were collected at 6 and 12 hours after 1-hour occlusion . at each data selection ,
the target venule was recorded for 30 seconds through a microscope , and the number of rolling leukocytes and leukocytes that adhered to endothelium were counted and documented ( fig .
the statistical significance of differences between the groups of apn - ko and wt mice in the measurements taken 6 and 12 hours after the reperfusion was assessed by the mann - whitney u - test .
all experiments were conducted according to the guidelines issued by the institutional animal care and use committee and complied with the national institutes of health ( nih ) guide for the care and use of laboratory animals . for the experiments of this study , 10 to 12-week - old adiponectin - deficient mice ( apn - ko ) ( n = 8) and wild - type mice ( wt ) ( n = 8) were prepared .
each group was sub - divided into 2 groups by reperfusion time ; 6h apn - ko , 12h apn - ko , 6h wt and 12h wt .
general anesthesia was given to mice using 2% isoflurane and 70% nitrous oxide , and 30% oxygen was supplied during the experiments via a face mask .
the mice 's body temperatures were maintained at 36.5 - 37.5 during the experiments , as measured by a rectal thermometer .
focal cerebral ischemia was induced using the intraluminal filament technique.11 ) after the left common carotid artery was dissected and completely exposed , the external carotid artery was tied by 4 - 0 silk .
thereafter , silicon - coated 8 - 0 monofilament was headed to the middle cerebral artery through the common carotid artery .
the inserted monofilament was tightened with a 6 - 0 silk suture to prevent bleeding while advancing the monofilament and removing the monofilament during reperfusion .
after preparation of the focal cerebral ischemia and reperfusion model , the mice were placed on a stereotactic frame to perform 46 mm - sized craniotomy in the left parietal area using a dental drill .
extreme caution was required to avoid damage to the dura mater and the tissues beneath it .
after the craniotomy , the dura mater was opened using 26-gauge needles to expose the brain cortex of the mca territory and the artificial cerebrospinal fluid was arranged to flow over the surface of the brain ( fig .
as a target vessel , a straight pial venule ( 100 m long and 30 - 40 m in diameter ) was selected . to observe the microcirculation ,
a fluorescence intravital microscope was used at 780 specimen - to - monitor magnification . using 1 ml fluorescein isothiocyanate - albumin that was intravenously injected shortly before data collection ,
a bright contrast was obtained , and the length and diameter of the microvessel were measured . using 1 ml of the 0.1% rhodamine that was intravenously injected 10 minutes before data collection , the leukocytes and platelets were selectively stained .
data were collected at 6 and 12 hours after 1-hour occlusion . at each data selection ,
the target venule was recorded for 30 seconds through a microscope , and the number of rolling leukocytes and leukocytes that adhered to endothelium were counted and documented ( fig .
the statistical significance of differences between the groups of apn - ko and wt mice in the measurements taken 6 and 12 hours after the reperfusion was assessed by the mann - whitney u - test .
the behaviors of the leukocytes in the target vessel of apn - ko and wt mice was observed and recorded for 30 seconds at 6 and 12 hours after the occlusion , using an intravital fluorescence microscope .
the number of rolling and adhesion leukocytes of each experimental group was counted and recorded and converted to per mm sec ( table 1 ) . in 6hwt mice ,
a mean of 55.48 per mm sec of rolling leukocytes were observed while a mean of 653.82 per mm sec of rolling leukocytes were observed in 6hapn - ko mice . in 12hwt mice ,
a mean of 405.92 per mm sec of rolling leukocytes was observed in all 4 groups . in the 12hapn - ko mice ,
rolling leukocytes were observed in all 4 groups , and in particular , leukocyte adhesion was observed in experimental group iii , with a mean of 1364.78 per mm sec of total leukocytes .
mann - whitney u - test was used to test for statistical significance of the outcomes .
leukocyte numbers between the apn - ko and wt mice 6 hours after the occlusion differed significantly with p = 0.029 .
the difference at 12 hours after the occlusion was also statistically significant with p = 0.029 ( fig .
adiponectin is an adipocyte - derived bioactive protein that initially attracted attention in the treatment of metabolic syndrome.14 ) clinically , the plasma adiponectin level is negatively associated with dyslipidemia , hypertension , and the c - reactive protein level,17 ) and hypoadiponectinemia ( defined as plasma adiponectin level < 4 g / ml ) increases the risk of type 2 dm , hypertension , and coronary heart disease.16)17 ) studies of the role of adiponectin in the cardiovascular system have been conducted using apn - ko mice .
these studies found that apn - ko mice showed exaggerated myocardial remodeling under pressure - overload conditions , and severe cardiac injuries were reported during ischemia - reperfusion.20)22 ) by contrast , when adiponectin was injected into the apn - ko mice , pathological cardiac hypertrophy and ischemia - induced myocardial damages were inhibited.18 ) these protective effects have driven research on the effects of adiponectin on the cerebrovascular system .
the most recent studies find that plasma adiponectin level is closely related with the cerebrovascular system .
chen at al . described hypoadiponectinemia as an independent and significant risk factor for cerebrovascular disease while efstathiou et al . reported an increased risk of mortality for hypoadiponectinemia patients who suffered ischemic insults.4)6 ) in addition ,
advanced intracranial atherosclerosis patients were observed to have had significantly low plasma adiponectin levels.1 ) in this study , the effects of adiponectin on the early stage of inflammation reaction in cerebral ischemia - reperfusion were investigated . at both 6 and 12 hours after the occlusion
, the apn - ko mice group showed significantly more rolling and adhesion leukocytes than the wt mice group did .
although firm adhesion of the leukocytes to the endothelium was observed only in experimental group iii of the 12hapn - ko mice , the rolling leukocytes would form a firm adhesion on the endothelium through the media of leukocyte adhesion molecule cd11b
/ cd18 ( integrin ) and its endothelial ligand icam-1 . the activated leukocytes that adhered to the endothelium release toxic mediators to damage the surrounding vasculatures or parenchymal cells , or induce a change in blood rheology and accelerated thrombosis by inducing platelet aggregation.7)8)10 ) inhibition of the endothelial adhesion - accumulation of the leukocytes after cerebral ischemia - reperfusion improves electrophysiological and neurological function , and reduces cerebral edema and cerebral infarction size.3)5)23 ) therefore , adiponectin that restrains the leukocyte - endothelium interaction is considered to inhibit the secondary inflammatory reaction and is neuroprotective in cerebral ischemia - reperfusion .
although the leukocyte accumulation in cerebral ischemia - reperfusion steadily increased to reach a peak after 24 - 48 in other studies,2)10 ) more advanced studies with a larger sample size may be needed in the future .
in this study , the effects of adiponectin on the early inflammatory reactions in cerebral ischemia - reperfusion were investigated . as a result
, statistically more rolling and adhesion leukocytes were observed in the apn - ko mice than in the wt mice in the experiments with the mcao - r model . in conclusion ,
adiponectin was observed to inhibit the interaction between the endothelium and leukocytes in cerebral ischemia - reperfusion , and accordingly , adiponectin might prevent the secondary insult caused by the inflammation reaction .
Output:
| objectivein this study , we investigate the role of adiponectin in the interaction between leukocytes and endothelium in the secondary inflammatory reaction of cerebral ischemia.methodsadiponectin knock - out mice group ( apn - ko ) ( n = 8) and wild - type mice group ( wt ) ( n = 8) were prepared .
each group was sub - divided into 2 groups by reperfusion time .
one - hour middle cerebral artery occlusion and reperfusion were induced using the intraluminal filament technique . at 6 and 12 hours after the occlusion
, the mice were placed on a stereotactic frame to perform craniotomy in the left parietal area .
after craniotomy , a straight pial venule was selected as a target vessel . with the fluorescence intravital microscope ,
the number of rolling leukocytes and leukocytes that adhered to endothelium were counted and documented at 6 and 12 hours after the reperfusion.resultsat 6 and 12 hours after the reperfusion , more rolling leukocyte and leukocyte adhesion were observed in the apn - ko mice than in the wt mice .
the difference in leukocyte numbers between the apn - ko and wt mice was found to be statistically significant ( p = 0.029 ) by mann - whitney u-test.conclusionwe found that adiponectin inhibits the interaction between the endothelium and leukocytes in cerebral ischemia - reperfusion .
therefore adiponectin might prevent the secondary insult caused by the inflammation reaction . |
PubmedSumm8861 | ***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: hiv testing and counselling ( htc ) is the cornerstone of treatment , care , and prevention [ 1 , 2 ] .
it is particularly through htc that the ambitious goal of 90 , 90 , 90 ( 90% of all people living with hiv will know their hiv status ; 90% of all people with diagnosed hiv infection will receive sustained antiretroviral therapy ; 90% of all people receiving antiretroviral therapy will have viral suppression ) , by 2020 can be reached .
previously , most efforts were focused on voluntary counselling and testing ( vct ) as the primary means of providing testing and encouraging people to become aware of their hiv status .
however , coverage remains low and many infected persons in both developed and developing countries remain undiagnosed . despite the availability of rapid test with the possibility to have the results approximately in 20 to 30 minutes , in some contexts
particularly , there are many who get tested but fail to return for their results [ 46 ] . for example , in the usa , data from hiv testing performed at publicly funded counselling and testing sites using conventional hiv enzyme immunoassay ( eia ) testing from 1999 through 2002 found that 19% to 22% of people with positive preliminary hiv tests did not return for their test results . in 2009 , a survey conducted in 12 sub - saharan africa countries with high hiv prevalence showed that only 10% of women and 12% of men were tested and received their test results . in an evaluation of five years of routine program data in vietnam ,
hong et al . found a failure to return ( ftr ) rate of 3.5% . in a study of female sex workers in china , xu et al . found a ftr rate of 47.1% .
( 2015 ) , respectively , found a ftr rate of 6.5% in a study conducted in a free and anonymous screening center and 14.5% in an hiv - positive population . identifying and targeting these people may improve the return rate for vct and the proportion of individuals who are aware of their status .
therefore , the objective of this systematic review is to identify the factors that prevent people who are tested for hiv from returning for their results or facilitate their doing so .
this systematic review examines barriers and facilitators associated with returning for hiv test results in various types of populations and settings .
the outcome variable , returning for hiv testing results , is dichotomous . from this point of view , some studies concerned factors associated with returning for hiv test results , while others focused on failure to return ( ftr ) .
this review was conducted in accordance with preferred reporting items for systematic reviews and meta - analyses ( prisma ) statement guidelines .
a comprehensive search strategy was developed to identify studies published between january 1985 ( introduction of hiv tests ) and june 2015 .
four electronic databases were searched ( pubmed / biomed central / medline , embase , psycinfo , and web of science ) , combining terms related to hiv , counselling / testing , and return / failure to return .
all identified records ( n = 3,019 ) were initially screened by two independent investigators and verified by a third researcher .
eligible studies had to meet the following criteria : ( 1 ) be an original research study ; ( 2 ) be written in english or in french ; ( 3 ) report adolescents , adults , pregnant women , men who have sex with men ( msm ) , injecting drug users ( idus ) , or female sex workers ( fsws ) ; ( 4 ) include participants undergoing hiv tests ; ( 5 ) use a quantitative method to assess return or failure to return for hiv test results ; and ( 6 ) report a statistical association between a potential predictor / correlate and return or ftr .
a short list of records was prepared and the full text reviewed independently by two authors .
uncertainties and disagreements about inclusion were resolved through discussion involving both investigators ( see figure 1 for flowchart of systematic review ) .
two authors independently extracted data from each study that fulfilled the inclusion criteria using a standard form .
study characteristics ( name of the first author , year of publication , country in which the study was conducted , study design , sampling approach , participating characteristics , and hiv testing procedure ) as well as key findings related to factors associated with return or failure to return for hiv test results were extracted .
any factors analyzed associated with ftr or return for hiv test results were listed , and the results of multivariate statistical tests for association ( odds ratio ) were noted . for studies where a multivariate statistical test was not done ,
when the result of the measure of association in multivariate analysis was not significant and not reported by authors , the factor was not considered in the synthesis .
the newcastle - ottawa scale ( nos ) for cohort studies and an adapted form of the newcastle - ottawa cohort scale for cross - sectional studies were used to assess methodological quality .
nos is a tool for assessing the quality of nonrandomized studies to be used in a systematic review .
each study is judged with a star system on three points : the selection of study groups , the comparability of the groups , and the ascertaining of exposure or outcome .
studies for which at least five out of nine items on the nos were deemed satisfactory and in which appropriate statistical analysis ( e.g. , multivariate controlling for confounders ) was conducted were considered to be of sufficient methodological quality and included in the review ( maximum score of 10 for cross - sectional studies and 9 for cohort studies ) . at each stage of the quality assessment ,
the reviewers discussed among themselves until a consensus was reached on which studies to include .
factors associated with either return or failure to return may be arranged into barriers and facilitators inspired by the socioecological model ( sem ) , which is a framework to examine the multiple effects and interrelatedness of environmental , contextual , and social factors on individual behaviour [ 46 , 47 ] . recognizing that most public health challenges are too complex to be adequately understood and addressed from single level analyses , the sem includes a more comprehensive approach that integrates multiple levels of influence to impact health behaviour and ultimately health outcomes .
these levels of influence include intrapersonal and interpersonal factors , organizational factors , and structural factors .
in this review , due to their small number , organizational and structural factors were grouped as contextual factors .
since we anticipate a potential variability of the methodology ( e.g. , measures of studied factors ) across the included studies , we used a random - effects model based on the inverse variance method to estimate the pooled odds ratio ( or ) for each factor potentially associated with returning for hiv test results and its 95% confidence interval ( ci ) [ 48 , 49 ] . the higgins 's i statistic was used to quantify the percentage of the variability in individual effect size estimates which is attributable to the heterogeneity [ 50 , 51 ] .
this heterogeneity was tested using a chi - squared test [ 50 , 51 ] .
moreover , we performed sensitivity analysis by removing the included studies from the pooled size estimation one at a time .
these analyses allowed us to explore the individual contribution of each study to the heterogeneity in the meta - analysis .
when we could not explain the heterogeneity , we have interpreted the pooled effect size estimates with caution because these effect sizes would be explained by other factors , which were not taken into account in our analyses .
the primary search strategy identified 3,019 potentially relevant citations . after the removal of duplicates and
the initial title and abstracts screening , 60 citations were kept for the full - text review .
studies were excluded if they did not report quantitative results ( n = 1 ) or just reported the rate of return or failure to return ( ftr ) without assessment of associated factors ( n = 23 ) .
the remaining 36 studies were appraised for their methodological quality and included in the analysis .
no study was excluded on the basis of quality assessment . a flow chart illustrating the selection process
of the 36 included studies , 10 were longitudinal cohort studies and 26 were cross - sectional studies .
seven of the studies were carried out in sub - saharan africa ; seventeen in the usa ; three in australia ; six in asia ; and one in brazil .
populations under study were diverse , including general population ( n = 16 ) , pregnant women ( n = 5 ) , injecting drug users ( n = 3 ) , men who have sex with men ( n = 3 ) , high - risk heterosexual individuals ( n = 2 ) , hiv - positive individuals ( n = 2 ) , factory workers ( n = 2 ) , individuals with psychiatric problems ( n = 2 ) , adolescents ( n = 1 ) , hiv - negative individuals ( n = 1 ) , and female sex workers ( n = 1 ) . the outcome of interest was dichotomous , with 20 studies focused on failure to return and 16 on return for hiv test results .
a total of 3 cohort studies scored 9/9 , one study scored 8/9 , and 6 studies scored 7/10 . for the cross - sectional studies , one study scored 9/10 , 11 studies scored 8/10 , 4 studies scored 7/10 , 4 studies scored 6/10 , one study scored 5/10 , and one study scored 4/10 . in total , 236 factors associated with returning for hiv test results were identified . among these ,
, factors were classified into sociodemographic characteristics ( n = 78 ) , risk behaviours ( n = 64 ) , perceived risk ( n = 9 ) , hiv knowledge ( n = 7 ) , reasons for visit / testing ( n = 11 ) , hiv test results ( n = 13 ) , history of testing ( n = 11 ) , psychosocial factors ( n = 5 ) , and other individual factors ( n = 4 ) .
factors grouped at the interpersonal level were risk partner behaviours ( n = 7 ) , social support ( n = 6 ) , knowledge of person with hiv ( n = 2 ) , domestic violence ( n = 3 ) , and other interpersonal factors such as partner age ( n = 1 ) , years in couple ( n = 1 ) , and communication within the couple ( n = 2 ) .
contextual factors comprised the type of clinic attended ( n = 6 ) , year of testing ( n = 1 ) , and characteristics of the testing center , such as availability of counselling ( n = 1 ) , condom distribution ( n = 1 ) , clinic visit ( n = 1 ) , confidential testing ( n = 1 ) , and location of the testing center in the same city as treatment center ( n = 1 ) ( see table 3 ) .
this factor has been reported as a barrier to returning for results in 7 studies [ 12 , 19 , 27 , 28 , 30 , 36 , 37 ] and as a facilitator in 5 studies [ 13 , 22 , 35 , 36 , 39 ] .
the association between age and returning for hiv test results was insignificant in 10 studies [ 10 , 1214 , 26 , 2830 , 35 , 41 ] . in these studies , being 30 years of age or over was reported as a facilitator in 4 studies [ 13 , 22 , 35 , 36 ] and as a barrier in just a single study . on the other hand ,
having less than 30 years of age was reported as barrier in 6 studies [ 12 , 19 , 27 , 28 , 30 , 36 ] and as facilitator in 2 studies [ 22 , 36 ] .
level of education was reported in nine studies . in 4 studies [ 15 , 17 , 26 , 30 ] ,
it was reported as a barrier to returning for hiv test results , especially for people with no education or a low level of education . in 3 studies [ 9 , 34 , 39 ] ,
it was reported as a facilitator for those with a medium or high level of education . in studies with a mixed population ( women and men ) when sexual orientation was reported ( n = 4 ) , being heterosexual or bisexual appeared as a barrier to returning for hiv test results [ 11 , 36 , 37 ] .
marital status was reported in six studies . in these studies , being married or living in a couple and being a widower emerged as facilitators of a return for results .
the number of sexual partners during the last 6 to 12 months was reported in 8 studies . in 5 of these studies [ 8 , 10 , 26 , 27 , 37 ] , having more than 5 sexual partners was reported as a barrier to returning for hiv test results .
otherwise , having a single sexual partner during the last 6 to 12 months [ 22 , 37 ] was not significantly associated with a return for results . using a condom
has been reported as both a barrier and as a facilitator [ 26 , 41 ] , but in most cases , the association was not significant [ 14 , 37 , 39 ] .
however , it was reported equally as a barrier [ 16 , 19 , 29 , 41 ] or a facilitator [ 13 , 22 , 25 , 31 ] as regards a return for hiv test results .
perceived risk has been reported in nine studies . in those studies , having low perceived risk ( n = 1 ) and not seeing oneself at risk [ 10 , 27 ] ( n = 2 ) was reported as a barrier to a returning for test results . however , this result is somewhat controversial because one of these two studies showed that having high - perceived risk was a barrier to a return for results , and having a medium perceived risk was reported at the same time as a barrier in one study and as a facilitator in another .
in addition , the association was insignificant for 4 studies [ 10 , 35 , 38 , 39 ] .
the association between the return for hiv test results and psychosocial factors showed divergent results ( n = 5 ) .
for instance , not believing in self - prevention from hiv , believing that hiv can be cured , and thinking that a medical follow - up can improve the course of hiv were reported as barriers to a return for test results .
however , having high self - esteem and positive coping skills appeared as a facilitator for a return for results .
feeling anxious about hiv was reported as a barrier [ 15 , 42 ] to a return for hiv test results .
the association between the existence of health coverage and a return for results was studied in two articles .
having health coverage appeared as a facilitator and not having health coverage as a barrier .
the association of these factors with a return for results was investigated in seven publications .
the hiv status of the sexual partner [ 8 , 19 , 41 ] ( n = 3 ) or being a client of a sex worker ( n = 1 ) was identified as a facilitator for a return for hiv test results in three studies .
having a sexual partner who is a sex worker [ 8 , 41 ] ( n = 2 ) , having a partner who drinks alcohol ( n = 1 ) or consumes drugs ( n = 1 ) , having a partner who is always travelling ( n = 1 ) , and having a partner who did not test ( n = 1 ) were all reported as a barrier to returning for results .
domestic violence ( abused by a partner ) and rape [ 16 , 29 ] were reported as barriers to a return for test results in three studies .
the association between a return for results and the availability of a social network has been studied in six studies .
on the one hand , it appears that having one or more gay friends , having a counsellor , or knowing someone infected with hiv are barriers to a return for results . on the other hand , having social support ( friends ) and lacking a family confidant were reported as facilitators of a return for test results .
a negative association was found between the return for hiv test results and having a confidential test in one study .
the same negative association was found when the testing was done in facilities such as family planning clinics [ 27 , 36 ] ( n = 2 ) , a detention facility ( n = 1 ) , a primary care clinic ( n = 1 ) , an hiv testing clinic ( n = 1 ) , a mobile clinic ( n = 1 ) , a prenatal / obstetric clinic ( n = 1 ) , a drug treatment center ( n = 1 ) , a health department [ 27 , 36 ] ( n = 2 ) , an outpatient medical service ( n = 1 ) , and a sexual health clinic ( n = 1 ) . however , the association was positive in the case of a physician clinic ( n = 1 ) and a college ( n = 1 ) .
other organizational factors , such as the year of testing ( n = 1 ) , condom distribution during the visit ( n = 1 ) , or having tested in a center located in the same city as the treatment center ( n = 1 ) and not having pretest counselling , emerged as facilitators of a return for results .
the pool estimates and sensitivity analysis of the association of the return for hiv test results with certain factors , including gender ( men versus women ) and race ( black versus white ) for studies conducted in the usa , injection drug use ( no versus yes ) , hiv test results ( positive versus negative ) , and hiv testing history ( no versus yes ) , are shown in table 3 .
the combined analysis showed that being female [ 8 , 1820 , 22 , 30 , 34 , 35 ] is significantly associated with a return for results ( or = 0.86 , 95% ci = 0.770.96 ) when studies with specific population ( msm , hiv negative , pregnant women ) are excluded . in the studies from the usa ,
black people tend to return less frequently for their results than white people ( or = 0.76 , 95% ci = 0.640.90 ) [ 12 , 18 , 22 , 27 , 3436 , 38 , 39 ] .
there is no significant association between returning for test results and hiv test results or hiv testing history . finally , the association between injection drug use and returning for test results was significant ( or = 0.85 , 95% ci = 0.750.96 ) [ 8 , 12 , 14 , 22 , 41 ] when only the general population was considered .
thus , being an iud appears as a barrier for returning for hiv test results .
the objective of this review was to report the factors that were statistically associated with the return for hiv test results in different studies , regardless of the target population , the hiv test method used ( standard or rapid tests ) , the waiting time for results , or the country . despite these different contexts , periods , and populations ,
the vast majority of reported factors are found at the individual level ( sociodemographic characteristics , risk behaviours , individual risk perception , and test results ) . very few studies have reported contextual factors , such as organizational factors , policies , economic factors , or social factors .
the differences in statistical analysis ( classification , categorization , and reference group ) introduced a great deal of heterogeneity with respect to the studies .
the factors not included in the meta - analysis were grouped into barriers and facilitators based on their statistical association with the dependent variable ( return for hiv test results ) . although the factors have been grouped into categories according to the ecological model , it is important to specify , in accordance with the socioecological approach , that the categories are not exclusive but rather influence each other .
however , the trend indicates firstly that young people and individuals with a low level of education were less likely to return for their results .
indeed , there is evidence that young people are often less informed about hiv and also exhibited a lower rate of hiv testing than adults [ 45 , 46 , 52 ] .
they are unaware of their risk behaviours and are less likely to return for their test results .
conversely , individuals with higher levels of education can better understand the importance of screening [ 44 , 53 ] and are more likely to return for their results .
the literature has shown an association between the return for test results and risk behaviours [ 52 , 54 ] .
in fact , people who display risk behaviours can also develop fear and anxiety with respect to knowing their test results . in these circumstances , they are less likely to return for their results even if they had the courage to get tested .
thus , in this review , the positive test result , injection drug use , a high number of sexual partners , getting paid to have sex , and having symptoms of sexually transmitted infections ( stis ) at a testing visit were reported as barriers to returning for test results .
studies that have examined the association between perceived risk and a return for test results are sometimes contradictory .
indeed , some studies have shown that people who have a high - perceived risk of contracting hiv were more likely to return for their results [ 33 , 55 ] .
other studies have shown that people with a low perceived risk do not return for their results [ 10 , 14 , 26 , 27 ] .
this second situation might be explained by the fact that many people at high risk of contracting hiv do not perceive themselves as at risk [ 5658 ] .
therefore , they do not see the importance of returning for their results and knowing their status .
this is why it is recommended that the education of individuals be intensified in order to foster a high and precise perception of risk .
the sexual partner 's risk behaviours were the most frequent group of factors influencing a return for test results . furthermore ,
having social support , having an hiv infected partner , or being a client of a sex worker have been reported as factors that encourage people to return for their results .
in fact , having sex with a high - risk person might increase the perceived risk , which leads the exposed person to learn his or her hiv status . on the other hand ,
the family and social network provide social support and reinforce social norms that might encourage a return for results .
in contrast , being a member of a social network of people at risk , such as a partner of a sex worker , of an alcoholic , or of a drug user , having gay friends , or knowing someone infected by hiv tend to hinder a return for results .
therefore , they are less likely to get tested , to return for their results , to disclose their hiv status to others , to adopt preventive behaviours , or to access treatment services , care , and support . finally , domestic violence ( intimate partner violence ) and sexual assault also hinder a return for results . despite the implementation of strategies that enable women to get tested at opportune moments such as during pregnancy or childbirth ,
first , the female victim of sexual violence is afraid to return for her results and know her hiv status because she is afraid of being rejected by her partner who can blame her for having tested without his consent and for being responsible for his contamination in the case of a positive result [ 62 , 64 , 65 ] .
second , the feeling of guilt and fear of victimization and stigmatization experienced by a raped woman can hinder her return for results even if she could be tested [ 62 , 66 , 67 ] . the hiv testing center and its characteristics
getting tested in most of the sites appeared as a barrier to returning for test results .
many of the studies in this review were conducted before the use of rapid tests .
recently , several hiv testing centers in developed countries and in developing countries have reported an increase in the demand for testing , the proportion of people who received posttest counselling , and the knowledge of status following the introduction of rapid tests [ 6872 ] .
other studies also showed that clients prefer the centers where they can receive their results without delay on the same day [ 7375 ] .
however , it is also reported that when the testing center is linked with the treatment , the pretest counselling is done well , and there is distribution of condoms , this set of factors encourages people to return for their results [ 1 , 7 , 32 , 53 ] .
firstly , the differences in the measurement of factors and the specificity of certain populations ( injection drug users , pregnant women , female sex workers , and men who have sex with men ) introduce heterogeneity and do not allow meta - analyses for all factors .
secondly , most of the studies were conducted before the advent of rapid testing , but nowadays hiv testing is performed by rapid tests .
therefore , the issue of failure to return for hiv test results is only important in very specific contexts .
a majority of the studies were conducted in the usa the countries of sub - saharan africa , which represent 2/3 of infected people worldwide , do not often publish their results , or only publish their results in local journal articles , which are not indexed in most databases .
only articles published in peer - reviewed journals were considered ; grey literature and conference proceedings were not .
however , the review included a large number of studies , covering different regions , a broad range of populations , and barriers and facilitators with respect to returning for hiv test results .
furthermore , to the best of our knowledge , this is the first review to focus on factors associated with returning for hiv test results .
helping more people learn their hiv status requires the strengthening of counselling and testing services . returning for hiv test results is the gateway for knowledge and acceptance of hiv status .
various recently implemented strategies , such as provider - initiated testing and counselling , community - based testing and counselling , home - based testing and counselling , and the use of rapid tests , might not be effective if the people tested are not well advised and do not accept their results .
this review identified important factors that need to be addressed to ensure that people return for their hiv test results .
individuals most likely to fail to return for their results must be identified and targeted by the counsellor and delivered a specific message .
Output:
| this systematic review aims to identify factors that facilitate or hinder the return for hiv test results .
four electronic databases were searched .
two independent reviewers selected eligible publications based on inclusion / exclusion criteria .
quantitative studies published since 1985 were included .
thirty - six studies were included in the final review .
individual level barriers included sociodemographic characteristics , such as being a male , of young age and low education level , risk behaviours such as injecting drugs , having multiple sexual partners , and psychosocial factors .
older age , higher education level , being a woman , having high self - esteem , having coping skills , and holding insurance coverage were identified as facilitators .
interpersonal barriers and facilitators were linked to risk behaviours of sexual partners .
contextual barriers included essentially the hiv testing center and its characteristics .
this review identified the most important factors that need to be addressed to ensure that people return for their hiv test results . |
PubmedSumm8862 | ***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: evidence - based medicine ( ebm ) has been defined as the integration of best research evidence with clinical expertise and patient values .
the first historical descriptions of ebm date back to the beginning of 1990s , when the work of gordon guyatt , david sackett and others established the emerging methodologies of ebm , .
the main products of ebm are evidence - based guidelines ( ebgs ) , systematically developed statements to assist practitioner and patient decision about appropriate health care for specific clinical circumstances .
costs , ethical concerns in placebo - controlled trials , publication bias and a real risk of reductionism are the most emphasized limitations of ebm . in order to overcome these limitations and improve ebgs quality standards , different societies ( among which the world health organization , who ) produced guidelines for guidelines developers .
preliminary steps for guideline development are evaluation of priority settings , composition of an expert panel , management of conflicts of interests , determination of appropriate group processes , of important outcomes and of which evidences have to be included .
then developers have to produce synthesis and presentation of evidences , exposing criteria for grading evidence and recommendations , integrating when possible values ( e.g. ethical considerations ) and consumer involvement .
next , considerations of cost - effectiveness , affordability and resource implications , of equity , applicability , transferability and adaptation should be included .
the final steps are the report of guidelines recommendations , the dissemination and implementation of guidelines and their evaluation .
the appraisal of guidelines for research and evaluation ( agree ) instrument was a validated , easy - to - use , and transparent tool , which was internationally developed and widely accepted .
it was developed through a process of item generation , selection and scaling , field - testing and refinement .
the final version of the instrument contained 23 items grouped into six domains : scope and purpose , stakeholder involvement , rigor of development , clarity and presentation , applicability , and editorial independence . despite the good review of the agree instruments , two important limitations are present : although it can be used to compare clinical practice guidelines , agree instrument does not set a threshold to classify them as good or bad , and it does not assess the quality of the evidence supporting the recommendations .
level of evidences and grade of recommendations in fact do not necessarily correlate , since the first is a measure of scientific strength and the latter of clinical utility .
recently , an improved version of the agree , i.e. the agree ii instrument , has been released , , partly overcoming the previous limitations . indeed , the introduction of the new item assessing the description of strengths and limitation of the body of evidences can be considered as a precursor for clinical validity or appropriateness of the recommendations .
the authors recognize the value of this point , in fact they state that the agree consortium is targeting this area as its next priority for further study in the agree a3 initiative . in our opinion , correlating level with grade could be a valid way to integrate the agree ii instrument and quickly display the internal consistence of ebgs .
the guidelines for the treatment of bone metastases by the italian society for medical oncology ( aiom ) are based on : european society for medical oncology ( esmo ) guidance on the use of bisphosphonates in solid tumors and on the management of aromatase inhibitor - associated bone loss ; cochrane network reviews ; critical review of the literature updated to june 2009 .
the topics covered by the aiom guidelines are use of bisphosphonates in metastatic cancers ; use of bisphosphonates in the prevention and treatment of cancer treatment induced bone loss ; safety of bisphosphonates use ; treatment of bone metastases pain ; role of bisphosphonates in specific settings ; role of orthopedic surgery in bone metastases ; role of radiotherapy in bone metastases .
level of evidences ( i vi ) and grade of recommendations ( a e ) were provided according to the recommendations of the italian centre for the evaluation of the efficacy of health assistance coordinated by the italian national health institute ( istituto superiore di sanit ) and are presented in table 1 .
we performed an analysis of levels of evidence and respective grades of recommendations of the guidelines for treatment of bone metastases by aiom .
spearman 's rank correlation coefficient was calculated per each topic of the guidelines , a p value < 0.05 was considered statistically significant .
the final correlation was performed using a linear regression model ( graphpad prims version 5.04 , la jolla california usa ) ; linear r value was reported to weight the results and a p value < 0.05 was considered statistically significant .
the results of our analysis showed a statistically significant correlation between the levels of evidence and the grades of recommendation in the following topics : use of bisphosphonates in metastatic cancers ( p<0.01 ) ; use of bisphosphonates in the prevention and treatment of cancer treatment induced bone loss ( p<0.01 ) ; safety of bisphosphonates use ( p<0.05 ) ; role of bisphosphonates in specific settings ( p<0.01 ) ; role of orthopedic surgery in bone metastases ( p<0.0001 ) ; role of radiotherapy in bone metastases ( p<0.01 ) .
finally , a statistically significant correlation was also found considering all the levels of evidence and grades of recommendation together regardless of the division in topics ( r=0.4454 , p<0.0001 ; fig .
ebgs represent a milestone for modern evidence - based clinical practice ; they indeed substantially improve clinical care .
nevertheless , ebgs frequently vary widely in quality , , thus their evaluation is of critical importance . among several evaluation tools ,
the agree instrument is the most widely used , even though it has known limitations , i.e. the impossibility to classify ebgs as good or bad and to assess the quality of the evidences supporting the recommendations . in order to overcome these limitations
, we performed an analysis of levels of evidence and respective grades of recommendations of the guidelines for treatment of bone metastases by aiom . in six out of seven topics ,
moreover , a statistically significant correlation was also found considering all the levels of evidence and grades of recommendation together regardless of the division in topics .
these results indicate that the authors of the guidelines worked scientifically with a correct approach and that these guidelines are likely to be adherent with modern medical literature .
however , we can not exclude that a significant correlation for some topics could be due to low levels of evidences from medical literature and consequent low grades of recommendations .
moreover , the lack of concordance in specific items could also derive from the impossibility for the physicians to prescribe a specific drug in a specific setting ( i.e. low grade of recommendation ) due to the delayed approval by regulatory agencies ( e.g. fda , ema ) even in presence of adequate scientific literature ( i.e. high level of evidence ) .
the critical evaluation of ebgs is an underestimated issue in current clinical practice . moreover , specific methodological aspects for the evaluation of ebgs are of increasing interest in the medical oncology community .
here we provide clinicians with a quick tool to evaluate the internal consistence of ebgs .
further analysis should confirm the reliability of this method , which could be easily implemented in future ebgs .
Output:
| modern clinical practice relies on evidence - based medicine ( ebm ) and evidence - based guidelines ( ebgs ) .
the critical evaluation of ebgs value is therefore an essential step to further improve clinical practice . in our opinion ,
correlating levels of evidence and grades of recommendation can be an easy tool to quickly display internal consistence of ebgs . |
PubmedSumm8863 | ***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: oncogenes are mutated forms of cellular genes that are responsible for driving rampant cellular proliferation .
however , the expression of an activated oncogene in normal human cells does not lead to their transformation , but to a permanent cell cycle arrest known as cellular senescence .
hence , oncogene - induced senescence ( ois ) serves as a tumor suppressor mechanism that restricts the progression of pre - neoplastic lesions .
the role of oncogene - induced reactive oxygen species ( ros ) production in cancer development has been a controversial subject .
ros is a collective term describing a number of highly reactive molecules and free radicals that are formed upon incomplete reduction of oxygen .
ros can either directly damage or modulate redox - sensitive signaling pathways , depending on the molecular concentrations at which they are present . in particular , the role of oncogenic ras - regulated ros production in cellular transformation has been the subject of several studies .
nonetheless , it remains unclear whether oncogenic ros have a direct role in genome instability and , if so , which molecular mechanisms are involved .
we approached this issue by taking a closer look at the mode of action of oncogene - induced ros in the model system of h - ras oncogenic activation in normal human fibroblasts .
we observed that removal of ros by the broad specificity scavenger n - acetyl cysteine ( nac ) inhibits oncogene - induced hyperproliferation , prevents activation of the dna damage response ( ddr ) , and reduces the establishment of senescence .
this experiment led us to propose the novel concept that oncogene - induced ros are modulators of cell hyperproliferation that engage the ddr by exposing cells to dna replication stress .
we then focused on the origins of the oncogene - induced ros , which are ubiquitously generated through diverse enzymatic pathways .
in particular , we turned our attention to the nox family of oxidases because initial studies suggested them as a source of ros in cancer .
our experiments identified the ras - rac1-nox4 axis as the pathway responsible for ros generation by oncogenic ras in human cells .
therefore , we propose that ras - induced ros are mitogenic signaling molecules for the initial hyperproliferative phase , which is causally associated with the altered dna replication that precedes and prompts ddr activation and ultimately leads to senescence .
cell transformation is associated with bypass of ois and ongoing rampant proliferation . since oncogene activation hijacks the ros - modulated proliferative cues for the initial hyperproliferative phase , we investigated the effect of ros scavengers and nox4 inhibitors on proliferating cells .
these cells either harbor mutations to bypass ois or are fully transformed , and either express oncogenic ras or do not .
we observed that the expression of oncogenic ras in a cell is sufficient to confer sensitivity to ros manipulations .
we also treated cells derived from human pancreatic cancer with gemcitabine , the standard of care chemotherapy treatment for pancreatic cancer , and nox4 inhibitors .
although we observed a modest effect of nox4 inhibitors alone , we discovered an exciting synergic effect of nox4 inhibitors and gemcitabine that reduced the half - maximal inhibitory concentration ( ic50 ) of this nucleoside analog by up to 6-fold .
deregulation of survival pathways by nox - derived ros through jak , stat , akt , and nfb pathways has been previously implicated ; however , the mechanism by which combined use of nox4 inhibitors and gemcitabine enhances apoptosis in cancer cells remains unclear .
using a well - established mouse model of ras - induced pancreatic cancer , we reported increased induction of nox4 during progression from the earliest neoplastic lesions to more invasive ones . in addition , we observed robust nox4 expression in a set of human pancreatic tumors , with signal intensity correlating with neoplastic stage .
importantly , and concordant with our results in cultured cells , nox4 levels in these human lesions correlated with markers of ddr activation .
cancer cells produce elevated levels of ros and exhibit altered metabolic pathways and regulatory mechanisms in order to maintain redox balance .
therefore , high levels of ros production are counterbalanced by an equally high antioxidant activity .
studies of the same murine model showed that an antioxidant system mediated by nrf2 and nqo1 is activated upon oncogenic ras activation .
however , on the basis of our experimental results it appears that this compensatory response to ras - induced ros production is not sufficient to fully buffer ras - mediated ros accumulation during the process of tumorigenesis .
another example of altered redox homeostasis resulting from an impaired nox4-nrf2 balance has recently been reported in the context of lung fibrosis .
a recent article proposed a novel axis involving activation of p38 through nox1 for ros generation and consequent malignant cellular transformation upon oncogenic k - ras activation in rodent fibroblasts .
another study reported that oncogenic h - ras cooperates with nox1 in rodent fibroblasts or with nox4 in human fibroblasts for establishment of ois .
therefore , it is worth exploring whether the oncogenes that transform both human and murine cells toward tumorigenicity exhibit different preferences for ros source between the two species .
noxzymes are differentially expressed not only among distinct tissues , but also among several different types of cancer ( see fig .
one member of the family is activated as the primary source , whereas the enzymes collaborate in other cancers , for example upregulation of both nox1 and nox4 in colorectal cancer .
understanding which oncogenic stimulus activates each nox enzyme as an initial source for transformation and later proliferation , and how this is influenced by the in vivo microenvironment during tumorigenesis , will undoubtedly help the design of better therapeutic strategies based on ros manipulations .
i am indebted to fabrizio dadda di fagagna for his support throughout the entire project , which is now complemented by a recent publication .
i also thank fabrizio dadda di fagagna , michael bremang , and hans - peter wollscheid for critically reading this manuscript .
Output:
| work carried out primarily in the laboratory of fabrizio dadda di fagagna unveils the mitogenic properties of ras - induced reactive oxygen species ( ros ) and their relationship with the dna damage response .
combined data from studies of cultured cells , zebrafish models , and clinical material consistently support a role of the ras - rac1-nox4 axis in ros induction , hyperproliferation , and senescence . |
PubmedSumm8864 | ***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: today s children are valuable human resources for future ; and how they are raised today guarantees the quality of human resources in future ( 1 ) . in april 2005 , the world health organization ( who ) chose the motto
let s care for all mothers and children s health , which implies the vast interest of nations as well as governments toward children ( 2 ) .
children and mothers are actually the vulnerable groups of the society and include almost 70% of the population in developing countries .
studies reveal that nearly 25% of children under 5 years old in our country suffer from different degrees of underweight condition ( 3 ) .
the easiest way to understand growth pattern children and evaluate their health is to monitor growth pattern as the first step the malnutrition for both mothers and children should be investigated at the same time , enables them to timely ( 4 ) what follows includes the steps which should be taken toward the growth monitoring :
engaging mothers in weighing their children .
identifying the children with growth retardation .
questioning the mothers about the affordable food as well as the quality food they consume .
making the mothers aware of the nutrition provided for their children ( 5 ) .
therefore , mothers are highly important since they are considered as the target group to be trained in order to monitor their children s growth regularly and prevent growth retardation , and they must be aware of the issues ( 6 ) .
health education is defined as the knowledge and the art of directing people s attention toward learning process to develop the desirable behavior to reach health ; therefore , it is considered as a helpful method in creating motivation and modifies the incorrect functions ( 7 ) .
the first step in designing an educational program is selecting a health education model which starts the program on the right way and guides it to the evaluation phase . in the present study ,
possible outcomes of an educational program are projected by this model , so planning is from a whole to the details .
nonetheless , before selecting a model for the health education program , its objectives as well as components must be studied .
the precede model emphasizes the process of designing the program ( 8) . the precede model was unique since it starts by the active involvement of the target community in order to identify its final results and then goes back to identify the factors which were prior to those results ( 9,10 ) .
salehi et al showed that nutritional behaviors could be improved using education based on precede model ( 11 ) .
improvement in breast feeding behavior using education based on precede model was reported by baghianimoghadam ( 12 ) .
other study also reported that this method could increase nutritional knowledge of preschool children ( 13 ) .
based on what was mentioned above , the precede model was used in the present study in order to achieve more effective results .. the present study , therefore , aims to determine the effect of mothers training program on growth adjusting and monitoring based on some components of the precede model on the mean weight in children(6 - 12 months ) at health centers in shiraz , fars province .
mothers and 6 - 12 months old children who had referred to health centers in shiraz participated in this interventional study in 2011 .
the inclusion criteria were the children s being single , benefiting exclusively from breast feeding , and not having any specific diseases such as : congenital and genetic diseases .
in addition , the exclusion criteria were the mothers not being interested in taking part in training classes , the children s being fed by formula , having chronic diseases , being hospitalized , and having accidents .
the population under study included 120 mothers who had 6 - 12 months old children .
four health centers were randomly selected from all health centers located in shiraz , iran .
the samples were chosen by referring to the lists provided by the office of child care .
of the four selected health centers , two were considered as the control and two as the experimental group .
in order to gather the data , a questionnaire ,
this model provided a framework which clarifies the factors affecting the behavior , such as the predisposing factors ( knowledge , attitude , etc . ) , enabling factors ( availability of resources , and skills ) , and reinforcing factors ( the effect of others , family members , peers , etc . ) , in identifying a training program .
the questionnaire consisted of 6 sections including demographic characteristics , questions on knowledge , attitude , enabling factors , and reinforcing factors , questions on maternal function , and measuring the children s weight .
also , it was checked by the specialists in health education , and then their opinions on the validity of the questionnaire were applied ( evaluated by two dieticians , an epidemiologist and two health education specialist for the assessment of face and content validity ) . moreover , in order to measure the reliability index the questionnaire was completed by 20 mothers and alpha cronbach s coefficient of 84% obtained ( a pilot study was also performed on 30 subjects ) .
twenty six questions regarding knowledge were scored from the lowest to the highest level from 1 to 5 .
there were also 14 questions about attitude with responses ranged from completely disagree to completely agree which scored from 1 to 5 , respectively .
responses to questions regarding capability and reinforcing factor and maternal functions were also scored from 1 to 4 .
then , based on the gathered data , the selected mothers in the experimental group underwent the educational intervention .
this intervention was conducted in 6 sessions each of which lasted for 55 - 60 minutes .
each session included giving speeches , question and answer , showing movies as well as slides , and practical teaching for preparing supplementary food .
mothers were also trained on the nutrition by food additives , appropriate pattern of nutrition , gradual variation in food , and growth monitoring .
the children in both groups were weighed before and four months after the educational intervention .
descriptive statistics was used to describe the characteristics of the subjects and distribution of variables involved in the study . based on the type of explanatory and outcome variables chi - squared test ,
independent and matched t - tests were used for data analysis in this study .
descriptive statistics was used to describe the characteristics of the subjects and distribution of variables involved in the study . based on the type of explanatory and outcome variables chi - squared test , independent and matched t - tests
both groups under study were not significantly different regarding age and household size ( table 1 ) .
patients education level was categorized as secondary and high school and patients job was housewife or employee .
education and job were not also different between the two groups under study ( table 2 ) .
the results of the present study revealed that , before the intervention , no statistically significant difference was found between the two groups regarding the means obtained for knowledge , attitude , enabling factors , reinforcing factors , and maternal functions to prevent the growth retardation , and to evaluate the mean of the children s weight .
four months after the educational intervention , however , the results of the matched t - test revealed both a great increase and significance difference in the mean of knowledge scores obtained by the experimental group ( p<0.05 ) .
moreover , the mean of the mothers attitude to monitor growth and preventing the growth retardation revealed a significant difference four months after the educational intervention ( p<0.001 ) .
this shows the great impact of education on mothers attitude . regarding the enabling and reinforcing factors ,
also , a significant difference was found between the two groups after the intervention ( p<0.05 ) .
the results of the t - test also depicted that the maternal function on growth monitoring and preventing the children s growth retardation four months after the educational intervention was significantly different in comparison to the period before the intervention ( p<0.05 ) .
( table 3 ) in addition , four months after the educational intervention , the mean of the children s weight increased in both groups ; however , the increase revealed to be more significant in the experimental group compared to the control group ( p<0.05 ) ( table 4 ) .
in general , a significant increase in the mean of the overall knowledge was observed in the experimental group , which shows the great impact of the educational intervention .
the results of the present study are in line with the results obtained by hazavehei on the relationship between increasing the mothers knowledge and ida in 1 - 5 year - old children ( 14 ) , soltani on preventing the growth retardation among children in tabriz ( 15 ) , sharifiraad on increasing the students knowledge of intestinal parasitic diseases ( 16 ) , and shakouri on controlling ida in high school girl students ( 17 ) .
shojaeizadeh et al . conducted a study about ida conclusion that a qualified educational program which is accompanied by group discussions leads to the increase in the knowledge score .
moreover , sufficient amount of knowledge about an issue can result in the importance as well as the belief toward that issue and , consequently , develop a positive attitude ( 18 ) .
in general , after the educational intervention
, the mean of attitude scores has increased in the experimental group , which reveals the effect of the precede model on increasing the positive attitude .
the results are in line with the results obtained in the studies conducted by hazavehei ( 14 ) , sabzmakan on the increase of the patients attitude scores after the coronary heart bypass surgery ( 19 ) , and shakouri ( 17 ) .
in the precede model ,
predisposing factors such as attitude are prior in behavior and , at the same time , are considered as behavior s stimulating factors . in the present study , also
, the positive attitude has resulted in appropriate maternal function for health monitoring and preventing the growth retardation .
the results of the present study depicted a significant difference between the two groups regarding the enabling factors .
similar results were obtained in the studies conducted by sharifiraad on the relationship between increasing the enabling factors and decrease in the intestinal parasitic diseases ( 16 ) and zigheimat on the effect of educating the epileptic patients ( 20 ) .
the results of the present study , also , revealed a significant difference between the two groups regarding the reinforcing factors , which shows the effect of utilizing the precede model on increasing the reinforcing factors .
this is in line with the studies conducted by zigheimat on epilepsy ( 20 ) , shakouri on controlling ida in high school girl students ( 17 ) , and hazavehei on controlling ida in 1 - 5 year old children ( 14 ) .
regarding the maternal function in monitoring health and preventing the growth retardation , the present study revealed a significant difference between the two groups , which proves the effect of knowledge , attitude , and reinforcing as well as predisposing factors on the rate of maternal function .
the study conducted by baghianimoghadam et al . in yazd province ( 12 ) as well as a study in chile ( 21 ) , also , revealed that education based on the precede model increases the mothers breast feeding behavior .
therefore , growth monitoring can encourage the mothers to perform positive activities . in order to achieve this aim , sufficient amount of time
cooperation of the mother and the family has a major role in the child s growth .
it is also quite important to strengthen the mothers , increase their motivation , discuss the child s growth with them , and receive their opinions ( 22 ) .
in a study which was conducted by emami and aref on the rate of maternal function in using iron as well as supplementary vitamins for infants
, it was shown that the mothers had a moderate function regarding this issue ( 23 ) .
the mean of the scores obtained for the maternal function significantly increased after the educational intervention in hazavehei s study on controlling ida in 1 - 5 year - old children using the precede model ( 14 ) .
performed studies in england and reached similar results ; i.e. conducting the iron supplementation program by mothers leads to success in ida control strategy .
his aim can be achieved by developing an effective relationship between the mothers and the health staff ( 24,25 ) .
dabagh and green , also , conducted a study on the application of theprecede and the proceed models as the framework of designing the programs as well as policies in preventing diarrhea in children in arab countries.in line with the objective of the study , the precede model was utilized as a diagnostic instrument for identifying and emphasizing the factors which affect the causes as well as controlling diarrhea in children in rural areas ( 26 ) .
the results of the present study revealed a significant difference between the control and the experimental group regarding the increase of weight .
although the increase in weight was observed in both groups , the experimental group revealed more increase in weight in comparison to the control group .
kilaru conducted an interventional study which included growth monitoring consultation accompanied by teaching nutrition to mothers and came to the conclusion that the children in the experimental group gained more weight after the intervention ( 5 ) .
in his study
, kumar considers starting the breast feeding 6 hours after birth and inappropriate supplementary food as the risk factors for underweight ( 27 ) .
this might be due to the fact that the mothers had not been educated in this respect .
in a study which was conducted on children in india ,
60% of the children had underweight , which had happened because of the mothers lack of knowledge about nutrition , their unhealthy habits , and undesirable cultural functions ( 28 ) .
the effectiveness of the precede model was also confirmed in a study which was conducted in vietnam in order to evaluate the need for educational interventions with respect to children s nutrition , breast feeding , and growth monitoring ( 29 ) .
these results , all , prove the effectiveness of the precede model in educating the mothers on the children s gain of weight .
one limitation of this study is that we did not have control over the study subjects regarding their contacts .
any contact between individuals in intervention and control group can affects their behaviour and the final outcome of the study .
educational programming based on the precede model positively affects different aspects of mothers behavior in children s growth monitoring .
the results of this study indicated that mothers training program based on the precede model was highly effective on the prevention of growth retardation in the study population .
Output:
| background : growth retardation in children is a result of nutritional ignorance , inappropriate care , and inadequate monitoring of growth monitoring .
this study was performed to assess the effect of mothers education program based on the precede model on the mean weight of children ( 6 - 12 months ) at health centers in shiraz , fars province .
methods : this quasi experimental study was conducted on 120 mothers ( 60 in the experimental and 60 in the control group ) with single child and exclusively on breast feeding who were cared by health centers in shiraz , fars province .
the data were gathered through a questionnaire which included demographic characteristics , the components of the precede model ( knowledge , attitude , enabling as well as reinforcing factors , and maternal function ) and child weight .
educational intervention was performed during 6 sessions each of which lasted for 55 to 60 minutes . the questionnaire was completed by the experiment a land control group before and 4 months after the training program .
results : the results showed that the educational intervention program in the experimental group caused significant increase in the means of knowledge ( p<0.001 ) and attitude scores ( p<0.001 ) .
this study showed that enabling and reinforcing factors ( and training sessions ) , performance score of mothers as well as weight of children among experimental group were significantly higher than control group ( p=0.01 ) .
conclusion : the results of this study can be used as a guideline prevents growth retardation in health centers and other related organizations . |
PubmedSumm8865 | ***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 most common cause of colo - vesical ( cv ) fistulae is diverticular disease , followed by malignancy and crohn 's disease .
the preferred management of cv fistula is primary resection with anastomosis performed as a 1-stage procedure .
however , there are reports of patients with cv fistula secondary to diverticular disease managed medically for prolonged periods of time without operative intervention but without achieving complete healing .
this article reports a patient with a cv fistula , which healed without any surgical intervention . to the best of our knowledge , this has not been reported previously in the literature .
a 62-year - old gentleman with known diverticular disease presented to accident and emergency ( a&e ) in june 2009 with suprapubic pain , pyrexia , haematuria and elevated inflammatory markers .
he was treated with ciprofloxacin for a urinary tract infection ( uti ) and was discharged .
he was also being investigated for lower abdominal pain and weight loss by a colorectal surgeon .
a clinical diagnosis of diverticular abscess was made which was confirmed on computed tomography ( ct ) scan .
the ct images demonstrated moderate diverticular disease in the sigmoid colon with a 7 cm 6 cm abscess and a small pocket of air in the urinary bladder but no direct cv fistulous communication seen ( fig .
a subsequent flexible cystoscopy revealed a raised , inflamed area on the posterior wall of the urinary bladder .
the patient gave a past medical history of osteoarthritis , appendicectomy and transurethral resection of the prostate .
a colorectal multidisciplinary team meeting decided that he should undergo a hartmann 's procedure , which was performed on 13th july 2009 .
the intra - operative findings revealed an inflammatory mass involving the sigmoid colon , which was attached to the bladder and a segment of small bowel .
the involved small bowel segment was resected and a side - to - side anastomosis was performed .
the diseased segment of sigmoid colon was resected and a colostomy was fashioned in the left iliac fossa .
the histology of the sigmoid colon was consistent with diverticulitis and the resected small bowel specimen revealed features consistent with peritonitis , with no evidence of malignancy in either specimen .
the rectal stump was mobilised and anastomosed at approximately 16 cm from the anal verge using a stapling device .
one week following the reversal he presented to his general practitioner ( gp ) with rigours , fever , dysuria , macroscopic haematuria and pneumaturia .
a uti was diagnosed by analysing a midstream urine specimen ( msu ) , which subsequently grew mixed faecal flora .
three days later , on 11th february 2010 he was admitted as an emergency , now with suprapubic pain and faecaluria .
microbiology advice was sought and intravenous gentamicin and metronidazole was commenced in addition to clarithromycin and trimethoprim .
the ct images revealed a direct fistulous communication with the urinary bladder containing oral contrast with the presence of air in the bladder ( fig .
unfortunately , in august 2010 he saw his gp with further supra - pubic pain and dysuria .
an msu revealed wbcs > 2000 with rbcs and a growth of escherichia coli .
3 ) which demonstrated no evidence of a collection and no air in the urinary bladder . the fat plane between the colon and the urinary bladder was intact .
he was reviewed on a final occasion in august 2013 and he remains asymptomatic . a ct scan done in september 2013 showed no communication between the bowel and urinary bladder and he was therefore discharged .
cv fistula is the most common type of fistula associated with diverticular disease of the colon .
diverticular fistulae occur when a phlegmon or abscess extends or ruptures into the adjacent bladder .
pneumaturia and faecaluria are common presenting symptoms and are considered pathognomic of a cv or an entero - vesical fistula .
the sensitivity of either cystoscopy or a barium enema in making the diagnosis of cv fistula is reported to be 3848% .
although useful in excluding other diagnoses , sigmoidoscopy and colonoscopy rarely permit visualisation of a fistula . staged surgical procedures remain the mainstay of cv fistula treatment .
there are case reports of cv fistulae treated conservatively because patients either did not want an operation or were too high a surgical risk .
only one case report documents complete healing of a procto - vesical fistula secondary to rectal cancer with the use of octreotide .
the authors postulate that octreotide reduces gastrointestinal tract secretions and therefore closure of the fistula may have been related to reduced inflow of gastrointestinal tract secretions into the bladder via the fistula .
six patients observed for 314 years encountered little inconvenience and were without significant complications while on intermittent antibacterial therapy alone . in another retrospective study ,
they were monitored over a 12-year period and were found to exhibit no significant changes in renal function and urosepticaemia was not documented . however
firstly , that he had a primary diverticular disease induced cv fistula at initial presentation , which came to light only after his reversal .
an alternative view is that it was an iatrogenic fistula that developed at the time of reversal of hartmann 's .
points supporting a primary fistula are that he had uti at first presentation , which is common in cv fistulae and rare in otherwise normal males .
patients with fistulae secondary to a benign cause tend to be commoner in men , suggesting that the uterus affords some protection against its formation in women .
secondly , cystoscopy demonstrated a raised inflamed area in the posterior wall of the urinary bladder suggestive of a cv fistula .
this gives credence to the second possibility of this being an iatrogenic fistula since it appeared after the reversal and with supportive radiological evidence .
there are reports of iatrogenic fistulae induced by surgical procedures , including colo - anal anastomoses augmentation cystoplasty , prostatectomy , rectal resections and laparoscopic inguinal hernia repair , or endoscopic procedures such as colorectal stenting for malignant obstruction . from the above examples ,
conservative management was documented in only one report , but this did not achieve complete healing .
whatever the aetiology this is the first time that such a fistula has been demonstrated clinically and radiologically to have healed spontaneously without surgery .
we would therefore suggest that in benign cv fistula resolution through conservative management might be considered as a first option , especially in those who , due to their co morbidities would be poor surgical candidates .
although some small studies have suggested that conservative management might be a reasonable option , no randomised controlled trials have supported conservative management . until such evidence becomes available careful selection with close follow - up
written informed consent was obtained from the patient for publication of this case report and accompanying images .
a copy of the written consent is available for review by the editor - in - chief of this journal on request .
Output:
| introductioncolo - vesical ( cv ) fistulae are the most common type of fistulae associated with diverticular disease .
surgery remains the mainstay of treatment , without which , cv fistulae rarely achieve complete healing.presentation of caseherein , we report the case of a 62-year - old man who developed a cv fistula after reversal of hartmann 's procedure ( initially for management of diverticular abscess ) , which healed with conservative management alone.discussionwe discuss possibilities of the aetiology of this fistula .
the cv fistula may have been initially present , which came to light only after his reversal . or an iatrogenic fistula that developed at the time of reversal of hartmann's.conclusionthis is the first time that such a fistula has been demonstrated clinically and radiologically to have healed spontaneously without surgery .
we recommend that conservative management of cv fistulae should be considered . |
PubmedSumm8866 | ***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: hereditary multiple exostoses ( hme ) , also known as multiple osteochondroma ( mo ) , is an autosomal dominant bone disorder with an incidence of 1 in 50,000 live births in western populations ( 1 ) . the morbidity rate is greater in males than females , with a ratio of 1.5:1 , due to the mutations exerting a weaker phenotypic effect in females ( 2 ) .
hme is characterized by the presence of multiple benign cartilage - capped tumors , localized primarily in the long tubular bones , particularly in the humerus ( 1050% ) , forearm ( 3960% ) , knee ( 33% ) and ankle ( 25% ) .
the majority of patients with hme ( ~70% ) have a family history of the condition ( 1,3,4 ) .
hme is a genetically heterogeneous disorder with two disease - causing genes identified , exostosin glycosyl transferase-1 ( ext1 ) and exostosin glycosyl transferase-2 ( ext2 ) located at chromosomes 8q24 and 11p11-p12 , respectively ( 5,6 ) .
the proteins encoded by human ext1 and ext2 are type ii transmembrane glycoproteins , localized in the endoplasmic reticulum .
the ext1/ext2 complex is involved in the biosynthesis of heparin sulphate ( hs ) proteoglycan ( hspg ) ( 7 ) .
prior to deacetylation , the ext1/ext2 complex catalyzes the elongation of the hs chain . ext1 and ext2 are ubiquitously expressed in developing limb buds , and in osteochondromas their expression was decreased in correlation with mutation status ( 8,9 ) . to date , ~422 separate pathogenic mutations in ext1 and ~221 mutations in ext2 have been identified .
mutations in ext1 account for 5678% of cases in mo families , whereas ext2 mutations have been identified in 2144% of cases ( 4,1015 ) .
however , in china , ext2 mutations are identified more frequently than ext1 mutations ( 16 ) .
the majority of patients have been identified in a single family or as sporadic cases .
nonsense , frameshift and splice - site mutations , which represent the majority of mo - causing mutations ( 80% ) , have been predicted to lead to the premature translational termination of the associated amino acids , and the subsequent production of a truncated protein ( 17 ) .
mutations in ext1 are dispersed along the gene , and may occur in various exons ( 14,18 ) ; however , ext2 mutations do not appear to occur in the final third of the gene - coding region ( 17 ) .
other than ext1 and ext2 , the ext3 gene has been mapped to chromosome 19p ( 19 ) .
it appears to be a minor locus in hme families and no causative mutations in ext3 have been identified ( 20 ) .
three additional ext - like genes , designated extl1 , extl2 and extl3 have been identified and mapped to chromosomes 1 ( 1p36 , 1p11-p12 ) and 8 ( 8p12 ) ( 2123 ) .
although the extl genes are considered strong candidate genes for mo , to date no hme family has been associated with these loci .
the present study investigated a rare large family with mo , and identified a novel splice - site mutation in ext2 .
written consent was obtained from all study participants , and the present study was approved by the ethics committee of the second xiangya hospital ( changsha , china ) .
the proband was admitted to the second xiangya hospital in 2012 , and presented with a large osteochondroma .
the five - generation chinese family of the proband was subsequently investigated and a pedigree constructed based on clinical and radiographical evaluations of all family members ( fig .
there were 13 affected individuals ( 11 males and 2 females ) aged 880 years ( average age , 52 years ) .
the incidence rate was therefore 40% within the family , and mo occurred in each generation .
the affected individuals had 616 exostoses , typically located at the juxtaepiphyseal regions of long bones ; however , these were not as large as those present in the proband .
there were no other lesions that were atypical of mo and no evidence of short stature ( average height of adult male and female was 165 and 156 cm , respectively ) .
all affected individuals had lesions detected prior to age 10 , but had never received surgery , with the exception of the proband .
the proband , family member iv-2 , a 42-year - old male , presented with 41-year history of multiple osteochondroma . physical examination revealed a large mass on the left side of the back ( fig .
2a ) , ( 393319 cm ) , and > 14 osseous nodules of varying sizes located on the prothorax wall , left scapula , bilateral forearms , knees and left ankle .
the patient had had an operation at age 22 due to a rapidly enlarging lumbar spinal osteochondroma .
x - ray analysis revealed a diffuse flocculent shadow with high density in the left lung field and multiple bony protrusions on limbs , as presented in fig .
2b . computed tomography ( ct ) angiography did not reveal any imaging of large arteries , indicating a potential chondroma ( fig .
ct revealed the left back mass was of mixed density and multiple flecked calcifications , which spread into the left side of the chest ( fig .
the patient was subsequently followed up once every three months in the first year , and once every year thereafter .
dna of all affected family members was extracted from peripheral blood as previously described ( 24 ) .
the coding regions of the ext1 and ext2 genes were amplified by polymerase chain reaction ( pcr ) using primer sets , as previously described ( 25 ) .
the pcr products were purified by bigdye terminator version 1.1 ( applied biosystems ; thermo fisher scientific , inc . ,
waltham , ma , usa ) followed by direct dna sequencing with an abi 3100 automatic sequencer ( applied biosystems ; thermo fisher scientific , inc . ) , using forward and reverse primers .
total rna was extracted from the tumor tissue of the proband and healthy lung tissue of an unrelated individual , using the qiagen rneasy mini kit ( qiagen , inc . ,
cdna synthesis was performed using revertaid first strand cdna synthesis kit ( fermentas ; thermo fisher scientific , inc . ) , using the following primers : forward , 5-aaccagaacacactgcgcatcaag and reverse , 5-agctccacgaagaaccacacagaa for exons 25 .
amplification of cdna was performed and products were purified by bigdye terminator version 1.1 followed by direct dna sequencing with an abi 3100 automatic sequencer .
written consent was obtained from all study participants , and the present study was approved by the ethics committee of the second xiangya hospital ( changsha , china ) .
the proband was admitted to the second xiangya hospital in 2012 , and presented with a large osteochondroma .
the five - generation chinese family of the proband was subsequently investigated and a pedigree constructed based on clinical and radiographical evaluations of all family members ( fig .
there were 13 affected individuals ( 11 males and 2 females ) aged 880 years ( average age , 52 years ) .
the incidence rate was therefore 40% within the family , and mo occurred in each generation .
the affected individuals had 616 exostoses , typically located at the juxtaepiphyseal regions of long bones ; however , these were not as large as those present in the proband .
there were no other lesions that were atypical of mo and no evidence of short stature ( average height of adult male and female was 165 and 156 cm , respectively ) .
all affected individuals had lesions detected prior to age 10 , but had never received surgery , with the exception of the proband .
the proband , family member iv-2 , a 42-year - old male , presented with 41-year history of multiple osteochondroma . physical examination revealed a large mass on the left side of the back ( fig .
2a ) , ( 393319 cm ) , and > 14 osseous nodules of varying sizes located on the prothorax wall , left scapula , bilateral forearms , knees and left ankle .
the patient had had an operation at age 22 due to a rapidly enlarging lumbar spinal osteochondroma .
x - ray analysis revealed a diffuse flocculent shadow with high density in the left lung field and multiple bony protrusions on limbs , as presented in fig .
2b . computed tomography ( ct ) angiography did not reveal any imaging of large arteries , indicating a potential chondroma ( fig .
ct revealed the left back mass was of mixed density and multiple flecked calcifications , which spread into the left side of the chest ( fig .
the patient was subsequently followed up once every three months in the first year , and once every year thereafter .
dna of all affected family members was extracted from peripheral blood as previously described ( 24 ) .
the coding regions of the ext1 and ext2 genes were amplified by polymerase chain reaction ( pcr ) using primer sets , as previously described ( 25 ) .
the pcr products were purified by bigdye terminator version 1.1 ( applied biosystems ; thermo fisher scientific , inc . ,
waltham , ma , usa ) followed by direct dna sequencing with an abi 3100 automatic sequencer ( applied biosystems ; thermo fisher scientific , inc . ) , using forward and reverse primers .
total rna was extracted from the tumor tissue of the proband and healthy lung tissue of an unrelated individual , using the qiagen rneasy mini kit ( qiagen , inc . ,
cdna synthesis was performed using revertaid first strand cdna synthesis kit ( fermentas ; thermo fisher scientific , inc . ) , using the following primers : forward , 5-aaccagaacacactgcgcatcaag and reverse , 5-agctccacgaagaaccacacagaa for exons 25 .
amplification of cdna was performed and products were purified by bigdye terminator version 1.1 followed by direct dna sequencing with an abi 3100 automatic sequencer .
written consent was obtained from all study participants , and the present study was approved by the ethics committee of the second xiangya hospital ( changsha , china ) .
the proband was admitted to the second xiangya hospital in 2012 , and presented with a large osteochondroma .
the five - generation chinese family of the proband was subsequently investigated and a pedigree constructed based on clinical and radiographical evaluations of all family members ( fig .
there were 13 affected individuals ( 11 males and 2 females ) aged 880 years ( average age , 52 years ) .
the incidence rate was therefore 40% within the family , and mo occurred in each generation .
the affected individuals had 616 exostoses , typically located at the juxtaepiphyseal regions of long bones ; however , these were not as large as those present in the proband .
there were no other lesions that were atypical of mo and no evidence of short stature ( average height of adult male and female was 165 and 156 cm , respectively ) .
all affected individuals had lesions detected prior to age 10 , but had never received surgery , with the exception of the proband .
the proband , family member iv-2 , a 42-year - old male , presented with 41-year history of multiple osteochondroma . physical examination revealed a large mass on the left side of the back ( fig .
2a ) , ( 393319 cm ) , and > 14 osseous nodules of varying sizes located on the prothorax wall , left scapula , bilateral forearms , knees and left ankle .
the patient had had an operation at age 22 due to a rapidly enlarging lumbar spinal osteochondroma .
x - ray analysis revealed a diffuse flocculent shadow with high density in the left lung field and multiple bony protrusions on limbs , as presented in fig .
2b . computed tomography ( ct ) angiography did not reveal any imaging of large arteries , indicating a potential chondroma ( fig .
ct revealed the left back mass was of mixed density and multiple flecked calcifications , which spread into the left side of the chest ( fig .
the patient was subsequently followed up once every three months in the first year , and once every year thereafter .
dna of all affected family members was extracted from peripheral blood as previously described ( 24 ) .
the coding regions of the ext1 and ext2 genes were amplified by polymerase chain reaction ( pcr ) using primer sets , as previously described ( 25 ) .
the pcr products were purified by bigdye terminator version 1.1 ( applied biosystems ; thermo fisher scientific , inc . , waltham , ma , usa ) followed by direct dna sequencing with an abi 3100 automatic sequencer ( applied biosystems ; thermo fisher scientific , inc . ) , using forward and reverse primers .
total rna was extracted from the tumor tissue of the proband and healthy lung tissue of an unrelated individual , using the qiagen rneasy mini kit ( qiagen , inc . ,
cdna synthesis was performed using revertaid first strand cdna synthesis kit ( fermentas ; thermo fisher scientific , inc . ) , using the following primers : forward , 5-aaccagaacacactgcgcatcaag and reverse , 5-agctccacgaagaaccacacagaa for exons
amplification of cdna was performed and products were purified by bigdye terminator version 1.1 followed by direct dna sequencing with an abi 3100 automatic sequencer .
dna was extracted from family members with hme ( fig . 1a , solid squares ) , and the possible mutations residing in the ext genes were scanned in the exon and intron junctions .
dna sequence analysis revealed a heterozygous mutation , c.939 + 1 g > t in ext2 ( fig .
3 ) in all family members with hme ; none of the unaffected family members carried this mutation .
4 . following rt - pcr at exons 25 , two bands were identified in the proband ; one band of normal size ( ~500 bp ) and one smaller band ( ~300 bp ) .
the size of one band was revealed to be 429 bp , and the other , 296 bp .
compared with cdna of ext2 , sequence analysis confirmed exon 5 skipping in the aberrant allele , resulting in an in - frame deletion of the ext2 protein .
the mo family investigated in the present study exhibited a ratio of male and female patients at 5.5:1 , which differs from the ratio of 1.5:1 reported previously ( 26 ) .
therefore , the present study performed a detailed physical examination of all healthy females in the 3rd to 5th generation , to rule out misdiagnosis due to a weak phenotype .
linkage analysis has confirmed that hme is genetically heterogeneous , and the genes that have indicated the greatest levels of association are ext1 , ext2 and ext3 .
it has been revealed that mutations in ext1 or ext2 are responsible for the majority of hme cases .
the proteins ext1 and ext2 form a hetero - oligomeric complex that functions in hspg biosynthesis .
this complex has a substantially greater glycosyltransferase activity than homo - oligomers of ext1 or ext2 ( 27 ) ; therefore , a mutation present in ext1 or ext2 may result in a critical reduction in hspg ( 9,28,29 ) .
this may subsequently alter the balance of fibroblast growth factor and indian hedgehog homolog signals ( 3032 ) .
thus , the normal signaling pathway involved in bone development may be affected , leading to premature differentiation of cartilage , cartilage cell proliferation and abnormal bone growth in the adjacent areas ( 33 ) , resulting in hme . according to the mo mutation database ( medgen.ua.ac.be/lovdv.2.0/home.php ) ,
713 mutations of the ext1 gene and 386 mutations of the ext2 gene have been identified ; however , no mutations in ext3 have been reported . among the 386 ext2 mutations , the majority are nonsense mutations , followed by frameshift and substitution mutations .
the present study revealed a novel splicing mutation ( c.939 + 1 g > t ) leading to deletion of 196 bp in exon 5 of ext2 , which may result in a truncated and subsequently pathogenic protein .
this mutation resulted in deletion from codon 744 to 939 of exon 5 of the mrna , causing a shift in the codon - reading frame , followed by the synthesis of 266 novel amino acids that terminate with a stop codon at position 994 .
certain studies have suggested that no mutations exist downstream of exon 8 ; however , according to the human gene mutation database ( www.hgmd.cf.ac.uk/ac/index.php ) , 3 patients with mutations in exon 10 and 4 patients with mutations in exon 11 have been identified .
the truncated protein that arises due to the c.939 + 1 g > t mutation in the family investigated in the present study did not contain the amino acids encoded for by exon 7 to l4 .
this alteration may cause disease ; however , whether it is associated with the rare large osteochondroma that occurred on proband remains to be elucidated .
the present study suggested that knudson 's two hit hypothesis or potential mutations in ext3 or extl may explain the occurrence of the osteochondroma . in conclusion , the present study demonstrated that the c.939 + 1 g > t ( ext2 ) mutation , present in a five - generation 33-member mo family , resulted in the splicing out of exon 5 .
Output:
| multiple osteochondromas ( mo ) , also known as hereditary multiple exostoses , is an autosomal dominant bone disorder .
mutations in exostosin glycosyl transferase-1 ( ext1 ) and exostosin glycosyl transferase-2 ( ext2 ) , including missense , nonsense , frameshift and splice - site mutations , account for up to 80% of reported cases .
the proteins ext1 and ext2 form a hetero - oligomeric complex that functions in heparan sulfate proteoglycan biosynthesis . a heterozygous ext2 mutation , c.939 + 1g > t , was identified in a five - generation 33-member mo family , and was present in all 13 affected members .
the mutation results in deletion of exon 5 in the mrna , producing a frameshift that leads to a premature termination codon .
the present study extends the mutational spectrum of ext2 . |
PubmedSumm8867 | ***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: tuberculous involvement of metacarpals and phalanges is a rare presentation of extrapulmonary tuberculosis in adult .
tuberculous infection of the metacarpals , metatarsal and phalanges of hands and feet is known as tubercular dactylitis .
a 65 years old female with history of pain and swelling at 1st metacarpal of left hand , since 3 months which gradual in onset and progressive in nature associated with multiple cervical swellings .
while radiographs showed a pathological fracture of the 1st carpo - metacarpal joint ( cmcj ) with soft tissue swelling , mri revealed a large heterogenous lesion at the carpo - metacarpal joint of the thumb with bony erosions of the trapezium and 1st metacarpal base on t2w - stir images .
the lesion was extending upto the palmar aspect of the hand and displacing flexor pollicis longus tendon medially . during surgery
, there was caseous material seen which was debrided and the fractured fragment was excised and sent for biopsy .
the cmcj was found to be unstable and a kirschner wire was used to stabilize the 1st cmcj and immobilized in a pop splint .
the k - wire had backed out partially at the end of 5 weeks which was then removed and range of motion was started . at end of 1 year follow up the patient had little restriction of movement as compared to the opposite hand with no pain and hindrance in daily activity .
osteoarticular tuberculosis comprises 1 - 4.3% of all tuberculosis cases and 10 - 15% of all extrapulmonary tuberculosis cases
. isolated involvement of bone by tuberculous infection is uncommon , and the clinical and radiological picture usually mimic chronic pyogenic osteomyelitis , brodie s abscess , tumors or granulomatous lesions[2 - 4 ]
. tuberculous involvement of the metacarpals and phalanges is a rare presentation with fewer presentation in adults .
tuberculous infection of metatarsal and phalanges of hands and feet is known as tubercular dactylitis .
we present to you an aged female with isolated tuberculous affection of the 1st cmc joint .
osseous affection by tuberculosis is usually treated with conservative treatment using anti - tuberculous therapy .
a 65yrs old female came to our department with complaints of pain and swelling of the left hand along the thenar eminence and the proximal aspect of the thumb .
the swelling was noticed two months ago and was progressive in nature and was painful on movements [ fig 1 ] .
she simultaneously developed multiple swellings in the cervical region which most likely pointed towards cervical lympadenopathy [ fig 2 ] .
she did not have any associated symptoms like loss of appetite , weight loss or any evening rise of temperature .
swelling on 1st metacarpal a plain radiograph of the patient was taken which showed pathological fracture of the base of 1st metacarpal along with lytic lesion at the base of the 1st metacarpal with haziness of the surrounding soft tissue [ fig 3 ] .
on x - ray we came to a provisional differential diagnosis of pathological fracture secondary to a pyogenic infection , tuberculous osteomyelitis or soft tissue swelling , malignancy .
the usg was done to rule out any malignant involvement of the soft - tissue [ fig 3 ] .
an mri scan showed a large heterogeneous lesion at the 1st carpo - metacarpal joint space along with joint space widening [ fig 3 ] .
the mri scan suggested an abscess like picture most likely due to infective etiology and less likely to be neoplastic lesion .
mri , x - ray and ultrasound of the left hand ( from left to right ) she was then posted for drainage of abscess and debridment with stabilization of the fracture fragment .
intra - operatively we found thick caseous material within the soft tissue and the fragment at base of the 1st metacarpal was freely mobile similar to a loose body [ fig 6 ] .
it was not possible to fix that fragment as it looked infected on gross inspection and hence it was removed and sent for biopsy and culture sensitivity along with the surrounding soft - tissue .
we also found that after removal of the fragment the joint was unstable and hence a kirschner wire was passed through the 1st carpo - metacarpal joint to stabilize it [ fig 7 ] .
post - operatively the hand was immobilised in a below elbow pop splint to give added stability .
a cervical lymph node biopsy was also taken during the same sitting and sent for histo - pathology to confirm if the lymph nodes were due to tuberculosis or some other cause like malignancy or viral respiratory infection which are common in indian scenario .
immediate post - op x - ray showing stabilization of the 1st metacarpo - phalyngeal joint with k - wire after excision of the 1 metacarpal base post - op range of motion and x - ray at end of 3 months 1 year follow up x - ray and range of motion with grip strength .
the biopsy report came back positive for tuberculous osteomyelitis which suggested fibro - collagenous tissue and few bony fragments showing large caseous necrosis with few epitheloidid cell granuloma .
the patient was then started on anti - tuberculous treatment emprerically while awaiting the culture report .
a combination of isoniazid ( 300 mg ) , rifampicin ( 450 mg ) , pyrazinamide ( 1500 mg ) and ethambutol ( 800 mg ) was started as intensive phase for a period of 6 months under the guidance of a chest physician and then the continuous phase for a period of 6 months where isoniazid ( 300 mg ) and rifampicin ( 450 mg ) was given .
the culture reports were obtained at the end of 6 weeks and the mycobacterium species showed sensitivity to the primary drugs which were started .
routine liver function tests were repeated every 3 months which were normal in the patient . at the end of 5 weeks
the kirschner wire backed out partially which was then removed and range of movement exercises were started .
the patient had 1 episode of recurrence of cervical lymphandenopathy at the end of 7 months of treatment which eventually regressed on the continuous phase of akt .
the patient had almost complete range of movement at the end of 3 months with no sequel due to tuberculosis as compared to the opposite hand with no joint instability [ figure 6 ] .
we did not plan any further intervention as the patient was having a stable joint at the end of 3 months and we decided to keep a regular follow up of the patient .
the patient was then followed up regularly upto end of 1 year and the ranges of movements were compared with the opposite hand .
there was very little restriction of movement of the thumb as compared to the opposite hand with a stable joint not subluxating on movements .
the grip strength was adequate to do any daily household activity which was the only requirement of the patient [ fig 7 ] .
mild pain and swelling , with slight warmth and associated cervical lymphadenopathy should alert a physician to rule out possibility of tuberculosis in an indian set - up . at times presence of a discharging sinus
tuberculous involvement of the tubular long bones is a rare presentation in itself and isolated presentation of tuberculous dactylitis is even rarer .
along with tubercular dactylitis differentials of pyogenic abscess , malignancy or post - traumatic soft tissue swellings should be borne in mind . around 85% of patients with tubercular dactylitis
very few patients having tuberculosis of the bone are diagnosed with concomitant active pulmonary disease .
our patient presented with no pulmonary involvement and only had painful , swollen 1st metacarpal with no previous history of any trauma .
a provisional diagnosis of tubercular dactylitis was made on radiographs and mri scan but tubercular dactylitis being rare in adults made it impossible for us to be sure a single diagnosis .
hence a surgical intervention was planned to take a biopsy and debride the joint with stabilization .
intra - operatively it was considered to remove the proximal fragment as there was infectious involvement of the joint and the proximal fragment .
after removal of the proximal fragment the joint was unstable and hence the joint had to be stabilized using kirschner wire which was passed through the 1st cmcj .
the fixation acted like an excision arthroplasty of the joint which needed stablilization and immobilization .
post - operatively we expected the joint to be unstable without support but the wire backed out partially at the end of 5 weeks and the joint was found to be stable and patient was started on range of motion exercises for the thumb . at 1 year of follow - up
the patient has good range with fair grip strength with no difficulty in doing daily activity as compared to the opposite hand along with a stable joint .
radiological features of bony tuberculosis ( sclerosis and osteolytic lesion ) are present in other conditions such as inflammatory arthritis , pyogenic osteomyelitis , brodies abscess , kaposi s sarcoma and other malignancies .
other radiological features such as osteopenia , soft - tissue swelling with minimal periosteal reaction , narrowing of joint space , subscondral erosions are non - specific and often delay the diagnosis .
the gold standard for diagnosis of osseous tuberculosis is culture and histo - pathological evidence of mycobacterium tuberculosis from the bone tissue . to obtain positive results of ziehl - neelsen staining for acid - fast bacilli
the colony count requires to be at least 104 acid - fast bacilli per millilitre of the speciemen and it does not differentiate between tuberculous mycobacteria and non - tuberculous mycobacteria .
treatment recommendations state the use 4-drug regimen which include isoniazid , rifampicin , pyrazinamide and ethambutol for a period of 2 - 4 months which is the intensive phase of the treatment followed by 2-drug regimen of isoniazid , rifampicin for period of 6 to 10 months depending on the patients functional recovery . in 2005 , agarwal et al stated that ziehl - neelsen staining and culture obtained during the course of surgery is a gold standard for diagnosis of tuberculous osteomyelitis . in 2008
kushwaha et al stated that tuberculous dactylitis is a difficult diagnosis and should be suspected in long standing cases with pain and swelling of the phalynges and metacarpals . in an endemic country like india
the diagnosis of tubercular osteomyelitis should be kept in mind while making the differential diagnosis of several osseous pathologies .
early diagnosis with prompt debridement of tubercular dactylitis is the key to avoid long term arthritic sequel and return of range of motion acivities .
excision arthroplasty for tuberculous affection of the 1st carpo - metacarpal joint has excellent results with joint remodelling as the end result .
Output:
| introduction : tuberculous involvement of metacarpals and phalanges is a rare presentation of extrapulmonary tuberculosis in adult . tuberculous infection of the metacarpals , metatarsal and phalanges of hands and feet is known as tubercular dactylitis.case report : a 65 years old female with history of pain and swelling at 1st metacarpal of left hand , since 3 months which gradual in onset and progressive in nature associated with multiple cervical swellings .
while radiographs showed a pathological fracture of the 1st carpo - metacarpal joint ( cmcj ) with soft tissue swelling , mri revealed a large heterogenous lesion at the carpo - metacarpal joint of the thumb with bony erosions of the trapezium and 1st metacarpal base on t2w - stir images .
the lesion was extending upto the palmar aspect of the hand and displacing flexor pollicis longus tendon medially . during surgery
, there was caseous material seen which was debrided and the fractured fragment was excised and sent for biopsy .
the cmcj was found to be unstable and a kirschner wire was used to stabilize the 1st cmcj and immobilized in a pop splint .
the biopsy of the fragment revealed tuberculous osteomyeltis . on follow - up
the k - wire had backed out partially at the end of 5 weeks which was then removed and range of motion was started . at end of 1 year follow up the patient had little restriction of movement as compared to the opposite hand with no pain and hindrance in daily activity.conclusion:the swelling subsided once anti - tubercular treatment was started .
the cervical lymphadenopathy also resolved over a period of 1 month . |
PubmedSumm8868 | ***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: obesity is a major public health problem , with prevalence increasing at amazing rates in many countries .
diagnosis of obesity and morbid obesity is based on determination of body mass index ( bmi ) , which is calculated as weight / height ( kg / m ) .
the world health organization ( who ) defines underweight as a bmi 18.50 , normal weight as bmi 18.5024.99 , overweight as bmi 25.0029.99 , obese class i as bmi 30.0034.99 , obese class ii as bmi 3539.99 , and obese class iii or morbidly obese as bmi 40 .
laparoscopic sleeve gastrectomy ( lsg ) , one of the foremost bariatric procedures , is believed to induce weight loss by physically restricting gastric capacity via removal of 80% or more of the stomach , including the fundus and greater curvature .
gastric emptying and intestinal transit seem to be faster after lsg and exaggerated release of the satiety gut hormones .
bariatric surgery reduce body weight by decreasing hunger , increasing satiation during a meal , changing food preferences , and increasing diet - induced energy expenditure .
manipulation of gastrointestinal anatomy through bariatric surgery has been shown to profoundly affect the physiological and metabolic processes that control body weight and glycaemia .
obesity is highly associated with increased morbidity and early mortality due to the increased prevalence of chronic diseases , such as diabetes mellitus , cardiovascular disease , hypertension , stroke , and sleep apnea syndrome .
although the effect of obesity on the eye has not been well documented , it has been associated with cataract , glaucoma , diabetic retinopathy , and age - related maculopathy .
spectral - domain optical coherence tomography ( sd - oct ) with faster scanning speed and higher spatial resolution has become essential clinical tools to diagnose and monitor retinal diseases .
the detection of such changes may provide a better understanding of the pathophysiological mechanisms of posterior segment eye diseases .
this is the first study to our knowledge which has investigated optical coherence tomography parameters in morbidly obese patients who undergo lsg . to clarify the relationship between optical coherence tomography parameters and obesity , we investigated the impact of weight loss on intraocular pressure ( iop ) , topographic optic disc parameters ( retinal nerve fiber layer ( rnfl ) , rim area ( ra ) , disc area ( da ) , cup volume ( cv ) , vertical cup / disc ( c / d ) ratio ) , central macular thickness ( cmt ) , total macular volume ( tmv ) , retinal ganglion cell layer ( rgcl ) , and subfoveal choroidal thickness ( sfct ) in morbidly obese patients who had undergone lsg .
the study protocol was approved by the local ethics committee of antalya training and research hospital and conducted in accordance with the declaration of helsinki . prior to initiation all subjects signed a detailed written consent form to confirm their understanding of the study procedures .
the inclusion criteria for all subjects were best - corrected visual acuity of 20/20 or more , refractive errors between + 2 d and 2 d spherical equivalent , primary diagnosis of morbid obesity ( bmi 40 ) , primary treatment of lsg for morbid obesity , and age 18 .
the exclusion criteria were morbid obesity with other endocrine disorders ( e.g. , diabetes mellitus or systemic arterial hypertension ) ; cardiovascular disease or other serious chronic systemic diseases ; history of smoking or alcohol consumption ; history of ocular surgery , laser therapy , ocular trauma , or anterior or posterior segment disease ; use of any medication within the previous 3 months ; strabismus ; amblyopia ; iop > 21 mmhg ; or glaucomatous findings ( e.g. , glaucomatous optic disc changes or visual field defects ) . from 45
morbidly obese patients who had undergone lsg between may 2014 and may 2015 after diagnosis of morbid obesity , 41 were included and 4 were excluded , 1 due to glaucoma , 1 due to keratoconus , and 2 due to pseudotumor cerebri .
the preoperative bmi and the 3- and 6-month postoperative bmi of the patients were calculated using the standard ( who ) formula ( kg / m ) .
all patients underwent a detailed ophthalmic examination that included visual acuity testing , refraction assessment , anterior segment slit lamp biomicroscopy , fundus examination , and iop measurement using a goldmann applanation tonometer .
topographic optic disc parameters ( rnfl , ra , da , cv , and vertical c / d ratio ) , tmv , cmt , and rgcl assessment using sd - oct ( cirrus hd oct , carl zeiss meditec , dublin , ca , usa ) preoperatively and at 3 and 6 months postoperatively .
subfoveal choroidal thickness ( sfct ) measurements were performed by two experienced retinal specialists ( muhammet kazim erol and berna dogan ) blind to the patients ' bmi using a high - speed and high - resolution sd - oct device .
the participants were asked not to consume caffeine for at least 12 h before examination .
three consecutive measurements of sfct were performed over 3 days and the average values were calculated .
sfct was measured perpendicularly from the outer edge of the retinal pigment epithelium to the choroid - sclera boundary at the fovea using a single line of 6 mm length centered horizontally on the fovea for visualization of the choroid .
the trutrack active eye tracking system , which enables the capture of multiple images in the same location , and the automatic real - time mean function , which combines these images , were used during each image acquisition .
as the sample size was smaller than 50 , the shapiro - wilks test was performed to examine normal distribution . according to the timing of each measurement
, the friedman test was performed if the measurements were not normally distributed and repeated measures anova was performed if they were normally distributed .
if the difference between the measurements was significant , paired comparison was performed using the bonferroni - dunn test for nonparametric tests or the bonferroni test for parametric tests .
the correlations between continuous variables not displaying normal distribution were analyzed using the spearman correlation test and the correlations between variables displaying normal distribution were analyzed using the pearson correlation test .
all analyses were conducted using the spss 22.0 software package ( spss , inc . , chicago , il , usa ) .
the clinical characteristics of the study cohort and statistical findings are summarized in table 1 .
the results of binary comparison of the parameters preoperatively and at 3 and 6 months postoperatively are shown in table 2 .
a statistically significant decrease in bmi was detected at 3 months and 6 months postoperatively ( p < 0.01 ) . a statistically significant increase in cmt , tmv , sfct , and rgcl
there was significant correlation between changes in bmi and changes in tmv ( p < 0.05 , r = 0.313 ) ( figure 1 ) .
there was also significant correlation between changes in bmi and changes in sfct ( p < 0.04 , r = 0.340 ) .
there was no significant difference between the women and the men in tmv , cmt , sfct , and rgcl .
no statistically significant differences were found between preoperative and 3- and 6-month postoperative ra ( p = 0.34 ) , da ( p = 0.64 ) , vertical c / d ratio ( p = 0.39 ) , cv ( p = 0.08 ) , or rnfl ( p = 0.90 ) .
obesity results from morphological and functional changes in the adipose tissue associated with changes in various inflammatory , hormonal , and metabolic factors [ 3 , 6 ] .
several possible pathophysiological mechanisms have been proposed to explain the association between morbid obesity and ocular diseases .
recent research has indicated that oxidative stress in obese individuals may increase as a result of hyperleptinemia , which may trigger pathological changes leading to elevated iop .
both the mechanical and vascular etiology theories of glaucoma may be related to obesity [ 4 , 10 ] . with regard to the mechanical theory ,
obesity has been postulated to exert an effect on iop by causing excessive intraorbital adipose tissue , increased episcleral venous pressure , and impairment of aqueous outflow facility [ 10 , 11 ] .
the vascular theory suggests that obesity has a significant effect on the human microcirculation , stapleton et al
. found that obese individuals have decreased nitric oxide ( no ) levels , which could result in impaired dilatation of the vasculature . also , increased levels of some vasoconstrictor molecules such as endothelin-1 ( et-1 ) and angiotensin - ii ( ang - ii )
might be associated with the reduction of blood flow to the optical nerve head . impaired vascular supply to the optic nerve head
several studies have found a significantly positive correlation between bmi and iop [ 1618 ] .
these findings suggest that obesity is an independent risk factor for increase in iop . in our study
, we found a statistically significant decrease in iop at 3 months and 6 months postoperatively but no statistically significant differences between the topographic optic disc parameters ( rnfl , ra , da , and cv ) preoperatively and at 3 and 6 months postoperatively .
whereas choroidal blood flow is reduced through sympathetic efferent nerve activation and the release of noradrenalin , choroidal blood flow is increased through parasympathetic efferent nerve activation via no signaling .
identifying this role is significant in understanding the effect of obesity on ct , as lower levels of no have been found in morbidly obese patients .
this finding , together with the positive association identified between bmi and levels of vasoconstrictor molecules , explains how disruption of the vasodilator and vasoconstrictor balance as a result of morbid obesity can affect ct .
found that the subfoveal ct was significantly thinner in obese children compared to nonobese children .
we found a statistically significant increase in sfct at 3 months and 6 months postoperatively .
bariatric surgery is the most successful treatment for significant weight loss , resolution of type 2 diabetes , and the prevention of future weight gain .
the impact of weight change ( weight gain or loss ) on eye diseases has not been well documented .
showed that patients with type 2 diabetes who underwent bariatric surgery had clinically stable diabetic retinopathy in the first postoperative year and a clinically negligible but statistically significant foveal thickening 6 months postoperatively .
found that the macula thickness was significantly thinner in obese children compared to nonobese children . in our study , morbidly obese patients who undergo lsg experience a statistically significant increase in central macular thickness , total macular volume at 3 months and 6 months postoperatively .
there was no significant difference between the women and the men in total macular volume , central macular thickness . in the macula , the area that contains the highest carotenoid concentration within the body the macular pigment is composed of lutein and zeaxanthin .
mainly present in the nerve fiber layers and rgcl , with peak concentrations in the fovea , the macular pigment is thought to function as a blue - light filter and antioxidant that enhances visual acuity by decreasing chromatic aberration , reduces visual discomfort by attenuating glare and dazzle , enhances detail by absorbing blue haze , and increases visual contrast . by doing so , macular
pigment protects the retina from damaging influences believed to play a role in the pathogenesis of age - related macular degeneration [ 24 , 25 ] .
adipose tissue could compete with the retina for uptake of lutein and zeaxanthin , resulting in less incorporation into the retina and lower macular pigment optical density ( mpod ) .
found that both men and women with a body fat percentage > 27% had a 16% lower mpod compared to subjects with a body fat percentage 27% and identified an inverse relationship between mpod and both bmi and the percentage of body fat . given that up to 80% of total carotenoids in the human body are stored in body fat , a higher body fat content and bmi may be expected to influence the quantities of lutein and zeaxanthin in the retina .
however , the precise relationship between both body fat and bmi and retinal carotenoid concentration remains unclear . in a rat retinal model , zhang et al .
found that lutein increased the number of rgcs after n - methyl - d - aspartate- ( nmda- ) induced retinal damage .
lutein is an antiapoptotic , direct free - radical scavenger that prevents macular damage and plays a neuroprotective role by decreasing oxidative stress ; it is unclear whether lutein directly protects rgcs . in another study of this relationship , van der veen et al . found a significantly positive correlation between mpod and central foveal thickness . supporting this finding , liew et al .
found a significantly positive relationship between mpod and central retinal thickness as measured by oct .
firstly , it is a single - center study and has a relatively small sample size .
secondly , we obtained sfct measurements manually using edi - oct , which we believe that it can cause errors in measurement . to help overcome this limitation ,
sfct measurements were performed by two experienced retinal specialists blind to the patients ' bmi .
three consecutive measurements of sfct were performed over 3 days and the average values were calculated .
another potential limitation is the lack of macular pigment optical density investigation that might support our findings .
morbidly obese patients who undergo lsg experience a statistically significant increase in central macular thickness , total macular volume , subfoveal choroidal thickness , and retinal ganglion cell layer at 3 months and 6 months postoperatively .
no statistically significant differences were found between preoperative and 3- and 6-month postoperative topographic optic disc parameters .
therefore , experimental , cellular , or molecular studies may expand our understanding of the impact of obesity on eye .
Output:
| purpose . to investigate changes in optical coherence tomography parameters in morbidly obese patients who had undergone laparoscopic sleeve gastrectomy ( lsg )
. methods . a total of 41 eyes of 41 morbidly obese patients ( bmi 40 ) who had undergone lsg were included in study . the topographic optic disc parameters , central macular thickness ( cmt ) , total macular volume ( tmv ) , and retinal ganglion cell layer ( rgcl ) were measured by spectral - domain optical coherence tomography ( sd - oct ) .
subfoveal choroidal thickness ( sfct ) was measured by enhanced deep imaging - optical coherence tomography ( edi - oct )
. results .
the mean cmt was 237.4 24.5 m , 239.3 24.1 m , and 240.4 24.5 m preoperatively , 3 months postoperatively , and 6 months postoperatively , respectively ( p < 0.01 ) .
the mean tmv was 9.88 0.52 mm3 , 9.96 0.56 mm3 , and 9.99 0.56 mm3 preoperatively , 3 months postoperatively , and 6 months postoperatively , respectively ( p < 0.01 ) .
the mean rgcl was 81.2 6.5 m , 82.7 6.6 m , and 82.9 6.5 m preoperatively , 3 months postoperatively , and 6 months postoperatively , respectively ( p < 0.01 ) .
the mean sfct was 309.8 71.8 m , 331.0 81.4 m , and 352.7 81.4 m preoperatively , 3 months postoperatively , and 6 months postoperatively , respectively ( p < 0.01 ) .
no statistically significant differences were found between the preoperative values and 3- and 6-month postoperative values in rim area ( p = 0.34 ) , disc area ( p = 0.64 ) , vertical cup / disc ratio ( p = 0.39 ) , cup volume ( p = 0.08 ) , or retinal nerve fiber layer ( p = 0.90 ) .
conclusions .
morbidly obese patients who undergo lsg experience a statistically significant increase in cmt , tmv , sfct , and rgcl at 3 months and 6 months after surgery . |
PubmedSumm8869 | ***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: on the development of new probes , atsushi miyawaki ( riken ) described new generations of fluorescent proteins that allow the use of light to switch them reversibly between bright and dim fluorescent states ( protein highlighting ; ando et al .
, 2004 ; dedecker et al . , 2006 ) , whereas gerard marriott ( university of wisconsin ) prepared organic probes that undergo rapid and reversible optical switching between states of widely different chemical and photophysical properties ( sakata et al .
when conjugated to target proteins , these probes could be used to measure the dynamics or manipulate the chemical state of the protein repeatedly .
for example , fluorescent protein highlighting was used to demonstrate the stimulation of bidirectional nuclear transport of map kinase upon growth factor activation ( ando et al . , 2004 ) , and optical switching has allowed researchers to reversibly and rapidly control protein dipolar interactions inside cells .
these techniques also can be used in combination with innovative strategies of frap , fret , and super - resolution imaging ( described later ) .
equally significant are new inorganic probes that are small , bright , and resistant to photodegradation ( robert dickson , georgia tech ; zheng et al . , 2004 ) .
once these probes are conjugated to specific targets , they should allow the detection of single molecules in living cells .
other biosensors can report the activation states ( e.g. , conformation and phosphorylation ) of endogenous proteins with minimal perturbation ( klaus hahn , university of north carolina ; nalbant et al .
these biosensors consist of an affinity element that binds only to the activated state of the target protein and a bright dye whose fluorescence emission responds to the binding .
the development of the affinity element was further facilitated by using a phage display library combined with high - throughput screening of sequences capable of reporting a wide range of protein activities .
a long - standing challenge with biosensors has been delivering them into living cells and targeting them to specific proteins or organelles of interest .
newly designed peptide sequences have now allowed the import of probes into living cells via nonendocytic pathways , thereby alleviating the problem of generating a constellation of brightly fluorescent vesicles ( klaus hahn ) .
in addition , alice ting ( massachusetts institute of technology ) described how to exploit natural enzymes for protein - specific labeling ( chen et al .
for example , escherichia coli biotin ligase is known to ligate biotin to a lysine side chain within a specific 15amino acid substrate sequence . by
genetically fusing the 15amino acid acceptor peptide to proteins of interest , coexpressing the biotin ligase , and providing a ketone analogue of biotin , her group showed that proteins in living cells could be specifically labeled with a variety of small - molecule probes , including fluorophores and photoaffinity labels .
the session on image informatics delivered the important message that a wealth of information , much beyond human vision , can be obtained automatically through the use of computational analyses .
the development is being driven both by the large volume of images collected via automated microscopy of live cells , and by the complexity and subtlety of patterns in three - dimensional ( 3d ) , time - series images .
even the analysis of conventional fluorescence images can benefit greatly from automated interpretation of subcellular patterns .
for example , gaudenz danuser ( scripps research institute ) described computational methods for the quantification of the dynamics of hundreds of thousands of fluorescent speckles , at a high spatial and temporal resolution , to probe with great detail the nonsteady state behavior of actin filament structures in migrating cells ( ponti et al . , 2004 ; ji and danuser , 2005 ; danuser and waterman - storer , 2006 ) .
bob murphy ( carnegie - mellon university ) described computer programs that can recognize the patterns of major subcellular structures better than trained human observers .
the information allowed the classification of proteins by their subcellular location and will facilitate the discovery of new distribution patterns as well as realistic simulations of protein distribution for modeling cell behavior ( chen and murphy , 2005 ; chen et al . , 2006 ) .
roland eils ( german cancer research center ) described a fast , automated method for analyzing a large collection of time - lapse image sequences for the purpose of screening the effects of sirna .
the process involves training a classifier to recognize various phenotypes , followed by applying the classifier to images in a time series .
this approach has permitted fully automated identification of genes involved in such important functions as cell cycle regulation .
the integration of multiple disciplines is evident in the recent advancement of several imaging techniques .
for example , fluorescence correlation spectroscopy ( fcs ) is being used with laser scanning microscopes , high - speed electron multiplying charge coupled device ( emccd ) cameras ( enrico gratton , university of california , irvine ; petra schwille , technische universitt , dresden ) , total internal reflection fluorescence ( tirf ) optics , and increasingly sophisticated mathematical analysis tools ( nancy thompson , university of north carolina , chapel hill ; enrico gratton ) to measure molecular concentrations , diffusion , binding , and aggregation densities both on the surface and inside living cells with high spatial and temporal resolution ( thompson et al . , 2002 ; lieto et al . , 2003 ; digman et al . , 2005a , b ; bacia et al . , 2006 ; ries and schwille , 2006 ) .
cross - correlation methods further allow direct comparison of the mobility of multiple components labeled with different color fluorophores and reveal their interactions within complexes ( petra schwille and enrico gratton ) .
these studies will benefit from new fluorescence dyes that can be excited at a common wavelength while emitting at easily separable wavelengths ( atsushi miyawaki ) .
another elegant example is the application of switchable fluorescent probes , as described above , to build images by switching on ( and bleaching off ) a few diffraction - limited spots ( airy disks ) at a time .
referred to as photoactivated localization microscopy ( palm ) , this approach provides superb spatial resolution ( although at the expense of temporal resolution , since it takes time to cover the entire image with hundreds of thousands of airy disks ) , as centroids of these individual airy disks are well separated and may be determined at nanometer precision
a number of clever optical strategies have increased both the resolution and versatility of microscopy .
for example , tony wilson ( oxford university ) showed that the quality of images with conventional optics can approach that of confocal images , by illuminating thick samples with a laser through a one - dimensional grid , followed by removal of the pattern with computer processing ( neil et al . , 2000 ) .
a second application of patterned illumination , combining stripe illumination at multiple orientations with computer image processing , was developed by the university of california , san francisco , cooperative ( john sedat , david agard , and mats gustafsson ) to overcome the diffraction limit and obtain unprecedented details from images of chromosomes ( fig .
, periodic illumination is used to extend the optical response of the microscope to high - frequency signals along a particular direction , by generating a moir interference effect with greater ( and therefore detectable ) periodicity ( gustafsson , 2000 ; wells , 2004 ) .
a technically more demanding technique of patterned illumination was described by betzig , who used complex optical interference phenomena to generate a 3d lattice of diffraction - limited illumination spots for high - speed , high - resolution imaging of thick samples ( betzig , 2005 ) .
these spots illuminate a large number of regions simultaneously , with a photon efficiency far exceeding that provided by a confocal microscope .
stereo pair of maize meiotic chromosomes imaged with structured illumination , stained using immunofluorescence against zmafd1 , a rec8 homologue , which localizes to the axis of each chromosome .
the maize nucleus has ten pairs of chromosomes ; for ease of viewing , three have been false - colored and computationally excised from the rest .
the 200-nm spacing of the chromosome axes is visible , as is the tendency of the axes to twist around each other .
courtesy of rachel wang ( university of california , berkeley ) and pete carlton ( university of california , san francisco ) . by combining optical manipulations with computation or innovative probes ,
in addition to patterned illumination and palm described above , this includes combining oblique focus scanning ( where optical sections are collected while the sample is shifted horizontally at the same time ) and deconvolution to generate stereo pairs ( wilson and sedat ) , and using flash illumination to limit how far single molecules diffuse during the detection phase as in strobe photography of high speed objects ( sunney xie , harvard university ; xie et al . , 2006 ) .
future developments may further incorporate new mechanisms to generate image contrast and to extend the usable range of electromagnetic waves , in order to take advantage of special chemical and physical characteristics of the materials .
for example , xie developed 3d coherent anti - stoke raman scattering ( cars ) microscopy ( evans et al . , 2005 ) , which combines two laser beams at different wavelengths to generate a beating frequency that matches the vibration frequency of target molecules .
these beams produce much stronger signals of raman light scattering than conventional raman scattering techniques .
the technique has been used to image the dynamics of lipid droplets and to distinguish different lipids in unstained living cells , based on their different vibration frequencies .
finally , carolyn larabell 's group ( lawrence berkeley lab ) is developing soft x - ray microscopy as a new tool for whole - cell imaging ( le gros et al . , 2005 ) .
the approach uses zone plate ( diffractive ) optics to focus x - rays onto the sample , and then onto a detector . at the wavelengths used ,
the technique should be capable of producing high - contrast , 3d images of unstained cells at a resolution as high as 10 nm .
half of the meeting was dedicated to the applications of cutting edge imaging techniques to various important biological problems .
a significant trend is the emphasis on single - molecule or single - organelle techniques , which remove the ensemble average in conventional fluorescence imaging to obtain behavior distributions , local dynamics , and kinetics without the need to synchronize individual molecules or cells . using single - molecule fret or single - particle tracking
, investigators can observe the kinetics of molecular interactions , the appearance of conformational intermediates , and the molecular responses to force applied by an optical trap ( xiaowei zhuang , harvard university ; taekjip ha , university of illinois , urbana - champaign ; mckinney et al . , 2005 ) .
single - molecule observations are also being used in cells to determine distances at nanometer accuracy , by accurately measuring the center of the diffraction - limited spot emanating from single molecules .
this approach has been used to reveal the mechanisms by which molecular motors such as dynein , kinesin , and myosin v move ( paul selvin , university of illinois , urbana - champaign ; kural et al . , 2005 ;
in addition , single - molecule tracking in cells is revealing distributions of diffusion coefficients for membrane proteins and lipids , as well as linear , directed motion arising from treadmilling of bacterial actin before and after cell division ( w.e . moerner , stanford university ) .
single - organelle techniques are being used to understand the mechanisms that underlie endocytosis , exocytosis , and viral entry into cells ( zhuang ; rebecca heald , university of california , berkeley ; sandy simon , rockefeller university ; jennifer lippincott - schwartz , national institutes of health ) , while correlation spectroscopy , speckle microscopy , and molecule counting regimes are being used to understand dynamics of the cytoskeleton and substrate adhesions ( clare waterman - storer , scripps research institute ; edward salmon , university of north carolina , chapel hill ; enrico gratton ) .
although imaging cells in tissues is not as well developed as studying cells in culture , it is a critical frontier , and progress is promising . if excitation light enters the specimen orthogonal to the objective lens ( using single plane illumination ) , fluorescence can be measured from all molecules that are located in the very narrow volume defined by the plane of excitation light
this greatly reduces photodamage and photobleaching and enhances the axial resolution ( ernst stelzer , embl , heidelberg ; huisken et al . ,
although such new instrumentation ( as well as lattice illumination described earlier ) is likely to make a strong impact , significant advances have already been made using commercially available confocal optics .
peter friedl ( university of wrzburg ) and john condeelis ( albert einstein college of medicine ) showed impressive imaging of cellular movements in skin and breast tissue , respectively , in live animals .
tumor cells in skin reside in a variety of states including single cells and collectives , and they migrate by either mesenchymal or amoeboid type motility ( wolf et al . , 2003 ) .
migration through collagen requires strategic clipping of collagen at constriction points as the cell squeezes through the matrix network , leaving a localized trail of oriented collagen fibers .
in addition , breast tumor cells undergo a chemotactic migration along collagen fibers , guided by epidermal growth factor secreted by perivascular macrophages ( goswami et al . , 2005 ) .
equally impressive is the mapping of neural responses in the visual cortex by applying calcium indicators and two - photon optics to the brain of live animals ( clay reid , harvard medical school ) .
the responses of neurons , monitored within cubes that have sides 300 m in length , show sharp changes as the animal receives the visual stimulation of a bar moving in different directions ( ohki et al . , 2005 ) .
finally , scott fraser and his colleagues ( california institute of technology ) have developed comprehensive imaging and informatic systems for high - throughput , parallel analysis of the cellular trajectories of hundreds or thousands of cells in live zebrafish embryos , with the ultimate goal of understanding the exact pathways of cellular movements during embryonic development ( forouhar et al . , 2006 ) .
the synergy and enthusiasm generated during the meeting reflect the importance of live cell imaging , the incisive applications to date , and the prospects for significant developments in the near future .
the localized nature of biological phenomena serves as the driving force for the development of technologies to observe , assay , and parse their mechanisms .
the meeting pointed to a very bright future for live cell imaging , by showing that higher resolution , better reagents , and more powerful methods of revealing interactions and dynamics are well within reach .
in addition , as suggested by roger tsien ( university of california , san diego ) , one of the keynote speakers , basic research in this area may soon lead to revolutionary advances in clinical diagnosis and treatments , both by direct applications of optical physiologythe probing and manipulation of physiological events with optical techniques and by spinning off techniques involved in probe development and delivery .
Output:
| a recent meeting entitled frontiers in live cell imaging was attended by more than 400 cell biologists , physicists , chemists , mathematicians , and engineers . unlike typical special topics meetings , which bring together investigators in a defined field primarily to review recent progress , the purpose of this meeting was to promote cross - disciplinary interactions by introducing emerging methods on the one hand and important biological applications on the other .
the goal was to turn live cell imaging from a technique used in cell biology into a new exploratory science that combines a number of research fields . |
PubmedSumm8870 | ***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 chiropractic profession continues to grow in collective thinking and progress in defining care rendered . in so doing ,
the profession participates in the investigation of the types of care rendered and in the translation of research into practice .
different types of care are developed from theories , clinical practice , and clinical observations and , ultimately , based on scientific evidence .
this article considers the scientific basis of the commonly practiced procedure of chiropractic maintenance care and whether a hypothesis of a physiological basis can be generated to explain findings and practice .
recent publications by the council of chiropractic guidelines and practice parameters have summarized clinical best practices for chiropractic care and identified some of the changes that chiropractic clinicians need to make to improve care for their patient population .
dehen et al defined the stages of chiropractic care into care for acute and chronic / recurrent conditions , and wellness care .
a distinction is made between the chronic / recurrent care and wellness or maintenance care .
care for chronic / recurrent conditions is defined as medically necessary care for conditions that are not expected to completely resolve , but in which one can provide documented improvement . according to dehen
et al , wellness or maintenance care may not be defined as being medically necessary for a current condition .
however , this type of care optimizes the levels of function and provides a process of achieving the best possible function and health .
this care includes chiropractic manipulative therapy in addition to exercise therapy , diet and nutritional counseling , and lifestyle coaching .
this concurred with surveys made by danish and swedish chiropractors who defined the purpose of chiropractic maintenance care as optimizing spinal function and decreasing the frequency of future episodes of back pain .
various definitions have been provided for maintenance care : ( 1 ) appropriate treatment directed toward maintaining optimal body function .
this is treatment of the symptomatic patient who has reached pre - clinical status or maximum medical improvement , where condition is resolved or stable ; ( 2 ) a regimen designed to provide for the patient 's continued well - being or for maintaining the optimum state of health while minimizing recurrences of the clinical status ; and ( 3 ) maintenance care was offered to patients that did not improve .
the current health care system more often focuses upon the doctors to fix problems that have developed over a number of years , instead of modifying patient behaviors to promote good health and prevent chronic illness .
musculoskeletal conditions may be prevented by years of appropriate diet and physical activities as wellness activities .
the allopathic profession defines wellness as the provision of diagnostic testing for early detection of disease processes .
the retail industry often uses the term in marketing to sell products that may make the person feel better , look better , and function better , or prevent onset of aging or disease .
wellness has been defined as both a process and an outcome . because of the multiple uses of the terms in the literature , for the purpose of this investigation , maintenance care and wellness care are used synonymously to represent the process of spinal manipulative therapy for an asymptomatic patient or a patient that has reached maximum therapeutic improvement after treatment of an acute condition , an acute exacerbation of a chronic condition , or an initial treatment regimen for a chronic condition .
some insurers have independently defined maintenance care as care provided for a stable condition without any functional improvement of the patient net health outcome over a 4-week period and further determine it as not being medically necessary .
jamison did a random survey of australian and american doctors of chiropractic to obtain a global definition of maintenance care .
she found that more than 90% opined that the purpose of maintenance care was to minimize recurrences or exacerbations , whereas greater than 80% responded that it would optimize the patients ' health .
ninety - seven percent of the american and 85% of the australian chiropractors report using manipulative therapy as a component of the maintenance care .
a combined greater than 93% also used exercise as part of the maintenance care , whereas a great majority also used patient education in eating habits and other lifestyle choices .
there was a greater than 91% agreement that the musculoskeletal system was most amenable to maintenance care , whereas many also felt that maintenance care was beneficial for stress ; respiratory system ; gastrointestinal system ; and , to a lesser degree , cardiovascular system .
this was all apparently based on clinical observation , personal philosophies , and experience because only 40% of the americans and 22% of the australians opined that the care was supported by adequate research .
rupert performed a similar study of us chiropractors in 2000 and had similar results showing that 95% of chiropractors recommended maintenance care to minimize recurrences or exacerbations of conditions and 90% recommended the care to optimize the health of the patient .
a study that interviewed patients and doctors regarding maintenance care noted that 96% of elderly patients who received such care believed that it was either considerably or extremely valuable .
the prevalence of the rendering of this type of care is again noted by rupert as contributing an average of 23% of the chiropractors ' income .
it is interesting to note that sarnat and winterstein found substantial cost savings in an independent practice association that used chiropractors as primary care providers despite the fact that 28% of the patients presented for wellness care and it was not uncommon for the patients to present twice a month for such care . despite this , the us preventive task force , which has been evaluating preventive health care measures for 27 years , fails to list this type of care as a preventive measure .
if the chiropractic profession feels that maintenance care is important to our patients , then we need further evidence of a scientific basis of the physiological responses to this care .
it has been reported that 79% of patients in chiropractic offices are recommended maintenance care and nearly half of those patients elect to receive these services .
the lack of third - party payment for such services in the us health care system may be a factor in how many patients elect to participate .
there are many questions surrounding maintenance care , and previous research has investigated some of these questions , the object of this article is to look at the available evidence for a possible physiological basis that might allow development of a theory of the reported clinical benefits of such care . given the positive clinical reports and the current state of knowledge of manipulative therapy , it is hypothesized that a theoretical physiological framework could be developed for future research .
the purpose of this article is to provide the initial bridge from the clinical observations and theories to proposed hypotheses for further investigation into the clinical meaningfulness of maintenance care .
the sampling strategy was purposeful to include chiropractic as the primary discipline for the defining of wellness or maintenance care .
however , other disciplines were included to obtain the research regarding the physiology or pathology relative to spinal manipulation .
the type of studies included were surveys of clinical practice to assess common practice and provide definitions .
when open access to full text was not available through current subscriptions , further search was conducted through the local hospital subscription service .
hand search was conducted regarding personally known work by various authors or to follow up on references from reviewed articles . because this subject is one that was only recently researched , the range of years of the search was from 1970 through 2011 .
the search was limited to those in the english language . because this was an interpretive narrative review , articles were reviewed for a common understanding of wellness care and maintenance care within chiropractic .
once this was established , the search strategy inclusion criteria were used to further narrow down the search to target spinal manipulative therapy while excluding other common chiropractic therapies .
the remaining literature was then reviewed for common themes of dosage and duration of care .
an additional search was then conducted with the commonly established findings of spinal manipulation effectiveness .
these were then reviewed for dosage and duration for onset of pathology and reversal or retardation of the pathology .
cross - referencing was then conducted between the common dosage and duration of chiropractic maintenance spinal manipulative therapy and the onset of pathologies .
reviews of abstracts were conducted ; and when articles met the inclusion criteria , full - text articles were obtained whenever possible . the search and exclusion /
a search of the electronic medline database was conducted through pubmed central ; and the manual , alternative , and natural therapy index system search was conducted through chiroaccess .
the key words and terms chiropractic maintenance care , maintenance manipulative care , maintenance manipulation , preventive spinal manipulation , spinal manipulation effectiveness , maintenance , and wellness were used in various combinations .
an additional search of the same databases was performed with known related topics such as hypomobility or immobility and adhesions , hypomobility or immobility and joint degeneration , neuronal and hypomobility , and neurology of hypomobility or immobility .
reviews were conducted to narrow the definition of maintenance care in chiropractic practice , to assess the dosage and duration of care , and to look at physiological parameters that would relate to this care ( fig 1 ) .
the search terms of spinal manipulation and maintenance revealed conflicting results , with some studies published that demonstrated a lack of benefit and other studies in which benefits were noted .
a 2011 study by senna and machaly was one of the few studies on spinal manipulation for maintenance care of the chronic nonspecific low back pain patient .
this was a randomized clinical trial in which 60 patients with this condition were randomized to ( 1 ) 12 sham treatments over 1 month , ( 2 ) 12 spinal manipulative treatments ( smts ) over 1 month without follow - up , and ( 3 ) 12 smt over 1 month followed by maintenance manipulative therapy ( mmt ) at a frequency of every 2 weeks for the following 9 months ( table 1 ) .
the results demonstrated that only the maintenance care group showed more improvement in pain and disability from the 1-month period to a 10-month follow - up .
in fact , the group that did not receive maintenance care returned to the pretreatment levels of pain and disability .
hawk et al performed a pilot study to look at this type of care with outcomes measured by the degree of pain , dizziness , and balance via their respective outcome measures .
this was a small group of 34 total patients , which limits the statistical application to the general population .
however , the randomized groups were similar to those in the study of senna and machaly .
one group received treatment for 8 weeks , a second group received treatment for 8 weeks followed by monthly treatments for 10 months , and the third group received no treatment except for an exercise booklet .
although there was no difference noted in balance , there was a difference in pain and dizziness .
pain was improved to a greater degree in the maintenance care group , whereas dizziness improved in both spinal manipulation groups and remained so at 1 year .
unfortunately , the chiropractic care consisted of more than just spinal manipulation ; so one could not draw conclusions about mmt as an isolated procedure . using the search terms of hypomobility / immobility ,
this study revealed that mean mobility values of lumbar joints in younger patients were reduced by both previous and current low back trouble when compared with nonsufferers .
this did not correlate with the findings in middle - aged adults with low back pain histories but did with the patients in this age group with sciatica history .
the authors suggested that it was possible that aspects of increased mobility in the middle - aged adults , such as localized segmental instability or abnormal coupled motions , may be associated with an increased frequency of recurrent low back trouble .
it is hypothesized that regular wellness / maintenance chiropractic care may correlatively be treating these abnormalities in the early stages .
subsequently , this may be preventing their progression and development of later - stage acute and chronic injuries and disease .
cramer et al used an established small animal model of spinal fixation of 3 contiguous lumbar segments ( l4 , l5 , l6 ) of rats to assess fixated zygapophyseal joints at 1 , 4 , and 8 weeks of fixation .
a total of 584 zygapophyseal joints ( left and right l3/l4 , l4/l5 , l5/l6 , l6/s1 ) and 1168 articular surfaces were evaluated macroscopically .
they found that the longer the animals were fixed , the greater the number of osteophytes that developed . differences found between control animals and spinal fixation animals at 1 , 4 , and 8 weeks were statistically significant ( p < .05 ) both for the total number of degenerated articular surfaces per animal and for average severity of articular surface degeneration .
they concluded that there appeared to be a threshold of time when osteophyte formation and articular surface degeneration become so severe that very little return to normal occurs even after a considerable length of time .
this study demonstrated that zygapophyseal joint changes occurred following spinal fixation and that the amount and severity of degeneration are time dependent with a threshold of between 4 and 8 weeks for osteophytes and less than 1 week for articular surface degeneration .
these findings may provide an explanation to the anecdotal findings reported in clinical practice in which patients report increased well - being and decreased incidence of spinal complaints with once per month preventive wellness manipulation .
the timing of common clinical treatment frequency at every 4 weeks correlates with the findings of the threshold of 4 weeks for irreversible degenerative osteophyte formation .
in addition , he had findings that facet articular degeneration began after only 1 week of fixation .
this finding correlates with the common practice pattern of progressive decreasing of the frequency of manipulation as the patients progress in recovery from an acute incident .
it also indicates that even when patients present for once per month asymptomatic preventive manipulation , the process of degeneration of the articular surfaces may have already begun .
this study monitored the onset of fibrotic adhesions over a similar period of 4 , 8 , and 12 weeks after joint fixation .
micrographs manifested initial synovial folds that progressed to mild adhesions in 4 weeks , moderate adhesions in 8 weeks , and severe adhesions after 12 weeks .
additional studies compared the fixated segments to nonfixated segments and noted a statistical difference in occurrence , therefore ruling out any natural process .
this has not been correlated with onset of symptoms in the human subjects , but it can be hypothesized that there is a period where the adhesions are forming without clinical symptoms . if this is true , then this would again support the common once per month clinical spinal examination .
although much has been written about manipulation breaking up adhesions , the correlation of this gapping to the breaking of adhesions has not yet been fully investigated .
if this were to be demonstrated , then this would lend additional support for the once per month clinically recommended spinal manipulative therapy .
the process of joint immobility , adhesions , degeneration , and onset of back pain would also explain the surveyed clinical opinions of the doctors in the study of hansen et al .
the nordic survey opined that the indications for maintenance care consisted of a prior history of low back pain along with a positive response to previous care . using the search terms neuronal , immobilization , and joint manipulation
also revealed possible neurological abnormalities that regular wellness / maintenance chiropractic care may be treating in the early stages and preventing their progression and development of later - stage acute and chronic injuries and disease states .
immobility was induced in a guinea pig knee joints , and -motor neuron activity was monitored by light microscope .
this revealed a progressive time - dependent shrinkage of the nuclear envelope and loss of dna .
in addition , electron microscopic evaluation showed demyelination of the nerves at the level of the primary motor neuron .
this time dependency showed loss of neurons after only 4 weeks of immobilization and got progressively worse thereafter .
surprisingly , there was an increase in neurons following release of fixation after the 4 weeks of immobilization .
this needs to be further investigated in regard to the physiological spinal joint fixation in human subjects , but does present an interesting hypothesis to resultant weakness in the related innervated muscles . such weakness with resultant
atrophy and fatty deposition of the multifidi muscles was demonstrated by kader et al when they looked at the magnetic resonance imaging ( mri ) changes in these muscles and the correlation to leg pain .
they also noted a time - dependent factor from normal muscles to mild , moderate , and severe muscular atrophy .
fahim took it one step further and noted in his electron microscopic analysis of extremity soleus changes in neuromuscular end plates .
he found that , with only 5 days of immobilization of the knee and ankle , there was degeneration of the soleus motor end plates , in addition to the muscle atrophy .
the neuromuscular junction changes consisted of nerve terminal disruption , exposed junctional folds , and postsynaptic areas that contained little or no postjunctional folds .
this was a preliminary laboratory study , but then lundby - jensen and nielsen looked at 12 human subjects ' h - reflexes of the soleus muscles with 2 weeks of immobilization of the foot and ankle .
they observed that there were an increase in the amplitude and a decrease in the long latency depression of the h - reflex .
this suggested that , with only 2 weeks of immobilization and disuse in humans , there were plastic changes in spinal interneuronal circuitries responsible for presynaptic control of ia afferent sensory input to the spinal cord and affecting the -motor neuron through decreased inhibition .
they were also able to reproduce this result in an upper extremity study with some further indications that it was happening at the cord level .
the question then arises whether the maintenance / wellness manipulative care in clinical practice would prevent neuronal degeneration and onset of muscle weakness , or change muscular recruitment patterns and predispose the patient to injuries .
it is suggested that if he 's findings in guinea pigs could be found to correlate in humans , then there may also be a possibility of reversal of the neuronal degeneration and muscular weakness through manipulation and remobilization of the joint . in summary , this narrative literature review manifested progressive physiological consequences as a result of joint immobility . when this is correlated with the biomechanical and neurological research finding of manipulative therapy ,
a line of reasoning arises that generates a theoretical framework for a physiological hypothesis of the basis of mmt .
there appears to be a correlation of time intervals of immobility and the onset of joint adhesions , spinal joint degeneration , aberrant ia neurological input , degeneration of the -motor neuronal pool , motor end plate degenerative changes , and onset of muscular weakness and atrophy .
this correlates with the usual clinical dosage of mmt as shown in clinician surveys in numerous countries and patient satisfaction ( fig 2 ) .
the graphic depiction clearly demonstrates that the clinical consensus of dosage of mmt has been found to be most beneficial at an average of once every 2 to 4 weeks .
we also see here that it closely correlates with the studies that show onset of facet joint degeneration , neural degeneration , neuroplastic changes , and muscular atrophy and weakness at an average of 2 to 4 weeks .
it is known that manipulative care mobilizes the joint to the end of the paraphysiological joint space and theorized that this breaks up adhesions .
taking into account the neurological and biomechanical consequences of manipulative therapy , it is plausible to hypothesize that monthly manipulative therapy retards the progression of adhesion formation , joint degeneration , neuronal changes , and changes in muscular strength and recruitment patterns .
this could result in improved function , decreased episodes of injuries , and improved sense of well - being .
this review represents a narrative of the literature that provides evidence to support the theoretical framework of the value of maintenance chiropractic manipulation and provides the basis to generate such a theory .
finally , it should be noted that the conclusions represent a theory and that this theory needs further higher evidence testing to support or refute it .
there is still ambiguity in the literature regarding the clinical benefits of maintenance or wellness manipulative care .
a previous report by leboeuf - yde and hestabek concluded that there was no evidence base for the indications or the nature of the use of maintenance care based on a 2008 literature review .
in addition , aker and martel in their qualitative literature review concurred that there was no scientific evidence to support the claim that maintenance care improves one 's health status , although anecdotal evidence from both doctors and patients is strong .
a recent randomized controlled trial of monthly preventive spinal manipulation of more than 10 months ' duration showed no difference in functional measures , range of motion , or visual analogue pain scales when compared with a control group of bimonthly reassurance or a combination of manipulation and home exercise .
this author concluded that the premise of stating that regular treatments , designed to preserve optimum health and minimize the recurrence of clinical problems , was more likely due to interventions of reassurance , patient education , help with self - management , and active care strategies .
in contrast , a different study looked at the pain levels and functional oswestry disability measures of 2 chronic low back pain groups .
then the maintenance care was provided to one group at a frequency of every 3 weeks for a 9-month follow - up , but not to the second group .
this study found that disability remained at the lowered post 4-week level for the maintenance group but returned to the previous levels for the control group .
they concluded that there were positive effects of preventive maintenance chiropractic spinal manipulation in maintaining functional capacities and reducing the number and intensity of pain episodes after the acute phase of treatment of low back pain patients .
this seemed to concur with the swedish surveys of chiropractors who found consensus on providing such care to prevent relapses .
there is a common thread of the time dependency noted in all the laboratory and clinical studies .
the periods of onset of the anatomical and physiological changes ranged from 2 to 4 weeks .
the clinical studies also provided mmt every 4 weeks and noted positive changes in the pain and disability measures .
this time interval also correlates with the common recommendations found in the surveys of chiropractic physicians .
although there have been physiological measures to assess the results of manipulative therapy , studies of these measures applied to preventive manipulation have not been conducted ; nor has there been any testing of physiological vs psychological contributions to the reported clinical benefits .
further investigatory studies in these areas would be able to tie together some of the laboratory and clinical findings . in the first conference on spinal manipulation in 1977 sponsored by the national institute of neurological and communicative disorders and stroke , haldeman presented the criteria for investigating the clinical basis of the mechanisms of manipulative therapy . these still apply today and can be paraphrased to apply to mmt.1.that the application of mmt must demonstrate consistent clinical results under controlled conditions in the treatment of a specific pathologic process , organ dysfunction , or symptom complex.2.that mmt demonstrates a specific effect on the musculoskeletal system to which it is applied.3.that the musculoskeletal effect caused by mmt
must be shown to have a specific influence on the nervous system.4.that the influence on the nervous system brought about by the manipulation must demonstrate a beneficial influence on abnormal function of an organ , tissue pathology , or symptom complex .
but we must be careful about presenting theory as fact . that the application of mmt must demonstrate consistent clinical results under controlled conditions in the treatment of a specific pathologic process , organ dysfunction , or symptom complex .
that mmt demonstrates a specific effect on the musculoskeletal system to which it is applied . that the musculoskeletal effect caused by mmt must be shown to have a specific influence on the nervous system . that the influence on the nervous system brought about by the manipulation must demonstrate a beneficial influence on abnormal function of an organ , tissue pathology , or symptom complex .
but we must be careful about presenting theory as fact . as science starts with a theory , the theory
currently , the theories involving mmt are evolving ; and there are initial investigations that may apply to this care . in response to the beliefs , positive anecdotal findings , patient satisfaction , and historical clinical reports , the following is a response to those directives .
it appears that the clinical opinions and the research to date have looked at the effect on low back conditions .
this would be a good starting point to research the efficacy of mmt in reducing the incidence of low back injuries or the severity of the episodes .
this has included the increase in population of proprioception , stimulation of -motor neuronal pool , and reflexogenic responses through the stretch reflex .
there is now increasing research available that is confirming much of this ; but further research is still warranted , especially in regard to these effects under mmt .
there is initial evidence of the effect of immobility on the ia afferent nerves , the -motor neuronal pool , the motor end plates , and the muscular end organs .
further research should be aimed at confirming these findings in human subjects and the reversal of these effects with the application of mmt procedures .
the influence on the nervous system from the manipulative therapy has been shown in the studies outlined in our literature search .
future research should look at the beneficial influence of mmt on patients with chronic musculoskeletal conditions before looking at healthy individuals .
population studies similar to those performed by senna and machaly and by hawk et al with larger populations should give us further insight into the clinical value of mmt .
in vivo assessment of neurological and musculoskeletal changes would be beneficial in providing further physiological evidence to support the recommendations of mmt .
this study is limited in scope because it is not a quantitative analysis of the literature , nor does it qualitatively evaluate the literature reviewed .
this was a narrative review to provoke thought , further debate and discussion on the topic , generate theories , and challenge future research directions .
the search terms of spinal manipulation and maintenance revealed conflicting results , with some studies published that demonstrated a lack of benefit and other studies in which benefits were noted .
a 2011 study by senna and machaly was one of the few studies on spinal manipulation for maintenance care of the chronic nonspecific low back pain patient .
this was a randomized clinical trial in which 60 patients with this condition were randomized to ( 1 ) 12 sham treatments over 1 month , ( 2 ) 12 spinal manipulative treatments ( smts ) over 1 month without follow - up , and ( 3 ) 12 smt over 1 month followed by maintenance manipulative therapy ( mmt ) at a frequency of every 2 weeks for the following 9 months ( table 1 ) .
the results demonstrated that only the maintenance care group showed more improvement in pain and disability from the 1-month period to a 10-month follow - up .
in fact , the group that did not receive maintenance care returned to the pretreatment levels of pain and disability .
hawk et al performed a pilot study to look at this type of care with outcomes measured by the degree of pain , dizziness , and balance via their respective outcome measures .
this was a small group of 34 total patients , which limits the statistical application to the general population .
however , the randomized groups were similar to those in the study of senna and machaly .
one group received treatment for 8 weeks , a second group received treatment for 8 weeks followed by monthly treatments for 10 months , and the third group received no treatment except for an exercise booklet .
although there was no difference noted in balance , there was a difference in pain and dizziness .
pain was improved to a greater degree in the maintenance care group , whereas dizziness improved in both spinal manipulation groups and remained so at 1 year .
unfortunately , the chiropractic care consisted of more than just spinal manipulation ; so one could not draw conclusions about mmt as an isolated procedure .
using the search terms of hypomobility / immobility , adhesions and degeneration revealed possible physiological abnormalities present in low back patients .
this study revealed that mean mobility values of lumbar joints in younger patients were reduced by both previous and current low back trouble when compared with nonsufferers .
this did not correlate with the findings in middle - aged adults with low back pain histories but did with the patients in this age group with sciatica history .
the authors suggested that it was possible that aspects of increased mobility in the middle - aged adults , such as localized segmental instability or abnormal coupled motions , may be associated with an increased frequency of recurrent low back trouble .
it is hypothesized that regular wellness / maintenance chiropractic care may correlatively be treating these abnormalities in the early stages .
subsequently , this may be preventing their progression and development of later - stage acute and chronic injuries and disease .
cramer et al used an established small animal model of spinal fixation of 3 contiguous lumbar segments ( l4 , l5 , l6 ) of rats to assess fixated zygapophyseal joints at 1 , 4 , and 8 weeks of fixation .
a total of 584 zygapophyseal joints ( left and right l3/l4 , l4/l5 , l5/l6 , l6/s1 ) and 1168 articular surfaces were evaluated macroscopically .
they found that the longer the animals were fixed , the greater the number of osteophytes that developed . differences found between control animals and spinal fixation animals at 1 , 4 , and 8 weeks were statistically significant ( p < .05 ) both for the total number of degenerated articular surfaces per animal and for average severity of articular surface degeneration .
they concluded that there appeared to be a threshold of time when osteophyte formation and articular surface degeneration become so severe that very little return to normal occurs even after a considerable length of time .
this study demonstrated that zygapophyseal joint changes occurred following spinal fixation and that the amount and severity of degeneration are time dependent with a threshold of between 4 and 8 weeks for osteophytes and less than 1 week for articular surface degeneration .
these findings may provide an explanation to the anecdotal findings reported in clinical practice in which patients report increased well - being and decreased incidence of spinal complaints with once per month preventive wellness manipulation .
the timing of common clinical treatment frequency at every 4 weeks correlates with the findings of the threshold of 4 weeks for irreversible degenerative osteophyte formation .
in addition , he had findings that facet articular degeneration began after only 1 week of fixation .
this finding correlates with the common practice pattern of progressive decreasing of the frequency of manipulation as the patients progress in recovery from an acute incident .
it also indicates that even when patients present for once per month asymptomatic preventive manipulation , the process of degeneration of the articular surfaces may have already begun .
this study monitored the onset of fibrotic adhesions over a similar period of 4 , 8 , and 12 weeks after joint fixation .
micrographs manifested initial synovial folds that progressed to mild adhesions in 4 weeks , moderate adhesions in 8 weeks , and severe adhesions after 12 weeks .
additional studies compared the fixated segments to nonfixated segments and noted a statistical difference in occurrence , therefore ruling out any natural process .
this has not been correlated with onset of symptoms in the human subjects , but it can be hypothesized that there is a period where the adhesions are forming without clinical symptoms . if this is true , then this would again support the common once per month clinical spinal examination .
although much has been written about manipulation breaking up adhesions , the correlation of this gapping to the breaking of adhesions has not yet been fully investigated .
if this were to be demonstrated , then this would lend additional support for the once per month clinically recommended spinal manipulative therapy .
the process of joint immobility , adhesions , degeneration , and onset of back pain would also explain the surveyed clinical opinions of the doctors in the study of hansen et al . the nordic survey opined that the indications for maintenance care consisted of a prior history of low back pain along with a positive response to previous care . using the search terms neuronal , immobilization , and
joint manipulation also revealed possible neurological abnormalities that regular wellness / maintenance chiropractic care may be treating in the early stages and preventing their progression and development of later - stage acute and chronic injuries and disease states .
immobility was induced in a guinea pig knee joints , and -motor neuron activity was monitored by light microscope .
this revealed a progressive time - dependent shrinkage of the nuclear envelope and loss of dna .
in addition , electron microscopic evaluation showed demyelination of the nerves at the level of the primary motor neuron .
this time dependency showed loss of neurons after only 4 weeks of immobilization and got progressively worse thereafter .
surprisingly , there was an increase in neurons following release of fixation after the 4 weeks of immobilization .
this needs to be further investigated in regard to the physiological spinal joint fixation in human subjects , but does present an interesting hypothesis to resultant weakness in the related innervated muscles .
such weakness with resultant atrophy and fatty deposition of the multifidi muscles was demonstrated by kader et al when they looked at the magnetic resonance imaging ( mri ) changes in these muscles and the correlation to leg pain . they also noted a time - dependent factor from normal muscles to mild , moderate , and severe muscular atrophy .
fahim took it one step further and noted in his electron microscopic analysis of extremity soleus changes in neuromuscular end plates .
he found that , with only 5 days of immobilization of the knee and ankle , there was degeneration of the soleus motor end plates , in addition to the muscle atrophy .
the neuromuscular junction changes consisted of nerve terminal disruption , exposed junctional folds , and postsynaptic areas that contained little or no postjunctional folds .
this was a preliminary laboratory study , but then lundby - jensen and nielsen looked at 12 human subjects ' h - reflexes of the soleus muscles with 2 weeks of immobilization of the foot and ankle .
they observed that there were an increase in the amplitude and a decrease in the long latency depression of the h - reflex .
this suggested that , with only 2 weeks of immobilization and disuse in humans , there were plastic changes in spinal interneuronal circuitries responsible for presynaptic control of ia afferent sensory input to the spinal cord and affecting the -motor neuron through decreased inhibition .
they were also able to reproduce this result in an upper extremity study with some further indications that it was happening at the cord level .
the question then arises whether the maintenance / wellness manipulative care in clinical practice would prevent neuronal degeneration and onset of muscle weakness , or change muscular recruitment patterns and predispose the patient to injuries .
it is suggested that if he 's findings in guinea pigs could be found to correlate in humans , then there may also be a possibility of reversal of the neuronal degeneration and muscular weakness through manipulation and remobilization of the joint . in summary , this narrative literature review manifested progressive physiological consequences as a result of joint immobility . when this is correlated with the biomechanical and neurological research finding of manipulative therapy ,
a line of reasoning arises that generates a theoretical framework for a physiological hypothesis of the basis of mmt .
there appears to be a correlation of time intervals of immobility and the onset of joint adhesions , spinal joint degeneration , aberrant ia neurological input , degeneration of the -motor neuronal pool , motor end plate degenerative changes , and onset of muscular weakness and atrophy .
this correlates with the usual clinical dosage of mmt as shown in clinician surveys in numerous countries and patient satisfaction ( fig 2 ) .
the graphic depiction clearly demonstrates that the clinical consensus of dosage of mmt has been found to be most beneficial at an average of once every 2 to 4 weeks .
we also see here that it closely correlates with the studies that show onset of facet joint degeneration , neural degeneration , neuroplastic changes , and muscular atrophy and weakness at an average of 2 to 4 weeks .
it is known that manipulative care mobilizes the joint to the end of the paraphysiological joint space and theorized that this breaks up adhesions .
taking into account the neurological and biomechanical consequences of manipulative therapy , it is plausible to hypothesize that monthly manipulative therapy retards the progression of adhesion formation , joint degeneration , neuronal changes , and changes in muscular strength and recruitment patterns .
this could result in improved function , decreased episodes of injuries , and improved sense of well - being .
this review represents a narrative of the literature that provides evidence to support the theoretical framework of the value of maintenance chiropractic manipulation and provides the basis to generate such a theory .
finally , it should be noted that the conclusions represent a theory and that this theory needs further higher evidence testing to support or refute it .
cramer et al used an established small animal model of spinal fixation of 3 contiguous lumbar segments ( l4 , l5 , l6 ) of rats to assess fixated zygapophyseal joints at 1 , 4 , and 8 weeks of fixation .
a total of 584 zygapophyseal joints ( left and right l3/l4 , l4/l5 , l5/l6 , l6/s1 ) and 1168 articular surfaces were evaluated macroscopically .
they found that the longer the animals were fixed , the greater the number of osteophytes that developed . differences found between control animals and spinal fixation animals at 1 , 4 , and 8 weeks were statistically significant ( p < .05 ) both for the total number of degenerated articular surfaces per animal and for average severity of articular surface degeneration .
they concluded that there appeared to be a threshold of time when osteophyte formation and articular surface degeneration become so severe that very little return to normal occurs even after a considerable length of time .
this study demonstrated that zygapophyseal joint changes occurred following spinal fixation and that the amount and severity of degeneration are time dependent with a threshold of between 4 and 8 weeks for osteophytes and less than 1 week for articular surface degeneration .
these findings may provide an explanation to the anecdotal findings reported in clinical practice in which patients report increased well - being and decreased incidence of spinal complaints with once per month preventive wellness manipulation .
the timing of common clinical treatment frequency at every 4 weeks correlates with the findings of the threshold of 4 weeks for irreversible degenerative osteophyte formation .
in addition , he had findings that facet articular degeneration began after only 1 week of fixation .
this finding correlates with the common practice pattern of progressive decreasing of the frequency of manipulation as the patients progress in recovery from an acute incident .
it also indicates that even when patients present for once per month asymptomatic preventive manipulation , the process of degeneration of the articular surfaces may have already begun .
this study monitored the onset of fibrotic adhesions over a similar period of 4 , 8 , and 12 weeks after joint fixation .
micrographs manifested initial synovial folds that progressed to mild adhesions in 4 weeks , moderate adhesions in 8 weeks , and severe adhesions after 12 weeks .
additional studies compared the fixated segments to nonfixated segments and noted a statistical difference in occurrence , therefore ruling out any natural process .
this has not been correlated with onset of symptoms in the human subjects , but it can be hypothesized that there is a period where the adhesions are forming without clinical symptoms . if this is true , then this would again support the common once per month clinical spinal examination .
although much has been written about manipulation breaking up adhesions , the correlation of this gapping to the breaking of adhesions has not yet been fully investigated .
if this were to be demonstrated , then this would lend additional support for the once per month clinically recommended spinal manipulative therapy .
the process of joint immobility , adhesions , degeneration , and onset of back pain would also explain the surveyed clinical opinions of the doctors in the study of hansen et al . the nordic survey opined that the indications for maintenance care consisted of a prior history of low back pain along with a positive response to previous care .
using the search terms neuronal , immobilization , and joint manipulation also revealed possible neurological abnormalities that regular wellness / maintenance chiropractic care may be treating in the early stages and preventing their progression and development of later - stage acute and chronic injuries and disease states .
immobility was induced in a guinea pig knee joints , and -motor neuron activity was monitored by light microscope .
this revealed a progressive time - dependent shrinkage of the nuclear envelope and loss of dna .
in addition , electron microscopic evaluation showed demyelination of the nerves at the level of the primary motor neuron .
this time dependency showed loss of neurons after only 4 weeks of immobilization and got progressively worse thereafter .
surprisingly , there was an increase in neurons following release of fixation after the 4 weeks of immobilization .
this needs to be further investigated in regard to the physiological spinal joint fixation in human subjects , but does present an interesting hypothesis to resultant weakness in the related innervated muscles .
such weakness with resultant atrophy and fatty deposition of the multifidi muscles was demonstrated by kader et al when they looked at the magnetic resonance imaging ( mri ) changes in these muscles and the correlation to leg pain . they also noted a time - dependent factor from normal muscles to mild , moderate , and severe muscular atrophy .
fahim took it one step further and noted in his electron microscopic analysis of extremity soleus changes in neuromuscular end plates .
he found that , with only 5 days of immobilization of the knee and ankle , there was degeneration of the soleus motor end plates , in addition to the muscle atrophy .
the neuromuscular junction changes consisted of nerve terminal disruption , exposed junctional folds , and postsynaptic areas that contained little or no postjunctional folds .
this was a preliminary laboratory study , but then lundby - jensen and nielsen looked at 12 human subjects ' h - reflexes of the soleus muscles with 2 weeks of immobilization of the foot and ankle .
they observed that there were an increase in the amplitude and a decrease in the long latency depression of the h - reflex .
this suggested that , with only 2 weeks of immobilization and disuse in humans , there were plastic changes in spinal interneuronal circuitries responsible for presynaptic control of ia afferent sensory input to the spinal cord and affecting the -motor neuron through decreased inhibition .
they were also able to reproduce this result in an upper extremity study with some further indications that it was happening at the cord level .
the question then arises whether the maintenance / wellness manipulative care in clinical practice would prevent neuronal degeneration and onset of muscle weakness , or change muscular recruitment patterns and predispose the patient to injuries .
it is suggested that if he 's findings in guinea pigs could be found to correlate in humans , then there may also be a possibility of reversal of the neuronal degeneration and muscular weakness through manipulation and remobilization of the joint . in summary , this narrative literature review manifested progressive physiological consequences as a result of joint immobility . when this is correlated with the biomechanical and neurological research finding of manipulative therapy ,
a line of reasoning arises that generates a theoretical framework for a physiological hypothesis of the basis of mmt .
there appears to be a correlation of time intervals of immobility and the onset of joint adhesions , spinal joint degeneration , aberrant ia neurological input , degeneration of the -motor neuronal pool , motor end plate degenerative changes , and onset of muscular weakness and atrophy .
this correlates with the usual clinical dosage of mmt as shown in clinician surveys in numerous countries and patient satisfaction ( fig 2 ) .
the graphic depiction clearly demonstrates that the clinical consensus of dosage of mmt has been found to be most beneficial at an average of once every 2 to 4 weeks .
we also see here that it closely correlates with the studies that show onset of facet joint degeneration , neural degeneration , neuroplastic changes , and muscular atrophy and weakness at an average of 2 to 4 weeks .
it is known that manipulative care mobilizes the joint to the end of the paraphysiological joint space and theorized that this breaks up adhesions .
taking into account the neurological and biomechanical consequences of manipulative therapy , it is plausible to hypothesize that monthly manipulative therapy retards the progression of adhesion formation , joint degeneration , neuronal changes , and changes in muscular strength and recruitment patterns .
this could result in improved function , decreased episodes of injuries , and improved sense of well - being .
this review represents a narrative of the literature that provides evidence to support the theoretical framework of the value of maintenance chiropractic manipulation and provides the basis to generate such a theory .
finally , it should be noted that the conclusions represent a theory and that this theory needs further higher evidence testing to support or refute it .
there is still ambiguity in the literature regarding the clinical benefits of maintenance or wellness manipulative care .
a previous report by leboeuf - yde and hestabek concluded that there was no evidence base for the indications or the nature of the use of maintenance care based on a 2008 literature review .
in addition , aker and martel in their qualitative literature review concurred that there was no scientific evidence to support the claim that maintenance care improves one 's health status , although anecdotal evidence from both doctors and patients is strong .
a recent randomized controlled trial of monthly preventive spinal manipulation of more than 10 months ' duration showed no difference in functional measures , range of motion , or visual analogue pain scales when compared with a control group of bimonthly reassurance or a combination of manipulation and home exercise .
this author concluded that the premise of stating that regular treatments , designed to preserve optimum health and minimize the recurrence of clinical problems , was more likely due to interventions of reassurance , patient education , help with self - management , and active care strategies .
in contrast , a different study looked at the pain levels and functional oswestry disability measures of 2 chronic low back pain groups .
then the maintenance care was provided to one group at a frequency of every 3 weeks for a 9-month follow - up , but not to the second group .
this study found that disability remained at the lowered post 4-week level for the maintenance group but returned to the previous levels for the control group .
they concluded that there were positive effects of preventive maintenance chiropractic spinal manipulation in maintaining functional capacities and reducing the number and intensity of pain episodes after the acute phase of treatment of low back pain patients .
this seemed to concur with the swedish surveys of chiropractors who found consensus on providing such care to prevent relapses .
there is a common thread of the time dependency noted in all the laboratory and clinical studies .
the periods of onset of the anatomical and physiological changes ranged from 2 to 4 weeks .
the clinical studies also provided mmt every 4 weeks and noted positive changes in the pain and disability measures .
this time interval also correlates with the common recommendations found in the surveys of chiropractic physicians .
although there have been physiological measures to assess the results of manipulative therapy , studies of these measures applied to preventive manipulation have not been conducted ; nor has there been any testing of physiological vs psychological contributions to the reported clinical benefits .
further investigatory studies in these areas would be able to tie together some of the laboratory and clinical findings . in the first conference on spinal manipulation in 1977 sponsored by the national institute of neurological and communicative disorders and stroke , haldeman presented the criteria for investigating the clinical basis of the mechanisms of manipulative therapy . these still apply today and can be paraphrased to apply to mmt.1.that the application of mmt must demonstrate consistent clinical results under controlled conditions in the treatment of a specific pathologic process , organ dysfunction , or symptom complex.2.that mmt demonstrates a specific effect on the musculoskeletal system to which it is applied.3.that the musculoskeletal effect caused by mmt
must be shown to have a specific influence on the nervous system.4.that the influence on the nervous system brought about by the manipulation must demonstrate a beneficial influence on abnormal function of an organ , tissue pathology , or symptom complex .
but we must be careful about presenting theory as fact . that the application of mmt must demonstrate consistent clinical results under controlled conditions in the treatment of a specific pathologic process , organ dysfunction , or symptom complex .
that mmt demonstrates a specific effect on the musculoskeletal system to which it is applied . that the musculoskeletal effect caused by mmt must be shown to have a specific influence on the nervous system . that the influence on the nervous system brought about by the manipulation must demonstrate a beneficial influence on abnormal function of an organ , tissue pathology , or symptom complex .
but we must be careful about presenting theory as fact . as science starts with a theory , the theory
currently , the theories involving mmt are evolving ; and there are initial investigations that may apply to this care . in response to the beliefs , positive anecdotal findings , patient satisfaction , and historical clinical reports , the following is a response to those directives .
it appears that the clinical opinions and the research to date have looked at the effect on low back conditions .
this would be a good starting point to research the efficacy of mmt in reducing the incidence of low back injuries or the severity of the episodes .
this has included the increase in population of proprioception , stimulation of -motor neuronal pool , and reflexogenic responses through the stretch reflex .
there is now increasing research available that is confirming much of this ; but further research is still warranted , especially in regard to these effects under mmt .
there is initial evidence of the effect of immobility on the ia afferent nerves , the -motor neuronal pool , the motor end plates , and the muscular end organs .
further research should be aimed at confirming these findings in human subjects and the reversal of these effects with the application of mmt procedures .
the influence on the nervous system from the manipulative therapy has been shown in the studies outlined in our literature search .
future research should look at the beneficial influence of mmt on patients with chronic musculoskeletal conditions before looking at healthy individuals .
population studies similar to those performed by senna and machaly and by hawk et al with larger populations should give us further insight into the clinical value of mmt .
in vivo assessment of neurological and musculoskeletal changes would be beneficial in providing further physiological evidence to support the recommendations of mmt .
this study is limited in scope because it is not a quantitative analysis of the literature , nor does it qualitatively evaluate the literature reviewed .
this was a narrative review to provoke thought , further debate and discussion on the topic , generate theories , and challenge future research directions .
this study is limited in scope because it is not a quantitative analysis of the literature , nor does it qualitatively evaluate the literature reviewed .
this was a narrative review to provoke thought , further debate and discussion on the topic , generate theories , and challenge future research directions .
the value of maintenance care must be demonstrated to substantiate use of this service and for it to be a covered service on par with other preventive care services such as annual physical examinations , colonoscopic examinations , prostate examinations in men , and mammograms in women .
the purpose of this discussion was to address mmt , its clinical care , and the body of evidence and to generate theories that might further investigate evidence on the same basis as other common preventive services .
therefore , a theoretical framework was developed based on the grounded theory of the common clinical practice of mmt and its common dosage .
this review suggests that there may be a correlation between clinical dosages with the time of onset of pathologies .
this article aimed to enlighten the debate between the clinical theories and the scientific evidence , and between the philosophy and science of mmt , while providing a physiological hypothesis of the benefits of and direction for future mmt research .
Output:
| objectthe purpose of this article is to discuss a theoretical basis for wellness chiropractic manipulative care and to develop a hypothesis for further investigation.methodsa search of pubmed and of the manual , alternative , and natural therapy index system was performed with a combination of key words : chiropractic , maintenance and wellness care , maintenance manipulative care , preventive spinal manipulation , hypomobility , immobility , adhesions , joint degeneration , and neuronal degeneration .
articles were collected , and trends were identified.resultsthe search revealed surveys of doctors and patients , an initial clinical pilot study , randomized control trials , and laboratory studies that provided correlative information to provide a framework for development of a hypothesis for the basis of maintenance spinal manipulative therapy .
maintenance care optimizes the levels of function and provides a process of achieving the best possible health .
it is proposed that this may be accomplished by including chiropractic manipulative therapy in addition to exercise therapy , diet and nutritional counseling , and lifestyle coaching.conclusionsit is hypothesized that because spinal manipulative therapy brings a joint to the end of the paraphysiological joint space to encourage normal range of motion , routine manipulation of asymptomatic patients may retard the progression of joint degeneration , neuronal changes , changes in muscular strength , and recruitment patterns , which may result in improved function , decreased episodes of injuries , and improved sense of well - being . |
PubmedSumm8871 | ***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: periodontal diseases are infectious diseases of humans and other mammals that result in damage to the soft tissue and periodontal ligaments of the gingiva , resorption of alveolar bone from the jaw , and , ultimately , loss of teeth .
it is becoming increasingly apparent that there is extensive interaction and cross - talk between the immune system and bone remodeling .
this new concept has wide - ranging implications for how we think about the causes and regulation of bone resorption and has engendered a new field called osteoimmunology [ 1 , 2 ] .
bone is constantly remodeling , with osteoblasts building bone and osteoclasts breaking it down . in a state of health , these two processes are in balance and the density of bone remains stable .
this balance is disrupted in various diseases , including the osteoclastic resorptive disease , chronic periodontitis . in this periodontal disease the progressive loss of alveolar bone
is largely activated by immune responses to a small subset of the more than 600 species of bacteria that colonize the oral cavity . in a murine model
that we have developed previously , we have shown that alveolar bone loss from the jaw can be triggered by oral infection with one of these 600 oral bacterial species , porphyromonas gingivalis , a periodontopathic gram - negative anaerobe from humans [ 3 , 4 ] .
we , and others , have shown that in response to oral infection b lymphocytes and cd4 t lymphocytes of the immune system trigger bone resorption [ 1 , 35 ] . despite the prevalence of periodontal disease ,
the pathways to bone loss are not fully understood . in the most well - characterized pathways , infection upregulates expression of ligand for receptor activator of nf-b ( rank - l ) on specific antigen - activated b and cd4 t lymphocytes .
these immune cells are then able to bind to rank on preosteoclasts , triggering bone resorption [ 47 ] .
we wished to explore whether there are other immune cell surface molecules that can induce bone loss . in this study
we have used mice deficient in their b lymphocyte expression of igd , a b cell surface immunoglobulin known to be involved in b cell / t cell cognate activation , but not known to be involved in bone remodeling . in immune normal mice and humans , expression of membrane bound igd along with igm indicates that a b cell has undergone affinity maturation and can begin to react with specific antigen and secrete soluble antibody to that antigen .
igh-5 mice have a targeted mutation that deletes expression of heavy chain-5 ( igh-5 ) , the delta - like heavy chain of igd immunoglobulin . mice deficient in igd display a delay in b cell affinity maturation .
in addition , b cell membrane igd is a ligand for igd receptors that are expressed on activated cd4 t cells .
binding of igd to igd receptors facilitates b cell antigen presentation to cd4 t cells by stabilizing t cell receptor binding to the antigen / mhc complex .
this cognate interaction increases both antibody responses by the b cells and antigen - specific clonal expansion of the t cells .
we therefore designed experiments using igh-5 mice to test the hypothesis that igd can contribute to alveolar bone loss in response to p. gingivalis infection .
specific pathogen - free balb / c - igh-5 mice that are igd deficient due to a specific deletion of the igh gene and the genetically matched immune normal strain balb / cj were received from the jackson laboratory ( bar harbor , me , usa ) .
mice were kept in the animal colony at bates college under conditions described previously . the experimental protocol was reviewed and approved by the institutional animal care and use committee , bates college .
p. gingivalis atcc 53977 ( a7a1 - 28 ) was maintained frozen in defibrinated sheep 's blood at 80c . for experiments , bacteria
were anaerobically grown under 5% co2 , 10% h2 and 85% n2 at 37c for 47 days on supplemented blood agar containing trypticase soy agar base with 0.1% yeast extract , hemin ( 5.0 g / ml ) , menadione ( 0.5 g / ml ) , and 5% defibrinated sheep 's blood .
bacteria were removed from the plates , gently suspended in phosphate - buffered saline ( pbs ) , and diluted to 10 colony forming units ( cfu ) per ml on the basis of optical density .
pilot experiments in which serial dilutions of p. gingivalis were plated for colony counts had shown that a 1:100 dilution of 10 cfu per ml of p. gingivalis has an optical density of 0.3 at 650 nm .
each experiment included ten age - matched female mice , 14 to 16 weeks old at the start of experiments .
mice were given sulfamethoxazole ( 0.87 mg / ml ) and trimethoprim ( 0.17 mg / ml ) ( sulfatrim , goldline laboratories , ft .
lauderdale , fl , usa ) , ad libitum in their drinking water for 10 days , followed by a 3-day antibiotic - free period .
mice were then infected by gavage needle and direct oral exposure three times at 2-day intervals with 10 cfu of live p. gingivalis in 100 l of pbs with 2% carboxymethylcellulose .
controls received the antibiotic pretreatment and three sham - infections with carboxymethylcellulose without p. gingivalis .
horizontal bone loss around the maxillary molars of defleshed skulls was assessed under a dissecting microscope ( 40 ) fitted with a video image marker measurement system ( model via 170 , boeckeler instruments , inc . ,
the distance from the cementoenamel junction ( cej ) , where the enamel of the tooth crown meets the cementum of the tooth root , to the alveolar bone crest of the jaw ( abc ) was measured at a total of 14 buccal sites per mouse ( for location of measurement sites see photographs in ) .
measurements were done in a blinded protocol by one investigator . as alveolar bone resorbs away ,
additional root cementum is exposed and the distance from the cej to the new location of the abc becomes larger . where the cej to abc is larger in infected mice than in sham - infected mice , bone loss has occurred .
the cej to abc distance is not zero ; consequently , the cej to abc distance at individual sites in infected mice was subtracted from the mean of the distance at that site in sham - infected mice , giving the mm of change in bone at that site . at the time of euthanasia , bacterial samples were collected from the oral cavity using one sterile paper - point per mouse placed along the cej for 5 seconds on the buccal surface of the three maxillary molars on the left and 5 seconds along the molars on the right .
sera were stored at 80c for later assessment of specific igm , igg , and iga antibody by enzyme - linked immunosorbent assay ( elisa ) , as described previously , in polystyrene plates ( costar , corning inc . ,
corning , ny , usa ) coated with formalin - killed whole p. gingivalis atcc 53977 .
the elisa titer was defined as the reciprocal of the highest serum dilution ( expressed in log2 ) that produced absorbance readings more than two standard deviations above background levels .
the p. gingivalis - specific titer of each infected animal was calculated by subtraction of the mean value from the sham - infected animals of that mouse strain .
fifty l of mouse spleen cells at a density of 2 10 cells / ml were washed in 4 ml of wash buffer ( 0.2 g kcl , 8.0 g nacl , 1.15 g na2hpo4 , 0.2 g kh2po4 and 0.2 g nan3 per liter at ph 7.2 ) and pelleted at 110 g for 10 minutes at 15c .
the pellets were resuspended in 1 ml of the same wash buffer and were blocked with 10 l of normal rat igg ( sigma chemical company , st .
cells were immunostained for 30 minutes at 7c with either 10 ul of prediluted hamster antimouse cd69 conjugated to fitc to show activation status , or phycoerythrin - conjugated hamster antimouse cd19 to mark b cells or hamster anti - mouse cd4 to mark cd4 t cells , and fitc- or phycoerythrin - labeled hamster igg as isotype controls ( the jackson laboratory , bar harbor , me , usa ) .
unadsorbed antibody was removed by adding wash buffer and centrifuging at 60 g for 10 minutes at 10c .
cells were resuspended in 0.5 ml flow cytometry buffer ( the wash buffer with 5 ml / l fetal bovine serum added ) .
five l of propidium iodide at 20 g / ml were added to determine cell viability .
data were acquired on a facsort ( becton - dickinson , san jose , ca , usa ) and were analyzed using cellquest .
lymphocytes were gated on the basis of forward scatter and side scatter of incident light .
differences between the infected and sham groups and between infected mice of different strains were evaluated by two - tailed , unpaired t - tests ( excel ; microsoft , redmond , wa , usa ) .
the effects of oral infection with p. gingivalis on alveolar bone are shown in figure 1 . in balb / cj mice with normal igd levels
the cej to abc distance was larger in infected mice than in sham - infected mice at each of the 14 measurement sites , indicating that the infected balb / cj mice had lost bone at every site ( figure 1(a ) ) .
in contrast , in igd deficient mice the cej to abc distances were the same in infected mice as in sham - infected mice , showing that without b cell igd mice did not lose bone at any site ( figure 1(b ) ) . summing the amount of bone change at all 14 sites additionally demonstrated that bone loss occurred in immune normal mice but not in igd deficient mice .
the summed change in infected b cell normal balb / cj mice was a mean of 0.302 0.035 mm of bone .
in contrast , the summed bone change in infected igd deficient mice was 0.040 0.024 mm ( p = 1.28 10 ) . to be sure that lack of bone loss could not be explained by a lack of infection , we reisolated p. gingivalis from the oral cavities by paper point .
p. gingivalis was present in each of the infected mice of both strains and was not present in any of the uninfected mice ( data not shown ) .
the p. gingivalis load was actually much higher ( a mean of 100 10 colonies per plate , n = 10 ) in the igd deficient mice than in the immune normal mice where the mean was only 2 1 colonies per plate ( data not shown ) .
the difference in bacterial load may reflect differences between the mouse strains in their production of p. gingivalis - specific serum antibody .
after infection , both mouse strains produced a specific antibody response significantly higher ( p < .05 ) than the background levels in sham - infected animals ( data not shown ) ; however , the titers of each of the three antibody isotypes in the infected mice were lower in the igd deficient mice than in the immune normal mice ( p < .05 ) ( figure 2 ) . despite the differences in serum antibody titers ,
this was confirmed in our experiments by flow cytometry measurements on the day of euthanasia , 42 days postinfection by comparing the sham - infected mice of the two strains .
the mean percentage of b cells was higher in igd knockout mice than in normal mice , but the difference between the two mouse strains was not statistically significant ( figure 3(a ) ) . in neither mouse strain did p. gingivalis - infection change the percentage of total b cells compared with sham - infected mice ( figure 3(a ) ) .
although total b cell percentages were unchanged , a higher percentage of b cells were activated in infected balb / cj mice than in infected igd knockout mice ( p < .05 ; figure 3(b ) ) .
we also examined the cd4 t cell populations in the two mouse strains . in balb / cj mice
p. gingivalis - infection led to a significant increase in the mean percentage of total viable cd4 t cells compared with sham - infected balb / cj mice ( p < .05 ) .
in igd deficient mice , however , infection did not increase the cd4 t cell population ( figure 4(a ) ) .
similarly , infection activated cd4 t cells in balb / cj mice , as shown by the increased percentage of cd69 cd4 t cells , but it did not activate t cells in igd deficient mice ( figure 4(b ) ) .
in this study , we show that mice with b cells lacking surface igd do not experience alveolar bone loss after oral infection with p. gingivalis ( figure 1 ) . one possible explanation for the lack of bone loss could be that the mice were colonized by with a diminished load of p. gingivalis .
reisolation of the bacteria eliminated this possibility ; igd deficient mice actually harbored higher numbers of this bacterium than immune normal mice .
higher colonization may be due to the lower antibody titers found in the igd deficient ( figure 2 ) .
these reduced titers are in line with earlier studies showing that diminished antibody response is due to the delayed affinity maturation characteristic of this igd mutation .
previous studies in immune normal mice have demonstrated that antibody may decrease bacterial load but antibody is not protective against bone loss : lower antibody titers do not lead to more bone loss .
we can not entirely exclude another possibility ; that is , that the resistance to bone loss seen in the igd deficient mice was due to residual contamination with alleles from the 129 or c57bl/6 progenitor strains .
the igh knockout was originally generated on the c57bl/6 genetic background by gene targeting with an embryonic stem cell line derived from murine strain 129 .
balb / c - igh-5 mice were produced by backcross onto the balb / cj strain for seven generations .
strain balb / cj is genetically susceptible to bone loss after oral infection with p. gingivalis , while strains 129 and c57bl/6 show moderate resistance to bone loss in some experiments ; however , mice within each cohort do lose bone after infection . in seven backcross generations the progenitor genotypes
are predicted to be diluted 1 in 2 , leaving less than 0.8% of the progenitor alleles carried into the balb / cj genome and then only if they are closely linked to the target igh gene . in the experiments presented in this paper , no infected balb / c - igh-5 mouse showed an increase in the cej to abc distance ( our measure of bone loss ) that was beyond one standard error of the mean value of the shams ; that is , the distance from the cej to the abc in every infected mouse was within the range of variation of the sham mice .
we therefore think it highly unlikely that the absence of bone loss observed in the infected mice is the result of passenger 129 or c57bl/6 gene loci but is instead an intrinsic feature of the igh deficiency .
we propose that the resistance to bone loss is due to the inability of igd deficient b cells to act as costimulators of antigen - specific t cells .
t cells have igd receptors that are lectins and bind to o - glycans on b cell surface igd immunoglobulin .
these igd receptors are present on very low numbers of peripheral t cells but are moved to the surface membrane in response to activation by antigen .
the upregulated igd receptor on an antigen - specific t cell binds to igd on a b cell bearing the same antigen , stabilizing the t cell receptor / mhc ii connection between the two types of lymphocytes , facilitating activation of both .
inflammatory bone resorption triggered by aggregatibacter ( formerly actinobacillus ) actinomycetemcomitans requires activation of th1 cd4 t cells , and this activation requires costimulation of b7 on the t cell surface . blocking of b7 abrogated costimulation and inhibited bone resorption in a rat model .
the present results suggest that b cell igd binding to cd4 t cell igd receptors is a pathway to costimulation of both b cells and cd4 t cells in p. gingivalis - induced disease .
our experiments show that oral infection of immune normal mice with p. gingivalis leads to both serum antibody response ( figure 2 , an indication of b cell activation ) and to higher numbers and activation of cd4 t cells ( figure 4 ) .
in contrast , igh-5 mice lacking igd showed signs of less activation of both b and t cells .
they produced lower antibody titers ( figure 2 ) , had fewer activated b cells ( figure 3 ) , and did not show an increase in t cell population or activation at 42 days after infection ( figure 4 ) .
the mechanism by which this cognate b and t cell activation stimulates bone loss is not known at this time .
it is not likely to be due to the effect of igd deletion on antibody secretion , as antibody is not protective against bone loss .
one well - studied immunological pathway to bone loss is upregulation of rank - l on activated lymphocytes .
both b cells and t cells express membrane bound and soluble rank - l after activation [ 16 , 17 ] , and bone loss can be triggered by the binding of this ligand to rank on preosteoclasts .
however , both cd4 and cd8 t cells can express rank - l after activation .
we have shown that cd4 t cells and their cytokines are involved in alveolar bone loss in mice , but that cd8 t cells are not .
others have also implicated cd4 cells [ 2 , 15 , 18 ] , suggesting that there may a pathway in addition to rank - l that is particular to cd4 but not cd8 t cells . although we have some preliminary data showing that the proportion of cd4 spleen cells expressing membrane surface rank - l was the same in infected immune normal mice that lost bone as it was in igd deficient mice that did not lose bone ( data not shown ) , we have not examined rank - l expression on t or b cells in the gingiva .
one pathway that could distinguish between cd4 and cd8 t cells is the pathway suggested by these experiments , that is , activation through the t cell igd receptor . in mice , only cd4 t cells express igd receptors and so cd8 t cells can not participate in the costimulation .
cd4 t cell/ b cell interaction may provide sufficient amplification of rank - l upregulation that the cells triggering osteoclasts are largely restricted to b cells and cd4 t cells .
han et al . have shown that adoptive transfer of antigen - responsive b cells can induce bone loss in rats that are congenitally athymic and therefore t cell deficient .
it is possible that b cells are alone responsible for the effects on bone loss seen in these experiments , but the activation of cd4 t cells over an extended period of time ( 42 days postinfection ; figure 4 ) would argue that t cell activation is playing at least an amplifying role , either through rank - l or through increased secretion of bone resorptive cytokines [ 3 , 20 ] .
genetic deletion of igd was shown here to diminish t and b cell activation and to inhibit alveolar bone loss in mice .
this study suggests a new pathway through which oral infection with p. gingivalis can result in loss of alveolar bone . in response to oral infection , igd on the surface of b cells
binds to igd receptors on cd4 t cells , resulting in coactivation of both b and t cells of the immune system .
such b and t cell activation can , in turn , activate osteoclasts and trigger bone loss .
chronic periodontitis is a widespread infectious disease ; therefore , elucidation of the mechanisms through which the immune responses to infection trigger damage rather than protection is of clinical importance .
Output:
| periodontal disease is one of the most common infectious diseases of humans .
immune
responses to infection trigger loss of alveolar bone from the jaw and eventual tooth loss .
we investigated the contribution of b cell igd to alveolar bone loss by comparing the
response of b cell normal balb / cj mice and igd deficient balb / c - igh-5/j mice to oral infection with porphyromonas gingivalis , a gram - negative periodontopathic bacterium
from humans .
p. gingivalis - infected normal mice lost bone .
specific antibody to p.
gingivalis was lower and oral colonization was higher in igd deficient mice ; yet bone
loss was completely absent .
infection increased the proportion of cd69 + activated b cells
and cd4 + t cells in immune normal mice compared to igd deficient mice .
these data
suggest that igd is an important mediator of alveolar bone resorption , possibly through
antigen - specific coactivation of b cells and cd4 + t cells . |
PubmedSumm8872 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: cardiovascular ( cv ) diseases are the leading cause of mortality in hemodialysis ( hd ) patients , accounting for nearly half of all deaths in this patient population .
the cv mortality rate of hd patients is higher by a factor of ~10 than that of the general population , even after adjustment for age , race , gender , and comorbidities [ 14 ] . in particular , scd has been identified as an important contributor of mortality .
scd is the single largest cause of death in hd patients responsible for 2229 % of all - cause mortality [ 13 , 5 ] .
given the extremely high incidence of cv diseases as well as the case fatality rate of cardiac events , early identification of individuals at risk for increased cv mortality is clinically highly relevant .
in cardiac diseases ecg is beneficial not only as a diagnostic but also prognostic tool .
t - wave abnormalities are among the most frequently encountered pathologic ecg findings in apparently healthy populations .
for example , the presence of even isolated minor t - wave abnormalities is associated with increased long - term cardiac mortality [ 69 ] .
ecg abnormalities are very common in hd patients , with st - t changes observed in 4060 % . moreover
, volume and electrolyte status can influence various ecg variables , with st - t changes frequently appearing in relation to hd timing and the hd process itself often inducing or potentiating ecg alterations , which additionally might compromise ecg interpretation [ 9 , 10 ] .
the prognostic role of t - wave changes in lead avr has long been underestimated .
several recent studies have validated the role of upright t - wave amplitude in lead avr ( tavr ) as a powerful , independent prognostic predictor of cv mortality in the general population [ 1113 ] as well as in some clinical settings [ 1417 ] . however , neither the prevalence nor the predictive value of a positive tavr has been evaluated in hd patients .
we designed this study to prospectively determine whether tavr was predictive of cv mortality and scd in a group of hd patients .
the exclusion criteria were : hd treatment less than 1 month , cardiac pacing , preexcitation , atrial fibrillation , right or left bundle branch block , and noncardiac diseases limiting the chance of a 1-year survival .
all patients gave a written consent , and the studies were approved by members of the local ethics committees .
surface 12-lead resting ecgs were recorded with a computer - based electrocardiograph ( cardioperfect , version 1.1 , cardiocontrol nv , rijswijk , the netherlands ) .
ecgs were conducted the day after a dialysis session while subjects were lying in the supine position and breathing normally after at least 5 min of rest .
positive tavr was defined as a wave with a positive deflection > 0 mv .
the representative ecgs of positive and negative tavr are presented in fig . 1 .
the width of qrs complex and qt interval were recorded automatically by the ecg machine .
st depression was defined as more than 0.5 drop in st - segment in lead v5 from the isoelectric line .
st elevation in lead avr was defined as the elevation 8 v from the isoelectric line .fig .
positive tavr was defined as a wave with a positive deflection > 0 mv .
negative tavr was defined as tavr 0 mm t - wave morphology in lead avr .
positive tavr was defined as a wave with a positive deflection > 0 mv .
negative tavr was defined as tavr 0 mm the following parameters were measured by automated analyzers at the beginning of the evaluation : serum sodium , potassium , calcium , phosphate , creatinine , urea , haemoglobin , intact parathormone ( pth ) , albumin , c - reactive protein ( crp ) , total cholesterol , high - density lipoprotein ( hdl ) cholesterol and triglycerides ( tg ) .
low - density lipoprotein ( ldl ) cholesterol was calculated using the friedewald equation : ldl ( mg / dl ) = total cholesterol hdl ( triglycerides/5 ) .
cardiac tnt in plasma was measured before dialysis by electrochemiluminescence immunoassay ( elecsys 2010 analyser , roche diagnostics ) with a detection limit of 0.01 g / l .
two - dimensional echocardiographic examination was performed using a 2.5-mhz transducer by the cardiologist who was blinded to the clinical data of the study subjects .
the lvm was calculated according to the formula of devereux and reicheck and this was indexed for body surface to obtain the lvmi .
all echocardiographic measurements were performed in the morning after dialysis according to the recommendations of the american society of echocardiography .
all patients were followed for at least 3 years after the day of the baseline assessment or until death or renal transplant .
cv death was defined according to standardized definitions for end point events in cardiovascular trials .
scd was defined according to hemodialysis ( hemo ) trial as witnessed and unwitnessed unexpected deaths , with a preceding duration of symptoms less than 24 h for witnessed deaths , and less than the interval since the last dialysis session for unwitnessed deaths .
when normally distributed , continuous variables were expressed as mean sd , and as median and range when non - normally distributed .
continuous data were compared using the student t - test when normally distributed and using mann
categorical data were expressed as frequencies and percentages and were compared using the test .
linear regression analysis was assessed using the pearson correlation coefficient or spearmans rank correlation coefficient when appropriate . for the survival analysis , patients were divided into tavr negative and tavr positive groups .
if patients underwent renal transplantation they were censored on the day of their last dialysis .
cumulative survival curves were constructed by using the kaplan meier method for cv mortality and scd .
relationships between baseline parameters and endpoints were analyzed with cox proportional hazard regression analysis . in the univariate analyses ,
explanatory variables with a p value < 0.01 in the univariate analysis were entered into a multivariate analysis .
the exclusion criteria were : hd treatment less than 1 month , cardiac pacing , preexcitation , atrial fibrillation , right or left bundle branch block , and noncardiac diseases limiting the chance of a 1-year survival .
all patients gave a written consent , and the studies were approved by members of the local ethics committees .
surface 12-lead resting ecgs were recorded with a computer - based electrocardiograph ( cardioperfect , version 1.1 , cardiocontrol nv , rijswijk , the netherlands ) .
ecgs were conducted the day after a dialysis session while subjects were lying in the supine position and breathing normally after at least 5 min of rest .
positive tavr was defined as a wave with a positive deflection > 0 mv .
the representative ecgs of positive and negative tavr are presented in fig . 1 .
the width of qrs complex and qt interval were recorded automatically by the ecg machine .
st depression was defined as more than 0.5 drop in st - segment in lead v5 from the isoelectric line .
st elevation in lead avr was defined as the elevation 8 v from the isoelectric line .fig .
positive tavr was defined as a wave with a positive deflection > 0 mv .
negative tavr was defined as tavr 0 mm t - wave morphology in lead avr .
positive tavr was defined as a wave with a positive deflection > 0 mv .
the following parameters were measured by automated analyzers at the beginning of the evaluation : serum sodium , potassium , calcium , phosphate , creatinine , urea , haemoglobin , intact parathormone ( pth ) , albumin , c - reactive protein ( crp ) , total cholesterol , high - density lipoprotein ( hdl ) cholesterol and triglycerides ( tg ) . low - density lipoprotein ( ldl )
cholesterol was calculated using the friedewald equation : ldl ( mg / dl ) = total cholesterol hdl ( triglycerides/5 ) .
cardiac tnt in plasma was measured before dialysis by electrochemiluminescence immunoassay ( elecsys 2010 analyser , roche diagnostics ) with a detection limit of 0.01 g / l .
two - dimensional echocardiographic examination was performed using a 2.5-mhz transducer by the cardiologist who was blinded to the clinical data of the study subjects .
the lvm was calculated according to the formula of devereux and reicheck and this was indexed for body surface to obtain the lvmi .
left ventricular hypertrophy ( lvh ) was defined by an lvmi over 131 g / m in males or over 110 g / m in females .
all echocardiographic measurements were performed in the morning after dialysis according to the recommendations of the american society of echocardiography .
all patients were followed for at least 3 years after the day of the baseline assessment or until death or renal transplant . cv mortality and scd were used as endpoints .
cv death was defined according to standardized definitions for end point events in cardiovascular trials .
scd was defined according to hemodialysis ( hemo ) trial as witnessed and unwitnessed unexpected deaths , with a preceding duration of symptoms less than 24 h for witnessed deaths , and less than the interval since the last dialysis session for unwitnessed deaths .
when normally distributed , continuous variables were expressed as mean sd , and as median and range when non - normally distributed .
continuous data were compared using the student t - test when normally distributed and using mann
categorical data were expressed as frequencies and percentages and were compared using the test .
linear regression analysis was assessed using the pearson correlation coefficient or spearmans rank correlation coefficient when appropriate . for the survival analysis
if patients underwent renal transplantation they were censored on the day of their last dialysis .
cumulative survival curves were constructed by using the kaplan meier method for cv mortality and scd .
relationships between baseline parameters and endpoints were analyzed with cox proportional hazard regression analysis . in the univariate analyses ,
explanatory variables with a p value < 0.01 in the univariate analysis were entered into a multivariate analysis .
of the total of 321 hd patients initially identified , 98 patients were excluded due to atrial fibrillation , noncardiac diseases limiting the chance of a 1-year survival , pacemaker rhythm , and bundle branch blocks .
the remaining 223 hd patients ( 115 females and 108 males ) , aged 4782 years ( mean 67.67 6.96 ) , who remained on hd from 2 to 94 months ( mean 40.01 20.34 ) entered the study .
the causes of end - stage renal disease ( esrd ) were diabetes ( n = 91 ) , chronic glomerulonephritis ( n = 46 ) , hypertensive nephropathy ( n = 22 ) , obstructive nephropathy ( n = 9 ) , polycystic kidney disease ( n = 9 ) , chronic pyelonephritis ( n = 6 ) , and unknown ( n = 40 ) . none of the hd patients received anti - arrhythmics ( class i or iii ) or digitalis . out of 223 patients who qualified for the study , 168 ( 75.3 % ) were taking angiotensin - converting enzyme inhibitors / angiotensin receptor blockers , 159 ( 71.3 % ) beta - blockers , 81 ( 36.3 % ) statins and 118 ( 52.9 % ) calcium blockers .
positive tavr was found in 37 ( 16.6 % ) of all patients with no difference between women and men .
patients with positive tavr were older ( p < 0.001 ) , more often had a history of mi ( p = 0.008 ) , had higher prevalence of diabetes mellitus ( p = 0.012 ) , and were more likely to be on beta - blocker therapy ( p = 0.019 ) .
with regard to echocardiographic parameters , patients with positive tavr had higher lvmi ( p < 0.001 ) and lower ef ( p < 0.001 ) in comparison to patients with negative tavr . with regard to ecg parameters , patients with positive tavr had increased width of qrs complex and qt interval ( p < 0.001 and p = 0.007 , respectively ) , higher prevalence of st - segment elevation in lead avr ( p < 0.001 ) , and higher prevalence of st depression ( p < 0.001 ) as well as negative t in leads ii and v6 ( p = 0.002 and p < 0.001 , respectively ) in comparison to patients with negative tavr .
additionally , patients with positive tavr had higher calcium phosphate scores ( p = 0.007 ) and higher tnt levels ( p < 0.001 ) .
more than 70 % of patients with st elevation in avr had concomitant positive tavr.table 1baseline characteristicsvariableall patientstavr
p
( n = 223)negative ( n = 186)positive ( n = 37)men / women ( n)0.940.940.950.843age ( years)69.57 5.9668.31 6.5375.78 6.25<0.001hd duration ( months)67.67 6.9667.29 7.1469.57 5.760.551mi ( % ) 26.022.045.90.008smoking ( % ) 18.418.816.20.411beta - blockers ( % ) 71.368.883.80.019ace / arb75.376.370.30.212statins36.335.540.50.248hypertension ( % ) 75.874.781.10.119diabetes mellitus ( % ) 37.234.461.40.012body mass index ( n)25.97 2,4425.99 2.6925.34 2.240.781heart rate ( b.p.m.)80.3 4.4579.4 4.4284.8 4.66<0.001qrs duration ( ms)107.9 19.47105.4 18.56120.59 17.87<0.001qtc bazett ( ms)432.6 33.5430.9 35.8441.2 29.50.007negative t in lead ii ( % ) 13.410.229.70.002negative t in lead v6 ( % ) 18.813.445.9<0.001st depression ( % ) 25.619.456.8<0.001st elevation in lead avr ( % ) 18.47.573.0<0.001lvmi ( g / m)146.5 45.18143.7 46.22159.8 43.11<0.001ef ( % ) 54.91 7.2155.82 7.2850.29 8.42<0.001haemoglobin ( g / dl)11.25 1.4611.21 1.3911.52 1.790.498sodium ( mmol / l)138.2 2.5138.2 2.6138.0 2.10.627potassium ( mmol / l)5.83
0.815.84 0.795.76 0.920.654calcium phosphate product ( mg / dl)48.96 10.3247.28 11.5657.40 9.790.007total cholesterol ( mg / dl)186.3 41.05186.8 41.56183.1 43.80.733ldl cholesterol ( mg / dl)112.3 32.03112.5 33.23111.0 37.680.427hdl cholesterol ( mg / dl)40.41 16.1940.38 16.0840.6 17.620.426triglycerides ( mg / dl)168.8 71.69168.4 69.02170.1 70.10.415albumin ( g / dl)3.81 0.373.83 0.393.76 0.400.252crp ( mg / dl)7.38 ( 0.3219.9)7.09 ( 0.3213.9)9.93 ( 7.3219.9)0.191pth ( pg / ml)379 ( 18.01736)361 ( 18.01736)401 ( 67.71350)0.255troponin t ( g / l)0.057 ( 0.000.813)0.051 ( 0.000.533)0.152 ( 0.000.813)<0.001kt / v ( n)1.442 0.2751.442 0.2811.446 0.2690.402
mi myocardial infarction , ace / arb angiotensin - converting enzyme inhibitors / angiotensin receptor blockers , ef ejection fraction , qtc qt interval corrected for heart rate using the bazett formula ( qtc = qt/rr ) , lvmi left ventricular mass index , pth partahormon , kt / v number used to quantify hemodialysis dialysis treatment adequacy baseline characteristics
mi myocardial infarction , ace / arb angiotensin - converting enzyme inhibitors / angiotensin receptor blockers , ef ejection fraction , qtc qt interval corrected for heart rate using the bazett formula ( qtc = qt/rr ) , lvmi left ventricular mass index , pth partahormon , kt / v number used to quantify hemodialysis dialysis treatment adequacy over the mean follow - up period of 25.43 3.56 months ( range 136 months ) , there were 79 all - cause deaths , 54 cv deaths including 25 scd .
the incidence of cv death was as follows : in negative tavr group 18.8 % and in positive tavr group 45.9 % ( p < 0.001 ) .
the incidence of scd was as follows : in negative tavr group 8.1 % and in positive tavr group 24.3 % ( p < 0.001 ) .
a kaplan meier analysis showed that the cumulative incidence of cv mortality was significantly higher in patients with positive compared to negative tavr ( log - rank , p < 0.001 ; fig . 2 ) .
to control for possible confounders , multivariate analysis was performed using a model consisting of univariate predictors of cardiac mortality .
the results of the univariate and multivariate cox proportional hazard regression analyses are shown in table 2 .
univariate regression analysis showed that age , history of mi , ef , tnt level , heart rate , qrs duration , st - segment elevation in lead avr , and positive tavr were univariate predictors of cv mortality . a multivariate analysis selected age [ hazard ratio ( hr ) 1.71 , p < 0.001 ] , heart rate [ hr 1.42 , p = 0.016 ] , and positive tavr [ hr 2.21 , p = 0.001 ] as independent predictors of cv mortality.fig .
2kaplan meier survival plots for cardiovascular mortality in hemodialysis patients stratified by positive and negative t - wave in lead avrtable 2uni- and multivariate predictors of cardiac mortalityparameterunivariate hr ( 95 % ci )
p
multivariate hr ( 95 % ci )
p
age1.25 ( 1.021.1.41)<0.0011.71 ( 1.511.90)<0.001male gender0.98 ( 0.781.21)0.734diabetes mellitus1.38 ( 0.85 - 1.96)0.133history of mi1.42 ( 0.912.11)0.012lvmi1.28 ( 0.692.35)0.279ef2.35 ( 1.252.77)0.0081.89 ( 0.853.61)0.353troponin t2.14 ( 1.323.07)0.0031.45 ( 0.932.72)0.071calcium phosphate product1.71 ( 1.072.34)0.228beta - blockers1.09 ( 0.782.67)0.677heart rate ( 10 b.p.m .
increase)1.58 ( 1.052.57)0.0061.42 ( 1.031.44)0.016qrs ( 10 ms increase)1.29 ( 1.171.49)0.010corrected qt interval1.18 ( 0.821.84)0.358negative t in lead ii1.26 ( 0.802.23)0.125negative t in lead v62.11 ( 1.272.97)0.009st depression in lead v51.79 ( 0.713.47)0.296st elevation in lead avr1.73 ( 1.251.89)0.0041.69 ( 0.972.46)0.202positive tavr3.03 ( 2.564.21)<0.0012.21 ( 1.762.79)0.001 in the multivariate analyses , parameters with a p 0.01 were entered
hr hazard ratio , ci confidence interval , mi myocardial infarction , lvmi left ventricular mass index , ef ejection fraction kaplan meier survival plots for cardiovascular mortality in hemodialysis patients stratified by positive and negative t - wave in lead avr uni- and multivariate predictors of cardiac mortality in the multivariate analyses , parameters with a p 0.01 were entered
hr hazard ratio , ci confidence interval , mi myocardial infarction , lvmi left ventricular mass index , ef ejection fraction kaplan
meier sub analyses were performed to assess the prognostic value of tavr with regard to scd .
figure 3 shows that the cumulative incidence of scd was significantly higher in patients with negative compared to positive tavr ( log - rank , p < 0.001 ) . to control for possible confounders ,
the results of the univariate and multivariate cox proportional hazard regression analyses are shown in table 3 .
univariate regression analysis showed that age , history of mi , lvmi , tnt , and positive tavr were univariate predictors of scd .
after controlling for univariate predictors of scd age [ hr 1.88 , p < 0.001 ] , and positive tavr [ hr 1.53 , p = 0.014 ] remained independent predictors of scd.fig .
3kaplan meier survival plots for sudden cardiac death in hemodialysis patients stratified by positive and negative t - wave in lead avrtable
3uni- and multivariate predictors of sudden cardiac deathparameterunivariate hr ( 95 % ci )
p
multivariate hr ( 95 % ci )
p
age1.15 ( 1.071.30)<0.0011.88 ( 1.452.03)<0.001male gender1.08 ( 0.691.47)0.804diabetes mellitus0.88 ( 0.252.37)0.533history of mi1.84 ( 1.132.98)0.035lvmi1.44 ( 1.142.21)0.018ejection fraction2.14 ( 1.192.68)0.0092.35 ( 0.973.87)0.294troponin t1.64 ( 1.022.97)0.014calcium x phosphate product1.01 ( 0.372.17)0.245beta - blockers0.95 ( 0.332.47)0.714heart rate ( 10 b.p.m .
increase)1.33 ( 0.982.47)0.203qrs ( 10 ms increase)1.19 ( 0.871.66)0.253corrected qt interval1.48 ( 0.912.74)0.309negative t in lead ii1.67 ( 0.762.53)0.311negative t in lead v61.43 ( 1.862.57)0.023st depression in lead v51.33 ( 0.613.37)0.325st elevation in lead avr2.23 ( 0.873.49)0.076positive tavr2.54 ( 2.123.59)0.0011.53 ( 1.122.74)0.014 in the multivariate analyses , parameters with a p 0.01 were entered
hr hazard ratio , ci confidence interval , mi myocardial infarction , lvmi left ventricular mass index , ef ejection fraction kaplan meier survival plots for sudden cardiac death in hemodialysis patients stratified by positive and negative t - wave in lead avr uni- and multivariate predictors of sudden cardiac death in the multivariate analyses , parameters with a p 0.01 were entered
hr hazard ratio , ci confidence interval , mi myocardial infarction , lvmi left ventricular mass index , ef ejection fraction
this study showed that tavr analysis provides prognostic information for hd patients beyond what is available from other known traditional risk factors .
the presence of positive tavr remained an independent and powerful predictor of cv mortality as well as scd even after adjustment for established cv risk factors .
positive tavr was superior to any other ecg findings in the identification of patients most at risk for cardiac events .
the kaplan meier curves began to separate early and then continued to stay separate until the end of follow - up for both cv mortality and scd .
lead avr often yields information from the right upper side of the heart that is not as readily available from other leads . when repolarization of injured myocardial cells is delayed compared to normal cells , the direction of the t - wave vector changes towards the injured myocardial region .
thus , positive t - waves in lead avr might represent the presence of ischemically injured myocardium in the apical , inferior , and lower lateral regions of the heart .
these areas of the heart are supplied with blood from left anterior descending ( lad ) , right coronary , or left circumflex coronary artery .
therefore , disease of these arteries or lesions located more proximally in left main coronary artery ( lmca ) would be expected to positively invert a normally negative tavr [ 21 , 23 ] .
the prevalence of positive tavr in our study ( 16.6 % ) was higher than the general population ( 2.2 % ) , and comparable to the prevalence of positive tavr in patients with heart failure ( 17.5 % ) and prior myocardial infarction ( 16.2 % ) .
previous studies have found that positive tavr is associated with lmca disease , multivessel disease , and proximal lad occlusion [ 1416 , 21 , 23 ] .
moreover , multivessel disease is observed in most cases and lmca disease is also very common in hd patients [ 24 , 25 ] .
however , in our study tavr was associated with cv events independent of tnt which is good surrogate marker of myocardial injury .
it may be due to the fact that tnt elevation in hd patients may result from reduced renal clearance , direct injury to myocardial cells ( toxins , hypoxia , stretching ) , reversible myocardial ischaemic release in the absence of myocardial necrosis and , from lvh .
elevated tnt levels have been observed in 3075 % of hd patients in the absence of an acute myocardial injury .
our results are in agreement with some previous studies indicating that the predictive accuracy of ef for cv events is limited . in our study
more than 70 % of patients with st - segment elevation in lead avr also had positive tavr .
that st - segment elevation in lead avr is predictive of cardiac mortality only when not accounting for positive tavr .
the effect of st - segment elevation in lead avr predicting cardiac events can be attributed in part to the presence of positive tavr .
the prognostic utility of upright tavr for predicting cv mortality in hd patients is in concordance with previous studies that have documented that positive tavr is a powerful marker for estimating risk of cv death both in the general population [ 12 , 13 ] as well as in some clinical settings such as heart failure , acute coronary syndromes , or myocardial infarction [ 14 , 15 , 28 , 29 ] . to our knowledge , this is the first study that has demonstrated the prognostic utility of upright tavr for predicting scd . given the ubiquity , inexpensiveness and convenience of ecg recordings and the fact that scd is the single largest cause of death in hd patients [ 13 , 5 ] , the results of tavr might be readily utilized for scd risk estimation in hd patients .
it currently remains unclear whether upright tavr is merely a marker of poor prognosis that reflects the high prevalence of the most severe forms of coronary artery disease , contributing to cv mortality , including scd , or whether it potentially identifies more distinct electrophysiological mechanisms that underlie increased mortality and scd .
nevertheless , the population was large enough to demonstrate a predictive value for a positive tavr .
second , the exclusion of patients with some clinical conditions potentially associated with a higher mortality , such as atrial fibrillation , may also add bias to the results .
third , it is possible that serial rather than single measurements of tavr may have changed the results , making tavr either more or less useful in predicting clinical events in hd patients .
positive tavr is associated with increased cv mortality as well as scd in hd patients .
this simple ecg parameter provides additional information beyond what is available with other known traditional risk factors and allows the identification of patients most at risk of cv events .
hd patients with a positive tavr , should be considered for additional diagnostic and preventive measures .
Output:
| backgroundgiven that cardiac disease is the leading cause of mortality in hemodialysis ( hd ) patients , identification of patients at risk for cardiac mortality is crucial .
the aim of this study was to determine if positive t - wave amplitude in lead avr ( tavr ) was predictive of cardiovascular ( cv ) mortality and sudden cardiac death ( scd ) in a group of hd patients.methods and resultsafter exclusion , 223 hd patients were prospectively followed - up for 25.43 3.56 months .
patients were divided into tavr negative ( n = 186 ) and tavr positive ( n = 37 ) groups .
myocardial infarction , diabetes and beta - blocker therapy were more frequent in positive tavr patients .
patients with upright tavr were older , had higher left ventricular mass index , lower ejection fraction , higher calcium phosphate product , higher troponin t level , higher prevalence of st - t abnormalities , and increased width of qrs complex and qt interval , compared with patients with negative tavr .
a kaplan meier analysis showed that the cumulative incidences of cv mortality as well as scd were higher in patients with positive tavr compared with those with negative tavr ( log - rank , p < 0.001 in both cases ) .
a multivariate analysis selected age [ hazard ratio ( hr ) 1.71 , p < 0.001 ] , heart rate ( hr 1.42 , p = 0.016 ) , and positive tavr ( hr 2.21 , p = 0.001 ) as well as age ( hr 1.88 , p < 0.001 ) , and positive tavr ( hr 1.53 , p = 0.014 ) as independent predictors of cv mortality and scd , respectively.conclusionin hd patients , positive tavr is an independent and powerful predictor of cv mortality as well as scd .
this simple ecg parameter provides additional information beyond what is available with other known traditional risk factors and allows the identification of patients most at risk of cv events . |
PubmedSumm8873 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: lupus vulgaris is the most common type of cutaneous tuberculosis , with most varied manifestations .
it is a chronic and progressive form occurring in individuals with high degree of tuberculin sensitivity and moderate immunity .
a characteristic feature of lupus vulgaris is its extremely chronic course with slow but steady growth of the lesions over a period of many years , even decades .
we report a case of lupus vulgaris with very large sized , multiple plaques occurring at less common sites .
a 40-year - old man presented with large plaques of 30 years duration over right upper limb , right side of the chest and back , and right lower limb .
the lesion started as a small papule over right upper limb near the elbow when he was 10 years old .
since then it steadily grew in size to involve whole of the limb and also the right side of the chest and back .
he developed similar lesions , one over the right thigh after about 2 years of the first lesion that gradually enlarged to involve most of the thigh circumferentially and one more lesion over the left side of the back since one year [ figure 1 ] .
there was no history of trauma prior to the onset of the lesions or the past history suggestive of tuberculosis of any part of the body .
clinical photograph showing a large plaque over right upper limb and right side of the chest before treatment on examination , there were three plaques , two large and one small , with well - defined borders and irregular margins :
plaque no .
1 : involving right upper limb , right side of the chest and back measuring about 60 45 cm.plaque no .
2 : about 6 3 cm over the left side of the back.plaque no .
3 : over right thigh , involving circumferentially , measuring about 40 cm longitudinally and 50 cm circumferentially .
plaque no .
1 : involving right upper limb , right side of the chest and back measuring about 60 45 cm . plaque no .
3 : over right thigh , involving circumferentially , measuring about 40 cm longitudinally and 50 cm circumferentially . within the plaque
, there were areas of thick hyperkeratosis and large , thick adherent crusts on an erythematous base .
ulceration at some places and areas of scarring and atrophy in between the areas of hyperkeratosis were present .
hematological investigations revealed anemia ( hb : 10.1 g% ) , raised erythrocyte sedimentation rate ( 67 mm / first hour ) .
the mantoux test was strongly positive with a reading of 22 20 mm at 72 h. chest x - ray was normal .
histopathologic examination of the biopsy specimen revealed hyperplastic epidermis , upper and mid - dermis showing numerous noncaseating epitheloid granulomas with langhan 's type of giant cells [ figure 2 ] .
skin biopsy showing hyperplastic epidermis , upper and mid dermis showing noncaseating epitheloid granulomas with langhan 's type of giant cells based on clinical features and investigations , a diagnosis of lupus vulgaris was made and the patient was started on antitubercular treatment cat - i .
there was dramatic improvement in skin lesions within 3 weeks and after 6 weeks the lesions showed 7080% of improvement .
after 12 weeks , there was almost total healing of the lesions [ figure 3 ] .
it usually occurs through contiguous extension of the disease from underlying affected tissue or hematogenous or lymphatic spread .
lupus vulgaris is the most common type of cutaneous tuberculosis in india and commonly seen in the lower half of the body involving legs , thighs , buttocks , and feet .
it is attributed to the habit of children playing without clothing or shoes and defecating in the open .
pyogenic infection of the gluteal region is also common in india and the breach in the integrity of the skin can serve as a portal of entry for the afb .
the initial lesion is a small , reddish - brown papule or nodule which later forms larger plaques by peripheral enlargement and coalescence that show evidence of healing and scarring in one area and activity in another .
atrophic scarring , with or without ulceration , is a prominent feature of lupus vulgaris .
the common variants are : plaque form , ulcerative and mutilating form , vegetative form , papular and nodular form and tumor - like ( hypertrophic ) form .
the plaque form is the common type that presents as flat plaques with irregular or serpigenous edges , surface may be smooth or covered with psoriasiform scale .
large plaques may show irregular areas of scarring with islands of active lupus tissue , the edge may be thickened and hyperkeratotic .
histopathology shows tuberculoid granulomas composed of lymphocytes , plasma cells , epitheloid cells and giant cells , scant or absent central caseation , in the superficial dermis .
after a thorough search of the literature , the largest size of lupus vulgaris lesion we could find was 30 25 cm .
ours may be the first case showing largest lesions measuring 60 45 cm and 40 50 cm .
other special features in our case were multiplicity ( lv commonly presents as a single lesion ) and extreme chronicity of the lesions , and occurrence at less common sites such as upper limb , chest , and back .
this case also shows the level of ignorance among patients and consequent failure to take proper anti - tuberculous treatment despite extensive campaign in print and audiovisual media .
Output:
| cutaneous tuberculosis continues to be an important public health problem even with the availability of highly effective anti - tuberculous drugs .
it constitutes 0.1% of all cases of extrapulmonary tuberculosis .
lupus vulgaris is the most common form of cutaneous tuberculosis that occurs in previously sensitized individuals with a moderate degree of immunity against tubercle bacilli .
the different types of lupus vulgaris include plaque , ulcerative , vegetative , papular and nodular , and tumor forms . a 40-year - old man presented with large multiple plaques over right upper limb , right side of chest and back , and right lower limb for the past 30 years .
histopathology showed numerous noncaseating granulomas with langhan 's type of giant cells .
the mantoux test showed strong positivity and there was excellent response to anti - tuberculous treatment .
this case is being reported because of its extreme chronicity of 30 years duration , unusually large size and multiplicity of lesions . |
PubmedSumm8874 | ***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: tumors of the pelvis are increasingly being irradiated for local treatment benefit , with the subsequent complication of anorectal injury .
tumors inside the pelvic cavity are suited to receiving radiotherapy as the exposure to healthy tissue can be minimized and high doses can be delivered to the target tumor .
however , the proximity of the rectum to the back of the prostate , the cervix and the uterus makes it anatomically impossible for the rectum not to receive radiation while irradiating these neighbor organs .
the term radiation enteritis refers to radiation injury of the colon and small intestine mucosa characterized by telangiectasias , pallor and friability , while the injury or the rectum due to that cause is referred to as radiation proctitis .
radiation proctitis is usually a result of pelvic irradiation for malignancies of the prostate , cervix , uterus , anus , rectum or urinary bladder and can be subdivided into two types : acute and chronic .
chronic colitis typically presents within 912 months with rectal bleeding or obstructed defecation due to strictures .
in addition , these patients seem to be at increased risk of developing rectal cancer . historically , treatment of rectal strictures has been limited to surgery with a high morbidity and mortality .
therefore , a less invasive therapeutic approach for benign rectal strictures , endoscopic balloon dilation with or without intralesional steroid injection , has become a common method of treatment .
we present a case of benign post - radiation rectal stricture treated successfully with balloon dilation and adjuvant intralesional triamcinolone injection .
a 70-year - old woman presented to the emergency room complaining of 2 weeks of diarrhea and meteorism .
she had been operated for adenocarcinoma of the uterus 11 years before and radiation therapy had been performed for 1 month post - hysterectomy .
she had also been operated for breast cancer 9 years earlier . the regular post - operation follow - up with thorax ,
she also suffered from type 2 diabetes , hypertension and hyperlipidemia and was receiving oral medication ( glimepiride 4 mg once daily 1 1 , sitagliptin ( 50 mg ) + metformin ( 1,000 mg ) 1 1 , perindopril arginine 5 mg 1 1 , nebivolol 5 mg 1 1 , and simvastatin 20 mg 1 1 ) . on physical examination
the patient was mildly dehydrated with a blood pressure of 155/85 mm hg and a heart rate of 98/min .
a stricture was palpated 10 cm from the anus into the rectum at digital rectal examination .
complete blood count revealed a normal leukocyte count ( white blood cells 8,200/l ) with mild neutrophilia ( 80.1% ) , hemoglobin 13 g / dl , hematocrit 39.6% , and platelets 305,000/l .
serum biochemical profile revealed hyperglycemia ( 277 mg / dl ) , normal renal function ( urea 40 mg / dl , creatinine 0.6 mg / dl ) and a c - reactive protein level of 1.35 mg / dl .
colonoscopy revealed a stricture 10 cm from the anus , reducing the rectal lumen to 5 mm in diameter , not allowing the endoscope to pass ( fig .
afterwards , multiple endoscopic biopsies were obtained from the stricture ; a deflated 17 mm guidewire - bearing dilating balloon , 5.5 cm long ( rigiflex , boston scientific , nattick , mass . ,
usa ) , was passed through the endoscope and was advanced through the stricture over the guidewire under direct endoscopic guidance .
the balloon was inflated to maximum pressure according to the manufacturer 's instructions ( fig .
after the dilation , the endoscope could be advanced through the stricture , which was 6 cm .
after satisfactory dilation had been achieved , triamcinolone ( 2 ml of 40 mg / ml diluted to 10 ml with normal saline ) was injected quadrantically into the stricture using a varix injection catheter with a 5 mm needle .
the procedure was uneventful ; the post - procedure abdominal x - ray was negative for pneumoperitoneum and the patient was discharged after 24 h without any treatment .
histologic examination of the biopsies revealed non - specific inflammatory changes of the rectal mucosa and no specific changes of the mucosa due to radiation .
the patient is stricture - free 12 months post - treatment as confirmed by repeated flexible endoscopy .
rectal strictures are chronic narrowings of the intestinal lumen by abnormal tissue , resulting in complete or partial bowel obstruction . this tissue may be scar tissue resulting from chronic rectal or anal inflammation , trauma , foreign bodies , prior surgery , perianal fistulas or pelvic irradiation . '
radiation enteritis ' refers to injury of the colon and small intestine after radiation and can be subdivided into acute and chronic . for radiation injuries of the rectum , the term radiation proctitis is used . in acute radiation enteritis , histopathological changes of intestinal mucosa are inflammatory cell infiltrate , reduced crypt micro - abscesses , epithelial denudation and ulceration .
patients with acute radiation enteritis or proctitis present diarrhea , abdominal pain or rectal bleeding shortly after a course of radiotherapy , but can be presented within 3 months .
histologic features of chronic radiation enterocolitis are obliterative endarteritis , lymphatic dilation , tissue ischemia and necrosis , submucosal fibrosis and collagen deposition , which can lead to severe transmural fibrosis and formation of strictures or fistulas .
chronic radiation colitis has been reported in up to 20% of patients receiving radiation in the pelvis , and the rate of intestinal obstruction due to strictures is referred to as 115% .
there are also patient and treatment factors which may increase the risk of developing chronic radiation colitis .
these factors include low body mass index , co - morbid conditions ( diabetes , hypertension , collagen vascular diseases , inflammatory bowel disease ) , smoking , volume of bowel inside the radiation field , radiotherapy dose , radiotherapy technique and simultaneous chemotherapy .
the clinician should have chronic radiation colitis in mind while evaluating patients with bowel obstruction after radiation therapy , especially in the pelvis .
patients affected by post - radiation strictures display obstructing symptoms , including diarrhea or tenesmus often producing narrow ribbons of feces or no feces at all . abdominal pain and
vomiting may occur in response to a stricture , but combined with a history of weight loss can also occur secondary to recurrent neoplasia .
the importance of this was presented by andreyev et al . , who reported the incidence of new or recurrent neoplasia with gastrointestinal symptoms 2 years after radiation of the pelvis in around 12% of patients , making this a common diagnosis .
patients with colonic symptoms must be investigated with colonoscopy , while patients with non - specific gastrointestinal symptoms should be investigated with ct with or without enteroclysis , looking for a tumor . in our patient ,
ct was unremarkable , while histopathology of biopsy specimens from the stricture during colonoscopy revealed inflammatory mucosal changes , compatible with but not specific for chronic radiation colitis , and was negative for malignancy .
traditionally , surgical techniques , such as line rectal pull - through , myotomy or stricturoplasty , have been performed to manage rectal strictures .
however , post - operative complications can occur in up to 30% , around half of the patients will require more than one surgery , and one third of them die in hospital .
surgery in these patients is complicated because of the extensive fibrosis and adhesions in the pelvis and should be avoided if possible .
endoscopy has recently gained an important role in chronic radiation colitis , with therapeutic options such as argon plasma coagulation for angiodysplastic lesions and balloon dilation for management of intestinal strictures .
endoscopic placement of self - expanding metallic stents has been used for management of malignant strictures , alternatively to surgery .
the success rate was extremely high ( < 92% ) and reported a complication rate < 5% .
there is also a case report in which a radiation stricture of the rectosigmoid was successfully treated with self - expanding metallic stents , and obstructing symptoms were relieved in a patient who lived without any complications for 4 months until he died of sepsis due to pneumonia and bedsores .
endoscopic balloon dilation is effective for managing both surgical anastomotic strictures and inflammatory disease strictures , with an up to 97% success rate and major complications < 3% . in a systematic review , hassan et al .
presented the results of 13 studies enrolling 347 patients treated with balloon dilation due to post - surgical anastomotic crohn 's strictures .
it is reported that 58% of the patients avoided surgery until 36 months of follow - up , while 59% of them needed a single session , 22% required 2 sessions , and 19% required more than 2 sessions with range from 3 to 18 .
presented the results of 17 patients who underwent balloon dilation due to pharyngoesophageal strictures caused by radiotherapy of the head and neck .
clinical success was achieved in 64.7% of patients with mean range of 2.4 sessions ( range 17 sessions ) . moreover
, intralesional steroid injection has been used together with balloon dilation to treat patients with colorectal anastomotic strictures or strictures secondary to crohn 's disease .
adjuvant intralesional steroid injection is safe and only adds a few minutes in procedure time .
, in a study of dermal keloids , reported that triamcinolone seems to inhibit collagen formation , enhance collagen breakdown and prevent cross - linking of collagen that results in scar contracture .
intralesional use of triamcinolone appears to enhance the effect of balloon dilation and even prolong the relapse interval .
post - radiation stricture is a rare complication after pelvis irradiation , but must be in the mind of the clinician evaluating a lower gastrointestinal obstruction .
endoscopic balloon dilation with adjuvant intralesional steroid injection can be a minimally invasive , safe and effective treatment option for the management of post - radiation benign rectal strictures .
the procedure appears to have a high success rate and a very low complication rate .
an alternative treatment option is the endoscopic placement of a metallic stent in the stricture area , and last choice surgery , a procedure with very high morbidity and mortality rates .
Output:
| post - radiation stricture is a rare complication after pelvis irradiation , but must be in the mind of the clinician evaluating a lower gastrointestinal obstruction .
endoscopy has gained an important role in chronic radiation proctitis with several therapeutic options for management of intestinal strictures .
the treatment of rectal strictures has been limited to surgery with high morbidity and mortality .
therefore , a less invasive therapeutic approach for benign rectal strictures , endoscopic balloon dilation with or without intralesional steroid injection , has become a common treatment modality .
we present a case of benign post - radiation rectal stricture treated successfully with balloon dilation and adjuvant intralesional triamcinolone injection . a 70-year - old woman presented to the emergency room complaining for 2 weeks of diarrhea and meteorism , 11 years after radiation of the pelvis due to adenocarcinoma of the uterus .
colonoscopy revealed a stricture at the rectum and multiple endoscopic biopsies were obtained from the stricture .
the stricture was treated with endoscopic balloon dilation and intralesional triamcinolone injection .
the procedure appears to have a high success rate and a very low complication rate .
histologic examination of the biopsies revealed non - specific inflammatory changes of the rectal mucosa and no specific changes of the mucosa due to radiation .
all biopsies were negative for malignancy .
the patient is stricture - free 12 months post - treatment . |
PubmedSumm8875 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: this supplement was made possible by the generous support of the american people through the support of the office of health , infectious diseases , and nutrition , bureau for global health , u.s .
agency for international development ( usaid ) , under the terms of grant number ghag000600002 to the global alliance for improved nutrition ( gain ) and by the bill and melinda gates foundation .
the contents are the responsibility of gain and do not necessarily reflect the views of usaid , the united states government or the bill and melinda gates foundation .
Output:
| abstractthe few available studies of programme effectiveness in nutrition find that programmes are less effective than would be predicted from the efficacy trials that are the basis for evidencebased programming .
some of these are due to gaps in utilisation within households . to a greater extent
, these gaps can be attributed to problems in programme design and implementation .
implementation research in nutrition is an emerging area of study aimed at addressing this problem , by building an evidence base and a sound theory to design and implement programmes that will effectively deliver nutrition interventions .
the purpose of this supplement to maternal & child nutrition is to contribute to this growing area of implementation research .
the series of papers presented and the reflections for policymaking and programmes , combined with the reflections on the application of ethnography to this area of inquiry , illustrate the value of systematic research undertaken for the purpose of supporting the design of nutrition interventions that are appropriate for the specific populations in which they are undertaken .
2015 blackwell publishing ltd |
PubmedSumm8876 | ***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: functional and structural ( mri ) brain data for each animal were co - registered to a standard space based on an age - appropriate rhesus monkey brain template .
whole - brain linear regression analyses examined the relations between fdg uptake and at . to account for potential confounds , age and sex
gray matter probability was also included as a voxelwise covariate to account for the possibility that structural differences affected the relation between brain metabolic activity and at .
the resulting 3d t - map was corrected for multiple comparisons using the idk equation ( 1 ( 1 )1 / n ) , which is similar to the bonferroni method and determined the statistical threshold of p=0.05 , corrected ( t > 5.47 ) . to estimate the heritability of at , phenotypic covariance / correlation amongst pairs of relatives was modeled as a function of expected pairwise kinship values to estimate the magnitude of additive genetic variance relative to that of the observed phenotypic variance .
age , age and sex were included in the mean effects model as covariates to control for these potential confounds .
the resulting heritability data were corrected for multiple comparisons based on the total volume of all the clusters correlated with at using a false discovery rate ( fdr ; q - value = 0.05 ) .
measured genotype analyses use the same variance components approach as the heritability analyses , and were implemented using solar .
measured genotype analyses simultaneously estimate the effect of specific genotypic differences among animals and the overall effect of pair - wise kinship , thus testing for the effect of a single polymorphism while accounting for background allele sharing across the genome due to genealogical relatedness .
Output:
| anxious temperament ( at ) in human and non - human primates is a trait - like phenotype evident early in life that is characterized by increased behavioural and physiological reactivity to mildly threatening stimuli 14 .
studies in children demonstrate that at is an important risk factor for the later development of anxiety disorders , depression , and comorbid substance abuse 5 . despite its importance as an early predictor of psychopathology , little
is known about the factors that predispose vulnerable children to develop at and the brain systems that underlie its expression . to characterize the neural circuitry associated with at and the extent to which the function of this circuit is heritable
, we performed a study in a large sample of rhesus monkeys phenotyped for at . using 238 young monkeys from a multigenerational single - family pedigree , we simultaneously assessed brain metabolic activity and at while monkeys were exposed to the relevant ethological condition that elicits the phenotype .
high - resolution 18f - deoxyglucose positron emission tomography ( fdg - pet ) was selected as the imaging modality since it provides semi - quantitative indices of absolute glucose metabolic rate , allows for simultaneous measurement of behaviour and brain activity , and has a time course suited to assess temperament - associated sustained brain responses .
results demonstrated that the central nucleus region of amygdala and the anterior hippocampus are key components of the neural circuit predictive of at .
quantitative genetic analysis demonstrated significant heritability of the at phenotype .
additionally , a voxelwise analysis revealed significant heritability of metabolic activity in at - associated hippocampal regions . however , activity in the amygdala region predictive of at was not significantly heritable .
furthermore , the heritabilities of the hippocampal and amygdala regions significantly differed from each other .
even though these structures are closely linked , the results suggest differential influences of genes and environment on how these brain regions mediate at and the ongoing risk to develop anxiety and depression . |
PubmedSumm8877 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: recently , transrectal color doppler sonography has been reported to be a very useful tool for measuring local blood flow in the female bovine reproductive tract .
this technique allows estimation of the corpus luteum ( cl ) physiological status since blood flow on the cl parenchyma reflects its structural and functional development .
moreover , acosta and miyamoto hypothesized that in the preovulatory follicle , in the developing and in mature cl in cattle , structural and functional changes of the vasoactive system occur .
luteal blood flow ( lbf ) gradually increases after ovulation along with increases in cl volume and plasma p4 concentrations from days ( d ) 2 to d5 of the estrus cycle .
lbf doubles during the static phase ( d8~16 ) and decreases rapidly during luteal regression ( d17~21 ) .
the cl is one of the few adult tissues that exhibit regular periods of growth ( cl formation ) , hormonal excretion , and luteolysis ( cl regression ) .
cl growth is predominantly regulated by angiogenic and luteotropic factors such as growth factors ( i.e. , insulin - like growth factors-1 and -2 ) , oxytocin ( oxy ) , and lh .
regression is initiated by luteolytic pgf2 secreted by the endometrium and is promoted by a complex and not well - elucidated cascade of mediators that include oxy .
it appears that oxy is not a main factor in the initiation of luteolysis in cattle although it can play a supporting and modulating role in early stages of luteolysis , as postulated in sheep and cattle . on the other hand
, oxy has a stimulatory effect on progesterone ( p4 ) secretion which is highest on d5~7 of the estrus cycle and declines from d8 to d12 .
therefore , it was suggested that luteal oxytocin affects the luteal function as a luteotropic or luteolytic autocrine / paracrine factor within the cl depending on the day of the luteal phase .
the purpose of this study was to investigate the effect of oxy administration on cl function during early to mid - diestrus by measuring luteal size ( ls ) and blood flow as well as peripheral plasma levels of p4 .
this experiment was conducted at the clinic for cattle of the university of veterinary medicine , hanover ( germany ) in seven non - lactating multiparous holstein - friesian cows .
the study was approved and conducted in accordance with the german legislation on animal welfare ( lower saxony federal state office for consumer protection and food safety , hannover , germany ) .
the animals were housed in tied stall barns and had ad libitum access to hay and water .
they were healthy and examined for any reproductive tract abnormalities before enrollment in the experiment .
afterwards , all cycling cows underwent an ovulation - synchronization ( ovsynch ) protocol in which they received a gonadotropin - releasing hormone ( gnrh ) ( 2.5 ml ; 10 g , intramuscularly ( i m ) ; receptal ; intervet , usa ) , prostaglandin f2 ( pgf2 , 2 ml ; 0.526 mg , i m ; estrumate ; intervet , usa ) 7 days later , and then gnrh ( 10 g , i m ) 48 h after pgf2 administration . at the time of the second gnrh administration
, the size of the ovulatory follicle was measured with b - mode sonography ( 8 mhz ; general electric , usa ) .
the time of ovulation ( d1 ) was determined by the disappearance of the ovulatory follicle between two consequent examinations performed at 24 , 28 , and 36 h after the last gnrh injection .
on d7 , the cows randomly received oxy ( 100 iu , 10 ml , oxykel ; agroscience , germany ) or placebo ( pl ; 10 ml of 0.9% sodium chloride ) diluted in 1,000 ml of 0.9% sodium chloride solution .
, the ovaries were evaluated by transrectal sonography to determine that the cl had no cystic cavity .
on d10 , a second ovsynch protocol was initiated in all cows with the animals assigned into the different oxy and pl groups receiving the exact reversed treatment protocol , according to a latin square model .
size and blood flow of the cl were examined with b - mode and power doppler sonography ( 10 mhz ; ge healthcare , usa ) , respectively , just prior to and 0.5 , 1 , 1.5 , 2 , 3 , 5 , 12 , 24 , 36 , 48 , 60 , and 72 h after infusion commencement .
lbf was determined by the relative blood flow area (= maximum blood flow area near the maximum cross sectional area of the cl / maximum cross sectional area of the cl ) .
the number of pixels with color was determined as a semiquantitative assessment of lbf using computer assisted image analysis software ( pixelflux ; chameleon software , germany ) .
three images each showing the maximum blood flow area and maximum cross sectional area of the cl were captured .
criteria for image selection included ones showing structures of interest that lacked artifacts , had constant color intensity and had intact borders with blood flow .
blood samples were collected via indwelling jugular catheters just before oxy infusion and every 15 min for two hours after commencing infusion .
after this period , blood was collected every 30 min for another 6 h and just after the sonographic examinations .
all blood samples were collected in evacuated tubes containing ethylenediaminetetraacetic acid as an anticoagulant ( s - monovette ; sarstedt , germany ) .
the samples were stored on ice until they were centrifuged ( 3,500 g for 15 min at 4 ) within 30 min after collection , and the plasma was stored at -20 until hormone analyses .
progesterone and prostaglandin metabolites ( 13,14-dihydro-15-keto - prostaglandin f2 , pgfm ) were measured by an enzyme immunoassay according to prakash et al . and mishra et al . ( monoclonal anti - p4 antibody , p-1922 ; sigma , usa ; polyclonal anti - pgfm antibody , provided by professor dr .
meyer , institute for physiology , technical university of munich , germany ; enzymes : 4-pregnen-3 , 20-dione-3-o - carboxymethyloxime - horseradish peroxidase and pgfm - horseraddish peroxidase ) .
the intra- and interassay coefficients of variation for p4 were both less than 10% ; for pgfm , these coefficients were less than 7% and less than 10% , respectively .
a shapiro - wilk test was performed for all outcome variables to determine the underlying distribution of the data .
anova using a general linear model within subject effects across time was conducted using proc glm ( sas , usa ) .
student 's t - test was used to evaluate differences within animals at a specific time point using proc univariate ( sas , usa ) .
this experiment was conducted at the clinic for cattle of the university of veterinary medicine , hanover ( germany ) in seven non - lactating multiparous holstein - friesian cows .
the study was approved and conducted in accordance with the german legislation on animal welfare ( lower saxony federal state office for consumer protection and food safety , hannover , germany ) .
the animals were housed in tied stall barns and had ad libitum access to hay and water .
they were healthy and examined for any reproductive tract abnormalities before enrollment in the experiment .
afterwards , all cycling cows underwent an ovulation - synchronization ( ovsynch ) protocol in which they received a gonadotropin - releasing hormone ( gnrh ) ( 2.5 ml ; 10 g , intramuscularly ( i m ) ; receptal ; intervet , usa ) , prostaglandin f2 ( pgf2 , 2 ml ; 0.526 mg , i m ; estrumate ; intervet , usa ) 7 days later , and then gnrh ( 10 g , i m ) 48 h after pgf2 administration . at the time of the second gnrh administration
, the size of the ovulatory follicle was measured with b - mode sonography ( 8 mhz ; general electric , usa ) .
the time of ovulation ( d1 ) was determined by the disappearance of the ovulatory follicle between two consequent examinations performed at 24 , 28 , and 36 h after the last gnrh injection .
on d7 , the cows randomly received oxy ( 100 iu , 10 ml , oxykel ; agroscience , germany ) or placebo ( pl ; 10 ml of 0.9% sodium chloride ) diluted in 1,000 ml of 0.9% sodium chloride solution .
, the ovaries were evaluated by transrectal sonography to determine that the cl had no cystic cavity .
on d10 , a second ovsynch protocol was initiated in all cows with the animals assigned into the different oxy and pl groups receiving the exact reversed treatment protocol , according to a latin square model .
size and blood flow of the cl were examined with b - mode and power doppler sonography ( 10 mhz ; ge healthcare , usa ) , respectively , just prior to and 0.5 , 1 , 1.5 , 2 , 3 , 5 , 12 , 24 , 36 , 48 , 60 , and 72 h after infusion commencement .
lbf was determined by the relative blood flow area (= maximum blood flow area near the maximum cross sectional area of the cl / maximum cross sectional area of the cl ) .
the number of pixels with color was determined as a semiquantitative assessment of lbf using computer assisted image analysis software ( pixelflux ; chameleon software , germany ) .
three images each showing the maximum blood flow area and maximum cross sectional area of the cl were captured . the average from these three images
criteria for image selection included ones showing structures of interest that lacked artifacts , had constant color intensity and had intact borders with blood flow .
blood samples were collected via indwelling jugular catheters just before oxy infusion and every 15 min for two hours after commencing infusion .
after this period , blood was collected every 30 min for another 6 h and just after the sonographic examinations .
all blood samples were collected in evacuated tubes containing ethylenediaminetetraacetic acid as an anticoagulant ( s - monovette ; sarstedt , germany ) .
the samples were stored on ice until they were centrifuged ( 3,500 g for 15 min at 4 ) within 30 min after collection , and the plasma was stored at -20 until hormone analyses .
progesterone and prostaglandin metabolites ( 13,14-dihydro-15-keto - prostaglandin f2 , pgfm ) were measured by an enzyme immunoassay according to prakash et al . and mishra et al . ( monoclonal anti - p4 antibody , p-1922 ; sigma , usa ; polyclonal anti - pgfm antibody , provided by professor dr .
meyer , institute for physiology , technical university of munich , germany ; enzymes : 4-pregnen-3 , 20-dione-3-o - carboxymethyloxime - horseradish peroxidase and pgfm - horseraddish peroxidase ) .
the intra- and interassay coefficients of variation for p4 were both less than 10% ; for pgfm , these coefficients were less than 7% and less than 10% , respectively .
a shapiro - wilk test was performed for all outcome variables to determine the underlying distribution of the data .
anova using a general linear model within subject effects across time was conducted using proc glm ( sas , usa ) .
student 's t - test was used to evaluate differences within animals at a specific time point using proc univariate ( sas , usa ) .
the luteal size did not differ between the two groups at any time point ( fig .
however , the size of the cl increased significantly over time in both groups ( p = 0.02 and p = 0.001 for the pl and oxy groups , respectively ) .
although the lbf increased from 0.3~0.4 cm to 0.7 cm in both groups , this difference was not significant ( fig .
plasma pgfm was not significantly different within the groups over time or between the groups at any time point ( fig .
however , it should be mentioned that the animals in the oxy group showed greater variability compared to the pl group as demonstrated by the substantially larger se for the oxy group ( fig .
4 ) . specifically , the p4 values tended to increase over time in the oxy group ( p = 0.07 ) whereas there was no significant change in the pl group ( p = 0.14 ) .
moreover , the p4 levels of the oxy group differed significantly from those of the pl group 360 min after the infusion ( 4.2 vs. 3.1 ng / ml , p = 0.01 ) and tended to be higher at 450 min , 48 h , and 72 h ( p = 0.08 for all ) .
increased blood flow during normal cl development underlines the importance of angiogenesis during this process because nearly every parenchymal cell in the mature cl is in contact with one or more capillaries .
the limited number of animals and large variation of the data in the present study were probably the reasons why increases in blood flow we observed did not reach statistical significant .
although lh and pgf2 are two of the primary endocrine factors controlling bovine cl function , modulatory or supporting roles of oxy in luteal development and regression have also been reported . in the present study oxy administration had no effect on the development of cls , which continued to increase in size .
d7 of the estrus cycle coincides with the onset of the first follicular wave and a relatively increased concentration of estrogen .
it was previously reported that estrogens enhance the formation of endometrial oxy receptors , but p4 reduces the concentration of endometrial oxy receptors during the luteal phase by blocking the estrogen action . on the other hand ,
a fully functional cl is present at the ovary on d7 and thus p4 production is high .
it is also known that the expression of oxy mrna level is high during the early luteal phase in bovine cls .
based on these findings , continuous infusion of high doses of oxy during the early luteal phase would be expected to alter p4 concentrations .
however , only a weak effect was observed in the present study similar to previous findings
. the supporting role of oxy to p4 concentration diminishes from d7 onwards of the estrus cycle .
this could explain why there was a tendency for p4 concentrations to increase in the present study , since the cls of some cows were still sensitive to oxy while others were not .
. recently confirmed this dual role of luteal oxy as luteotropic ( during the early luteal and mid - luteal phases ) and luteolytic ( during the late luteal phase after initiation of the luteolytic cascade ) , highlighting the modulatory effect of oxy on local secretion of vasoactive substances within the cl .
infusion of oxy in sheep has been previously reported to evoke a modest increase in pgf2 secretion during the early and late but not the mid - luteal phases .
it seems likely that cyclical variation in the ability of oxy to evoke uterine pgf2 secretion is due to cyclical changes in the concentration of endometrial oxy receptors .
have also reported that there is no increase in pgfm ( a stable metabolite of pgf2 ) concentration after oxy administration .
results of the present study , showing that oxy administration had no effect on endometrial production of pgf2 ( measured as pgfm ) , support these findings .
it is worth mention that large variations in pgfm concentrations were detected within both groups in our study .
this could reflect variation of pgf2 secretion as early as d7 in each animal since high or low concentrations were detected in the same animals regardless the group they were assigned to in the latin square design ( data not shown ) .
it was previously reported that luteolytic doses of pgf2 affect blood flow in the mature cl .
in contrast , no change in blood flow was observed in developing cls ( d4 ) after pgf2 administration since plasma p4 levels and cl volume continues to increase after pgf2 administration . in the present study , oxy administration did not cause any increase in pgfm concentration .
although the cl is sensitive to luteolytic doses of pgf2 during mid - cycle ( d7 ) , it seems unaffected by oxy administration , even at relative high doses ( 100 iu ) .
the possible explanations for this observation are either that there were not enough oxy receptors in the uterus , or there was not enough available pgf2 that could be released from the uterus .
nevertheless , the fact that there were no changes in cl blood flow , which continued to increase during and after infusion , supports the hypothesis , that oxy is not directly involved in the mechanism(s ) governing blood flow in the developing cl .
further investigation is needed to elucidate the role of oxy in cl blood flow during different periods of the luteal phase .
Output:
| the objective of this study was to investigate the effects of oxytocin infusion on corpus luteum ( cl ) function during early to mid - diestrus by measuring luteal size ( ls ) and luteal blood flow ( lbf ) along with plasma levels of progesterone ( p4 ) and prostaglandin metabolites ( 13,14-dihydro-15-keto - prostaglandin f2 , pgfm ) . on day ( d ) 7 of the estrus cycle ( d1 = ovulation ) , seven cows received 100 iu of oxytocin ( oxy ) or placebo ( pl ) following a latin square design .
ls and lbf increased in both groups over time and no differences were observed between the groups .
pgfm did not differ either within the groups over time or between the groups at any time point .
p4 of the oxy group was higher compared to that of the the pl group 360 min after the infusion ( p = 0.01 ) and tended to be higher at the time points 450 min , 48 h , and 72 h ( all p = 0.08 ) .
results from this study support the hypothesis that oxy is not directly involved in the mechanism(s ) governing blood flow of the cl and has no remarkable effects either on luteal size or p4 and pgfm plasma levels .
further investigation is needed to elucidate the role of oxy in cl blood flow during early and late luteal phases . |
PubmedSumm8878 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: congenital cataract is the leading cause of treatable blindness in children worldwide [ 13 ] .
surgical management of congenital cataracts is a challenging task because of the elastic capsule , high pressure of the posterior chamber , and elevated inflammatory reaction due to irritation of the iris . in the mid-1970s , the utilization of vitreous suction - cutting devices to perform primary posterior capsulotomy and anterior vitrectomy revolutionized pediatric cataract surgery [ 4 , 5 ] . the introduction of microincision vitrectomy instruments further minimized surgically induced trauma and inflammation and therefore hastened postoperative recuperation and enabled immediate optical correction and amblyopic treatment [ 6 , 7 ] .
there are two approaches to performing primary capsulotomy and anterior vitrectomy using the microincision vitrectomy system for the management of congenital cataracts : through the limbus [ 811 ] and through the pars plana [ 1214 ] . when managing infantile congenital cataract without primary intraocular lens ( iol ) implantation , the pars plana approach has the advantages of a more sufficient lensectomy and anterior vitrectomy , reduced surgical trauma , and postoperative inflammation , and therefore it is recommended by most surgeons [ 1214 ] . when managing older children with primary iol implantation , another limbal incision is required and the surgical procedure is complex .
some studies have advocated the limbal approach for the advantages of more precise manipulations under direct vision , a more stable anterior chamber , and a shorter learning curve .
we also used the limbal approach for pediatric congenital cataract , but the problem of increased irritation to the iris resulting in elevated inflammatory reactions could not be ignored [ 810 ] . despite the advantages and disadvantages of the two approaches presented in past studies , including ours , the current management of congenital cataract uses the microincision vitrectomy system with only a single one of the above - mentioned approaches .
the question regarding which approach is more appropriate for the management of cataracts in older children with primary iol implantation remains unaddressed .
we therefore conducted a retrospective study to compare the visual outcomes and adverse events of the limbal versus the pars plana approaches .
we retrospectively reviewed all patients with congenital cataracts who underwent cataract removal through a limbal or a pars plana incision using a 23-gauge vitrectomy system with primary iol implantation between august 2009 and august 2013 at the eye and ent hospital of fudan university .
patients who underwent the cataract surgery through the limbal approach were included in the limbal group .
children who had cataract removal using a pars plana approach were included in the pars plana group .
exclusion criteria were traumatic , subluxated , or complicated cataracts and evidence of any ocular or systemic anomalies .
this study was carried out with the approval of the institutional review board of the eye and ent hospital of fudan university and in accordance with the declaration of helsinki .
each patient underwent a detailed preoperative evaluation under sedation by chloral hydrate including intraocular pressure ( iop ) measurement , slit - lamp examination , corneal endothelial cell density ( ecd ) calculation , and b ultrasound .
axial length was measured by an ultrasonic a - scan ( nidek us-800 ; nidek , fremont , ca , usa ) .
all surgeries were performed under general anesthesia by one surgeon ( y. luo ) with the millennium microsurgical system ( alcon , fort worth , tx , usa ) and the 23-gauge microincision vitrectomy system . for children in the limbal group
, cataract surgery was performed through two limbal incisions made by a 23-gauge trocar with a microcannula .
a 23-gauge infusion cannula was inserted through the 4 or 8 o'clock limbal incision to maintain the anterior chamber with balanced salt solution ( bss ; alcon ) .
a cutting tip of the 23-gauge vitrectomy instrument was introduced through an incision at the 12 o'clock position .
lens material was removed at a cutting rate of 600 cuts per minute and a maximum suction pressure of 400 mmhg ( figures 1(a ) and 1(b ) ) .
a posterior capsulotomy of 4.04.5 mm diameter was created followed by a limited anterior vitrectomy ( figures 1(c ) , 1(d ) , and 2 ) .
the microcannula at the 12 o'clock incision was then removed without suturing ( see video 1 in supplementary material available online at http://dx.doi.org/10.1155/2016/8951053 ) . for children in the pars plana group ,
briefly , a 23-gauge infusion cannula was inserted through a limbal port incision to maintain the anterior chamber with bss .
a pars plana incision was made at the 10 o'clock position and a 23-gauge vitrectomy cutter with a microcannula was introduced . because the pars plana is not well developed in young children , the options for the sclerotomy sites differ according to each patient 's age . in our series
, a sclerotomy site was chosen 2.5 mm posterior to the limbus in patients aged 1.5 to 3 years and 3.0 mm in those aged 3 to 6 years .
a central anterior capsulotomy , lensectomy , posterior capsulotomy , and limited anterior vitrectomy were performed using the cutter at the same setting described above ( figures 3(a)3(d ) and 4 ) .
the microcannula at the pars plana incision was then removed without suturing ( supplementary material , video 2 ) .
for eyes in the limbal group , the 12 o'clock limbal incision was enlarged to 2.6 mm .
for eyes in the pars plana group , another 2.6 mm limbal incision was made at the 12 o'clock position .
after the ophthalmic viscosurgical device ( ovd ) ( discovisc ; alcon ) was injected , a one - piece foldable iol ( acrysof sa60at ; alcon ) was implanted into the capsular bag ( figures 1(e ) and 1(f ) ) .
the limbal incision was closed with one or two 10 - 0 nylon sutures ( ethilon 9033 ; allmedtech , beverley hills , ca , usa ) , and the corneal stroma at the limbal side port was hydrated with bss after removal of the infusion cannula ( figures 3(e ) and 3(f ) ; supplementary material , videos 1 and 2 ) .
postoperatively , topical eyedrops containing 0.3% tobramycin and 0.1% dexamethasone were used three times daily for 2 weeks , and pranoprofen ophthalmic solution was used three times daily for 1 month .
spectacles or contact lenses were prescribed to correct any residual refractive error in pseudophakic eyes . in unilateral cases , occlusion therapy for the fellow eye
the patients were examined postoperatively at 1 day , 1 week , and 1 month and at intervals of 3 months thereafter .
each examination included a complete ophthalmological evaluation and update of optical correction and monitoring of amblyopia treatment .
definitions for intraoperative complications were as follows : iris prolapse , extrusion of the iris through the operative wound during surgery ; iris aspiration , inadvertent aspiration of iris tissue by the vitrector with or without subsequent injury to the iris during surgery ; iris injury , permanent structural change to the iris occurring during surgery ; lens fragments in the vitreous , known loss of lens fragments into the vitreous requiring a pars plana approach for removal ; and tear of the posterior capsule , tear of the posterior capsule to the equator of the lens during the procedure .
best - corrected visual acuity ( bcva ) data were converted to the logarithm of the minimum angle of resolution ( logmar ) scores for statistical analysis .
numerical variables were compared using a t - test or wilcoxon rank sum test for independent samples and a paired student 's t - test for paired samples . a p value of < 0.05 was considered statistically significant .
all analyses were conducted using spss , version 16.0 ( spss inc . , chicago , il , usa ) .
this retrospective study consisted of 40 eyes of 26 children who underwent cataract surgery through a limbal approach ( limbal group ) , and 41 eyes of 30 children had removal of lens material using a pars plana approach ( pars plana group ) .
the follow - up period was significantly longer in the pars plana group compared with the limbal group ( p < 0.001 ) .
preoperatively , 41 patients ( 56 eyes , 69.1% ) could cooperate with measurement of visual acuity . at last follow - up
the mean logmar bcva was significantly improved after cataract surgery ( p < 0.001 ) .
twenty - six eyes ( 65.0% ) in the limbal group and 25 eyes ( 61.0% ) in the pars plana group had a logmar bcva of 0.3 or less .
the significantly higher mean refraction at last follow - up in the limbal group ( p = 0.001 ) was associated with the shorter follow - up period resulting in younger ages at last follow - ups ( table 2 ) .
there were significantly more eyes with one or more intraoperative complications in the limbal group than in the pars plana group ( p = 0.032 ) ( table 3 ) .
there were significantly more eyes with iris aspiration in the limbal group than the pars plana group ( p = 0.005 ) .
ten of the 13 incidences in the limbal group and the three in the pars plana group of iris aspiration resulted in no known adverse sequelae because of immediate release of the iris .
iris prolapse usually occurred during limbal incision made for iol placement or during iol implantation .
one eye in the limbal group resulted in iris incarceration in the 12 o'clock limbal incision the first day after surgery and required surgery to reposition the iris . in the other case of iris injury , and following iris aspiration , a 11 mm defect of the iris resulted in a pupil that was not round .
the other three cases were minor defects of less than 0.5 mm in diameter .
a three - piece iol ( ar40e ; amo , santa ana , ca , usa ) was implanted in the sulcus .
lens fragments in the vitreous occurred in one eye of the limbal group and necessitated a pars plana approach to removing it at the time of original surgery .
further analyses of the age distribution of eyes with intraoperative complications found significantly more eyes within the age range of 1.53 years in the limbal group versus the pars plana group ( table 4 ) .
thirteen eyes had a three - piece iol implanted in the sulcus . besides the eight eyes with posterior capsule tears , the others had large posterior polar cataracts and a posterior capsulotomy of 5.56.0 mm was made .
more eyes in the limbal group developed postoperative complications and required additional intraocular surgery though the difference was not significant ( table 3 ) .
the optimal surgical technique for the removal of congenital cataracts in children using the microincision vitrectomy system remains unknown .
the decision on whether to use the limbal or the pars plana approach requires balancing the visual benefits of the surgery against the risks associated with the procedure . during the follow - up period
, there were no significant differences between the mean logmar bcva in eyes with congenital cataract that were operated on with either the limbal approach or the pars plana approach .
however , in our hands , there were significantly more intraoperative complications and a trend of more postoperative complications using the limbal approach .
children 's delay in presentation for congenital cataract surgery is common in developing countries , making the visual rehabilitation more challenging for the ophthalmologists [ 1621 ] .
the mean delay between identification and surgery was 20.7 months to more than 8 years in different studies [ 1620 ] .
reported a mean delay of presentation for surgery of 35.7 months in pediatric patients with congenital cataract in china .
lack of awareness , access to medical resources , and financial burdens deprive many children with congenital cataract of timely surgical treatment [ 20 , 22 ] .
delayed surgical treatment is the major reason for severe visual impairment in pediatric patients with cataract in china .
deep seated amblyopia occurred in these patients and aggressive amblyopic treatment after surgery is required .
although most cases surpassed the critical timing for surgery , performing cataract operation as soon as possible was the only effective option for these patients . even in cases with years of delay for cataract treatment , visual improvement could still be achieved after cataract removal [ 1820 ] .
postoperatively , appropriate optical correction and amblyopic treatment were initiated and efforts were made to encourage development of binocular function .
early detection of congenital cataract has been fulfilled by routine birth detection in developed countries , which makes it possible for ophthalmologists to perform cataract surgery at the proper time . in china , more ophthalmologists are now making great efforts to avoid visual impairment resulting from late detection and surgery for congenital cataract .
establishment of a national screening system to ensure that all newborns are assessed for lens opacities , training of screening doctors and community medical practitioners , and education to caregivers of infants are of vital significance to enable children to access timely detection and treatment of congenital cataract [ 19 , 21 , 22 ] . to achieve good visual outcomes , a minimally invasive surgical procedure that accelerates postoperative recovery and enables immediate optical correction and
the 25-gauge vitrectomy system has some limitations in the removal of less soft crystalline lenses or dense membranes and is only suitable for very young children .
the 23-gauge vitrectomy system offers improvements in cutter efficiency and rigidity and is suitable for older children [ 5 , 8 ] .
reported that no visual acuity , iol position , or postoperative complications were found to be statistically significant between the limbal versus pars plana approach with primary capsulotomy , anterior vitrectomy , lensectomy , or posterior chamber iol implantation in children using the 20-gauge vitrectomy system .
more complications were associated with disturbance and irritation to the iris in the limbal group . manipulating the surgical instruments in the relatively small space of the shallow anterior chamber of children was a technical challenge when first using the technique in children .
inadvertent aspiration of iris tissue with the vitrectomy probe was common during the lensectomy and capsulotomy procedure , especially in eyes with small pupils .
ways to reduce iris prolapse and having the iris enter the cutting tip are as follows : ( a ) full dilation of the pupil ; ( b ) deep level of general anesthesia using a depolarizing agent prior to making the first incision ; ( c ) using intravenous mannitol if the globe is not sufficiently soft ; ( d ) low flow on the infusion ; ( e ) using a coaxial sleeve for irrigation around the cutting instrument ; ( f ) biplanar incision construction ; ( g ) using the incision as the fulcrum when repositioning the cutting tip . using the incision to move the globe will stretch the incision , and prolapse will occur .
immediate release of the iris when iris aspiration occurs could help reduce the rate of iris injury . in cases of iris prolapse ,
injection of an ophthalmic viscosurgical device for repositioning and another suture for limbal incision are recommended to avoid iris incarceration . with surgical experience ,
the higher incidence of iol pigmentation resulted from pigment dispersion and did not interfere with the visual axis .
the incidence of iris related complications was higher in our study compared with the previous reports using the microincision vitrectomy system for the management of congenital cataract [ 913 ] .
the difference of intraoperative complications between the limbal and pars plana group is almost exclusively due to the problems associated with iris .
however , this difference needs to be put into perspective , both short and long term . in order to compare the two surgical approaches more in detail ,
unlike other studies , we included the mild intraoperative complications that did not cause adverse sequelae .
the surgery to reposition the iris is simple and fast and has not been associated with additional complications .
the four iris injuries were mild and did not interfere with the visual axis . in long - term perspective , at last follow - up , there were no significant differences in mean logmar bcva between the limbal and pars plana group . the intraoperative complications associated with the iris mostly occurred among the initial 20 eyes we performed using both approaches . with surgical experience ,
the incidence of iris related complication dropped dramatically and no other case requiring additional surgery occurred .
if the iris problem was solved , the complication rate between the limbal and pars plana group may be not significantly different .
there is reason to believe that as experience is gathered and technique is refined , the visual results and number of the complications between the two groups will become more even over the long term . a more precise capsulotomy and more sufficient lensectomy and anterior vitrectomy were achieved using the pars plana approach . by inserting the 23-gauge vitrectomy cutter at the equator of the lens
, the surgeon could turn the cutter upward to perform the anterior capsulotomy , forward and around to remove the lens materials , and downward to perform the posterior capsulotomy and anterior vitrectomy .
cutting was precise and sufficient and the chances of retained lens material resulting from insufficient removal of the central posterior capsule and the anterior vitreous were minimized .
the surgical procedure was simplified by enlargement of the main limbal incision for primary iol implantation in the limbal approach .
surgically induced trauma was minimized and the learning curve of the limbal approach for the anterior segment surgeon was shorter than the pars plana approach .
the more significantly intraoperative complications in the limbal group were mainly distributed in eyes within the age range of 1.53 years .
therefore , we recommend the limbal approach for children older than 3 years for a simplified procedure . finally , closure and water tightness of the incisions were easier using the limbal approach .
the center of the limbal incision was relatively round because of the insertion of the microcannula and only one suture at this site was required .
an additional suture was occasionally required to ensure the incision was watertight . for primary iol implantation via the pars plana approach , another 2.6 mm limbal incision was made at the 12 o'clock position .
therefore , greater care should be taken to ensure that the three incisions are adequately closed and watertight at the end of the surgery .
it is of vital significance to educate the children 's caregivers to avoid any actions that might place pressure on the globe after surgery .
a multicenter , prospective , randomized trial is needed to determine the optimal surgical approach for eyes with congenital cataract using the microincision vitrectomy system . however , gathering sufficient patients , controlling the variations in the surgical procedures , accomplishing the surgery at an earlier age , and conducting the procedure comparison in a time interval that would preclude advances in instrumentation or alterations in the procedure as improved techniques evolve are quite difficult in the short term .
the perspective and information gained from the present study provide some basis for comparing the techniques in the management of congenital cataract with the microincision vitrectomy system . in conclusion
, the visual results were encouraging for the removal of congenital cataract using the microincision vitrectomy system and did not differ between the limbal and pars plana groups .
the rates of intraoperative and postoperative complications were numerically higher in the limbal group but had no significant impact on long - term visual outcome . when operating on children with congenital cataract with primary iol implantation using the microincision vitrectomy system , we recommend using the pars plana approach for a better safety margin . also , greater care should be taken to make sure
the limbal approach should be reserved for children older than 3 years and caution exercised to minimize disturbance to the iris due to the potential risk of complications .
Output:
| purpose . to compare the surgical outcomes of limbal versus pars plana vitrectomy using the 23-gauge microincision system for removal of congenital cataracts with primary intraocular lens implantation
. methods .
we retrospectively reviewed all eyes that underwent cataract removal through limbal or pars plana incision .
main outcome measures included visual outcomes and complications .
results .
we included 40 eyes ( 26 patients ) in the limbal group and 41 eyes ( 30 patients ) in the pars plana group .
the mean age was 46 months .
there was no significant difference in best - corrected visual acuity between the two groups ( p = 0.64 ) .
significantly , more eyes had at least one intraoperative complication in the limbal group than in the pars plana group ( p = 0.03 ) that were mainly distributed at 1.53 years of age ( p = 0.01 ) .
the most common intraoperative complications were iris aspiration , iris prolapse , and iris injury .
more eyes in the limbal group had postoperative complications and required additional intraocular surgery , but the difference was not significant ( p = 0.19 ) .
conclusions .
the visual results were encouraging in both approaches . we recommend the pars plana approach for lower incidence of complications .
the limbal approach should be reserved for children older than 3 years of age and caution should be exercised to minimize iris disturbance . |
PubmedSumm8879 | ***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: fetal cholelithiasis is uncommon during pregnancy although its frequency of diagnosis has increased over the last years , probably due to both the improved accuracy and the increasing use of ultrasound examination in clinical practice.15 despite the remarkable number of fetal scans performed annually worldwide , little is known about the causes , natural history , and clinical significance of echogenic foci in the gallbladder during fetal life , unlike in the pediatric or adult patient.68 we report a case of cholelithiasis in the fetal gallbladder identified sonographically in the late third trimester of pregnancy during a routine obstetric scan .
a 34-year - old - woman , gravid 2 , para 1 , was referred at 35 weeks of gestation for a routine obstetric ultrasound examination in our prenatal center .
high risk pregnancy as the result of a preexisting maternal medical condition or one that had appeared later was excluded .
a healthy prepregnancy body mass index ( bmi ) and a correct weight gain during pregnancy were recorded . a previous ultrasound examination performed in another center at 23 weeks demonstrated a live singleton fetus with no apparent structural abnormalities and normal morphological development .
an ultrasound evaluation was achieved before 35 weeks . in the third trimester , a traditional scan and traditional organ system evaluation scan of the fetus was unremarkable except for a large nonshadowing multiple small echogenic foci within the gallbladder in a transverse image through the fetal abdomen ( fig .
was realized , using different 3-d imaging techniques ( rendering , tomographic ultrasound imaging [ tui ] , virtual organ computer - aided analysis [ vocal ] , angio - power doppler ) ( figs .
a female infant weighing 3650 grams was born at 38 weeks of gestation by cesarean section for previous abdominal delivery , with apgar scores of 9 and 10 at 1 and 5 minutes , respectively . at 1 day of age
a satisfactory health status was confirmed by bilirubin and neonatal screening test for metabolic pathologies . at 2 days of life ,
a normal - sized gallbladder with minimal neonatal cholelithiasis was detected . in consideration of the liver chemistry including hematological indices within normal ranges and reassuring ultrasound result , the infant was discharged on the third day of life .
an ultrasound follow - up was performed at 2 months of life , revealing a normal size gallbladder deprived of echogenic stones , biliary tract anomalies , or obstructions . in consideration of the resolution of abnormal findings , further evaluation was not planned .
in a review in 1928 , potter identified several descriptions of neonatal gallstones and cited 2 poorly documented cases of fetal cholelithiasis diagnosed at the time of autopsy9 , though the first prenatal diagnosis by beretsky and lankin occurred in 1983.2 anomalies of the gallbladder , including sludge and gallstones , are extremely uncommon in fetal life , with an incidence of 0.42% , as reported recently in a large cohort of 9235 pregnancies , with a slightly greater male predilection.5,10 in the last decades , maternal conditions and fetal or obstetrical predisposing risk factors have been proposed to have a causative role , but none of them appears conclusive ( table 1 ) . in the condition placental abruption , fanaroff suggested that the placental cross of hemoglobin transformed into bilirubin increases the indirect bilirubin levels , responsible for sludge or gallstones in the fetal gallbladder.11 conversely , brown proposed that an increase in estrogen levels might predispose to the formation of pigment stones stimulating the secretion of cholesterol and reducing the synthesis of biliary acids.5 in some cases , maternal narcotic use , methadone particularly , should modify gastrointestinal activity with an increased transition time and the formation of solid echogenic material.12,13 augmented cellular degradation is known to predispose to calculus formation in postnatal life .
thus , a corresponding situation could be involved during hemolytic anemia and blood group incompatibilities ; both conditions are recognized as predisposing factors in the development of echogenic material in the bile.14 in addition to the risk factors previously described in the literature , kiserud suggested that chromosomal aberrations , cardiac malformations , gastroschisis , influence of prostaglandin , and possibly prenatal leukemoid reaction may cause the presence of material in the fetal gallbladder.14 taking into consideration the largest single series reported by brown and the equally significant results reported by kiserud , characterized by scans performed for indications , it can be concluded that in the centers receiving a variety of referrals , more than half of the cases with echodense contents of the fetal gallbladder have maternal or fetal complications.5,14 sonographically , after 14 weeks gestation , the fetal gallbladder can be recognized as an anechoic , oblong , teardrop - like structure with a thin echogenic wall , located at the inferior surface of the right lobe of the liver . accurate assessment and identification of the fetal gallbladder require prior visualization of the umbilical vein , because they have a similar appearance .
after 20 weeks of gestation , the fetal gallbladder can be visualized in 37.5% to 64.7% of the cases.4 stones and sludge identified in the fetal gallbladder are almost absent in the second trimester , resulting in a specific phenomenon of the third trimester due to abnormal production , composition , and mode of transportation of bile in the biliary tract.2,15 a wide spectrum of findings regarding homogeneity , echogenicity , and degree of acoustic shadowing can be detected.5,16 echogenic material in the gallbladder may be visualized by transverse sections through the fetal abdomen in the form of single , multiple , or diffuse foci.8 frequently , the echogenic material completely fills the gallbladder lumen.6 unlike in the adult patient , this material produces different degrees of acoustic shadowing .
small echogenic foci from 2 to 3 mm in size and sludge may not cause shadowing if they do not lie in the center of , or in the focal range of , the beam , while foci greater than 3 mm may produce acoustic .
schirmer underlined the importance of the nature of the calculi , concluding that none of calcified ( radiopaque ) stones disappeared spontaneously after birth , contrary to the cholesterol , urate , or pigment stones ( nonradiopaque).17 in the literature , cases of fetal gallstone diagnoses complicated by contracted gallbladder with a stone localization have been reported as no clear finding.1,15 in this condition , the calculi could be confused with liver calcification , calcified liver mass , or meconium peritonitis . in an attempt to precisely specify the relationship between the gallbladder , its content , and nearby structures , we speculated whether a 3-d approach might provide more information in diagnostic processing than a traditional 2-d ultrasonography . by an offline processing , 3-d rendering surface and tui showed the relationship between the gallbladder and the cholelithiasis .
the volume of the gallbladder was measured by vocal , and the visualization of the vessels surrounding the gallbladder was demonstrated by angio - power doppler .
overall , in contrast to conventional 2-d ultrasound that only allows imaging of single planes , the 3-d approach offers several image displays that do not exist in 2-d imaging . in obstetrics , in particular
, it offers a precise demonstration of the normal and abnormal anatomy of the fetus to the obstetrician .
digital storage of volumes permits virtual examinations by reloading of volumes and navigating through them in the absence of the patient .
the value of a 3-d scan is indisputable in specific clinical situations when the traditional scan results are poorly defined , not precise , or not clerly interpreted . in literature
, there is evidence suggesting that 3-d ultrasound improves the diagnosis increasing the visualization quality of the anatomical landmarks , with minimal impact on the examination time required .
furthermore , cardiac or brain volumes can be successfully analyzed off - line locally or sent by internet to experts for review.18 to date , after an initial enthusiasm for the innovative techniques in obstetric ultrasound and their application in several conditions , an in - depth revaluation about the possible risks related to use , or better the abuse , has been required.18 3-d modalities should be used only in selected cases requiring an effective investigation and analyzed postprocessing only by skilled operators . generally , fetal cholelithiasis appears as a quite clear finding , detectable easily for anatomical reasons and for advanced gestational age at diagnosis time.18 complications are very rare and , in most series , gallstones disappear spontaneously within the first year of life .
only 1 case of a laparoscopic cholecystectomy in a 16-day - old infant has been reported.19 in the review of suchet et al , 30 cases of fetal cholelithiasis with a long - term follow - up in 21 out of 30 babies were described.12 in only 3 patients , a persistent echogenic material in the gallbladder after 2 weeks of life was observed without any abdominal symptoms.12 stringer et al reported a series of 3 male fetuses examined sonographically in late gestation with evidence of gallbladder cholelithiasis.13 postnatally , all 3 were asymptomatic , but they had variable ultrasound findings . in 2 of these , the abnormalities noted sonographically resolved spontaneously in 6 weeks , while in third , a persistent gallbladder calculus until 6 months has been detected.15 in the 2 cases described by suma et al , the fetal gallstones showed complete resolution at the follow - up sonography at 2 and 3 months of life without any treatment.3 munjuluri et al described 2 cases treated with ursodeoxycholic acid ( dosage 57 mg / kg / die ) , reporting the complete resolution of gallstones at 2 and 4 months of life , respectively.16 recently , iroh tam and angelides described the first case of fetal gallstones in 3 siblings ( a male term neonate with gallstones and 2 male twins by dizygotic dichorionic pregnancy , twin a with gallstones and twin b with sludge in the gallbladder).1 both siblings with gallstones were treated with ursodeoxycholic acid after birth with complete resolution . in both cases ,
the therapeutic decision was based on undocumented side effects of the infant health and for obtaining a more rapid resolution of the stones.16 in consideration of previous studies and in our experience , fetal cholelithiasis is confirmed to be a self - limiting disease without complications and with a spontaneous resolution in the first year of life . although no morbidity that would be amenable to treatment has been documented , there are still theoretical neonatal risks related to the cholelithiasis therapy , including the possibility of recurrance by the end of treatment with a rare long - term freedom from stones.20 therefore , if further investigations are necessary in order to clarify the potential risks of the pharmacological approach , we discourage some forms of therapy such as ursodeoxycholic acid administration due to unknown and potential side effects in childhood or adulthood . in conclusion , several questions remain unanswered about the etiology , the risks of further gallstone formation , and long - term effects of pharmacological treatment in cholelithiasis detected during pregnancy .
a close follow - up is indicated in these patients until spontaneous resolution is demonstrated by traditional ultrasound .
the 3-d imaging techniques might show some advantages in difficult clinical conditions , through an off - line processing of stored images . considering the high rate of spontaneous resolution ,
the best practice is to reassure parents and to observe the clinical evolution with periodic ultrasound examinations without any treatment .
only future follow - up studies will be able to respond fully to current open questions .
Output:
| fetal gallstones and cholelithiasis , detected by routine third trimester ultrasound , have been described in the literature with controversial clinical significance .
we report a case of fetal cholelithiasis detected at 35 weeks gestation during a routine scan .
the diagnosis was performed using an integrated 2-dimensional ( 2-d ) and 3-dimensional ( 3-d ) ultrasound approach in order to obtain a better definition of the fetal gallbladder and its content .
a neonatal follow - up was achieved .
the present study has a twofold purpose : firstly , to update the diagnostic approach using the innovative 3-d modalities and secondly , to review the management of this condition during fetal and postnatal life . |
PubmedSumm8880 | ***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: prostate biopsy has been widely performed in clinical practice in patients with high prostate - specific antigen ( psa ) levels , and the incidence of prostate cancer has increased .
although a serum psa level of 3.0 or 4.0 ng / ml is used as a cutoff value for screening for prostate cancer , it is relatively difficult to discriminate prostate cancer from benign prostatic hyperplasia ( bph ) in men with gray - zone psa values ( 4 - 10 ng / ml ) . to increase the diagnostic accuracy of prostate biopsy , various parameters including psa velocity , percent free psa ,
age reference psa ranges , and psa density ( psad ) have been used in clinical practice .
psad values of 0.15 are generally regarded as being highly suspicious of prostate cancer . with developments in prostate ultrasound and biopsy instruments ,
prostate biopsy can be performed under local anesthesia on an outpatient basis in most cases .
the development of prostate biopsy techniques has reduced patient discomfort , but a considerable number of patients still complain of pain or discomfort . some patients refuse to undergo prostate biopsy because they recall the pain of previous biopsy procedures . to reduce this discomfort ,
prostate biopsy is sometimes performed under general anesthesia or spinal anesthesia , which is often costly and time consuming . in cases in which the psa level is within the gray zone , but
the psad value is low , this increased psa level is mostly attributed to bph , suggesting a lower possibility of prostate cancer .
if combined prostate biopsy and transurethral resection of the prostate ( turp ) is safe , the pain or discomfort experienced when prostate biopsy is performed separately can be avoided .
this study was conducted to examine whether simultaneous transrectal prostate needle biopsy ( tpnb ) is safe and effective in patients who are scheduled for turp because of an increase in psa levels .
this study included a total of 42 patients aged 60 years who had psa levels of 4 to 10 ng / ml and psad values of 0.12 and who underwent combined tpnb and turp at our hospital . the mean age , prostate volume , psa level , and psad value of the patients were 71.35.7 years , 75.927.7 g , 6.02.0 ng / ml , and 0.0840.026 , respectively ( table 1 ) .
prostate volume was calculated by using the following formula : where l = length , w = width , and h = height .
after prostate biopsy was performed with the patient under spinal anesthesia , the patient 's position was changed into the lithotomy position for turp .
prostate biopsy was conducted under transrectal ultrasound guidance by using the 8 core method before february 2008 and the 12 core method after march 2008 .
after surgery , the degree and duration of fever , the absence or presence of sepsis , and the development of complications , such as epididymitis or orchitis , were assessed .
fever was defined when the highest measurement was 37.5. the diagnostic accuracy was determined , and the results of histological examinations were evaluated according to tpnb alone or combined tpnb and turp .
the gleason score was measured in patients with a confirmed diagnosis of prostate cancer ( pca group ) .
clinical characteristics , prostate volume , psa , and psad were analyzed in patients with a confirmed diagnosis of bph ( bph group ) and in the pca group .
diagnostic accuracy was analyzed in two groups of patients according to age : those < 70 years and those 70 years .
all statistical analyses were performed by using spss 12.0 ( spss inc , chicago , usa ) .
comparisons of clinical characteristics and parameters were made by using the mann - whitney test .
the mean volume of the resected specimen after turp was 32.421.6 g. the durations of urethral catheter placement and admission were 2.60.8 and 5.51.6 days , respectively ( table 1 ) .
of the total 42 patients , fever was noted in 9 patients ( 21.4% ) , 4 ( 9.5% ) of whom had a fever of 38. all of the 9 patients had fever the day after surgery , and the fever subsided within 24 hours .
there was no significant difference in the duration of hospital stay between the patients with fever and those without .
of the total 42 patients , 6 ( 14.3% ) were definitively diagnosed as having prostate cancer .
prostate cancer was diagnosed in 2 patients by tpnb alone , in 3 patients by turp alone , and in 1 patient by both procedures .
the gleason score was 6 points in 3 patients and 7 points in 3 patients ( table 2 ) .
the psa level was 4.77 ng / ml in the pca group and 6.22 ng / ml in the bph group , but the difference was not statistically significant .
the psad value was 0.075 in the pca group and 0.086 in the bph group , but the difference was not statistically significant ( table 3 ) . according to the reference age of 70 years , there were no significant differences in prostate volume , the psa level , or the psad value between the two age groups of < 70 years and 70 years .
the diagnostic accuracy was 25.0% ( 4/16 ) in the patients aged < 70 years and 7.8% ( 2/26 ) in the patients aged 70 years ( table 4 ) .
with advancements in psa screening tests , transrectal ultrasound , and biopsy instruments , prostate biopsy is widely performed in clinical practice . although complications after prostate biopsy are not serious , many patients hesitate to undergo prostate biopsy because of pain or discomfort .
zisman et al reported that about 96% and 89% of patients undergoing prostate biopsy complained of pain and discomfort , respectively .
many attempts to reduce pain during prostate biopsy have been made . among them , infusion of lidocaine jelly is simple to use but its effect is controversial .
a previous study documented that about 82% of patients reported " no " to the question " will you undergo prostate biopsy again if needed ? " .
when prostate biopsy is performed under general anesthesia to avoid such discomfort or pain , the procedure costs are increased , although patient discomfort or pain can be reduced .
such problems can be solved if combined tpnb and turp are performed in patients who need prostate biopsy although there is a low possibility of prostate cancer based on a psa level within the gray zone but a low psad value .
shen et al reported that combined tpnb and turp is safe without notable complications other than fever , which agrees with our results .
of the total 42 patients in the present study , 9 ( 21.4% ) had fever after surgery , 4 ( 9.5% ) of whom had a fever of 38. fever subsided in all 9 patients within 24 hours .
there were no significant differences in the durations of urethral catheter placement and hospital stay between the patients with fever and those without fever .
it has been reported that fever occurs in 4.4% or 6.2% of patients after tpnb alone . in our study ,
a fever of 38 occurred in 9.5% of the patients without any significant difference between tpnb alone and combined tpnb and turp .
palisaar et al indicated that open radical retropubic prostatectomy after turp gives favorable surgical and functional outcomes without an increase in the incidence of complications or sexual dysfunction . in our study ,
open radical retropubic prostatectomy was performed on 5 of the 6 patients with a confirmed diagnosis of prostate cancer , and there was no increase in the incidence of complications .
psad is used to increase diagnostic accuracy in patients who have gray - zone psa values ( 4 - 10 ng / ml ) .
some investigators have proposed that prostate biopsy is indicated for patients with a psad value of 0.15 , and others have advocated that the criteria should be lowered .
gohji et al reported that in a study of 287 patients with a psa level of 2.1 - 10.0 ng / ml , the psa level had a sensitivity of 90% , a specificity of 36% , and a positive predictive value of 14% in those with a psad value of < 0.12 .
a recent study showed that in patients with a psa level of 4 - 10 ng / ml , the psa level had a sensitivity of 90% and a specificity of 33.7% at a psad cutoff value of 0.134 . in our study ,
combined tpnb and turp was performed on patients with a psa level of 4 - 10 ng / ml as well as a psad value of < 0.12 . as a result , 6 patients ( 14.6% ) were definitively diagnosed with prostate cancer .
prostate cancer was diagnosed in 2 patients ( 4.9 ) by tpnb alone , 3 patients ( 7.3% ) by turp alone , and 1 patient ( 2.4% ) by combined tpnb and turp .
this result suggests that the diagnostic accuracy of tpnb alone is 7.3% in patients with a psad value of < 0.12 .
it is generally recognized that turp is effective in diagnosing prostate cancer in patients with negative tpnb results .
of the 6 patients diagnosed with prostate cancer , prostate cancer was definitively diagnosed by turp in 4 patients , 3 of whom were diagnosed by turp alone .
in other words , if tpnb alone had been performed on the aforementioned 3 patients , the results might have been negative and the patients might have needed to undergo repeated tpnb or turp .
on the basis of these findings , we can infer that combined tpnb and turp may be more effective than repeated tpnb in the diagnosis of prostate cancer in patients with previous tpnb - negative results .
the normal range of psa has been reported to be 2.4 - 3.5 ng / ml in the 50 to 59 year group , 3.6 - 5.4 ng / ml in the 60 to 69 year group , and 5.2 - 7.5 ng / ml in the 70 to 79 year group [ 21 - 24 ] .
therefore , it is estimated that in elderly patients , the diagnostic accuracy of the psa level may decrease in patients with low psad values .
meshref et al reported that the diagnostic accuracy of the psa level in patients with a psa level of 4.1 - 10 ng / ml was 0% in the 50 to 59 year group , 4.1% in the 60 to 69 year group , and 0% in the 70 to 79 year group at a psad cutoff value of 0.15 or less .
they also reported that the diagnostic accuracies of the psa level were 4.2% , 1.5% , and 0% , respectively after adjustment for age ( 3.6 - 10 ng / ml for the 50 to 59 year group , 4.6 - 10 ng / ml for the 60 to 69 year group , and 6.6 - 10 ng / ml for the 70 to 79 year group ) .
those authors concluded that the diagnostic accuracy of the psa level was 0% at a psad cutoff value of 0.15 or less in the 70 years age group .
kobayashi et al showed that diagnostic accuracy is low in patients aged 70 years with large prostate volumes .
thus , because the increased psa level is probably due to bph in the 70 years age group , prostate biopsy should be avoided in patients aged 70 years with large prostate volumes .
similarly , we found that the diagnostic accuracy of the psa level was 25% and 8% , respectively , for the age groups of < 70 and 70 years . because there is a high possibility of the presence of diabetes mellitus or use of anticoagulant medications , the incidence of complications after tpnb may be high . in bph patients
aged 70 years who are scheduled for turp because they have a psa level within the gray zone , separate tpnb can be avoided by performing combined tpnb and turp .
first , it was retrospective in nature and the number of subjects was relatively small .
second , even though turp can enhance the diagnostic yield of prostate cancer in this group of patients , at the same time it could miss some chances of radical prostatectomy without prior turp .
however , we confirmed that combined tpnb and turp is safe and that the possibility of prostate cancer may be reduced in elderly patients as found in previous studies .
because combined tpnb and turp is a safe procedure , it should be performed on patients who need the 2 procedures . in particular , this combined procedure may be useful for patients with tpnb - negative results who need turp .
moreover , because there is a low possibility of prostate cancer in bph patients with a psad value of < 0.12 and aged more than 70 years old , combined tpnb and turp can prevent unnecessary tpnb before turp .
Output:
| purposethis study was conducted to examine whether simultaneous transrectal prostate needle biopsy ( tpnb ) owing to an increase in prostate - specific antigen ( psa ) levels is safe and effective in patients who are scheduled for transurethral resection of the prostate ( turp ) for benign prostatic hyperplasia ( bph).materials and methodscombined tpnb and turp was performed in a total of 42 patients aged 60 years and older who had gray - zone psa values ( 4 - 10 ng / ml ) and psa density ( psad ) values of 0.12 and less .
the frequencies of fever , sepsis , and epididymitis were assessed after surgery .
the diagnostic accuracy was assessed , and the results of histologic examination were evaluated in terms of tpnb or turp . in addition , the diagnostic accuracy was assessed according to age.resultsprostate cancer was diagnosed in 6 ( 14.3% ) of the 42 patients : 2 patients were diagnosed with prostate cancer by tpnb only , 3 patients by turp only , and 1 patient by combined tpnb and turp .
four ( 25% ) of the 16 patients aged under 70 years and 2 ( 7.8% ) of the 26 patients aged 70 years and older were diagnosed with prostate cancer .
fever was observed in 9 patients ( 21.4% ) , 4 ( 9.5% ) of whom had a fever of higher than 38. the fever normalized the day after surgery in all 9 patients .
no septicemia was noted .
there were no serious complications related to combined tpnb and turp.conclusionsthe results of this study suggest that combined tpnb and turp may be safe and effective in patients who require turp . |
PubmedSumm8881 | ***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: maintaining fidelity of dna replication is essential to the survival of even the simplest organisms . based on mammalian models , lack of faithful dna replication by dna polymerases
is associated with a large number of human diseases including , but not limited to , cancer and a variety of precancerous conditions [ 17 ] .
a number of repair mechanisms exist to correct errors that occur during dna synthesis , including mismatch repair , base and nucleotide excision repair , and recombination repair , and these mechanisms have been reviewed recently elsewhere [ 811 ] . despite the existence of these repair mechanisms , a major determinant of replication fidelity
this ability is promoted not only by the high fidelity with which the polymerase selects correct versus incorrect nucleotide , but also by the reduced capacity for the polymerase to extend or replicate through primer / templates ( p / ts ) containing distortions such as mismatches , abasic ( ap ) sites , or oxidative or bulky lesions [ 1217 ] .
this kinetic barrier to extension causes the replicative polymerase to stall . in many organisms , including prokaryotes , archea , and eukaryotes , stalling of the replicative polymerase is required to permit a short - term exchange with a low - fidelity polymerase ( including one or more y - family polymerases , or the b - family dna polymerase ) .
this occurs via exclusive interactions of the respective polymerases with processivity factor in order to permit lesion bypass [ 1827 ] . although these lesion bypass polymerases are generally more error - prone and do not repair the lesion , they rescue the organism from lethal replication failure when dna is damaged [ 28 , 29 ] .
the stalling of a replicative polymerase at dna lesions or following misincorporation also appears to be important for self - correction by allowing engagement of the intrinsic 3 to 5 exonuclease ( exo ) activity to proof - read replication errors as they occur or to sense the presence of dna lesions [ 14 , 3037 ] .
pre - steady - state and steady - state kinetic analysis of polymerases with or without a functional exo activity have been instrumental in understanding the mechanisms that permit dna polymerases to copy dna with high fidelity , as well as how they avoid the permanent mutagenic effects of misincorporated nucleotides or dna damage [ 14 , 15 , 33 , 34 , 3840 ] .
this review analyzes the different mechanisms that control replication fidelity that are intrinsic to replicative dna polymerases , with a specific focus on those that are utilized by the polymerase encoded by herpes simplex virus type 1 ( hsv-1)the prototypic member of a family of viruses which cause high morbidity in the human population . because of the ease with which they can be genetically manipulated , viruses have also proven to be excellent models to better understand the functions required for faithful genome duplication [ 4145 ] .
moreover , viral polymerases , including the hsv-1 dna polymerase and the human immunodeficiency virus ( hiv ) reverse transcriptase , are important therapeutic targets of antiviral drugs [ 4648 ] . a summary of studies that have reported the pre - steady - state and steady - state kinetics of hsv-1 dna polymerase are provided and compared to those of other replicative polymerases to gain insight into the similarities and differences by which these polymerases control fidelity . by understanding how activities required for high - fidelity dna replication are modulated and coordinated by the hsv-1 dna polymerase
, it may be possible to design novel antiviral approaches to thwart replication of this important human pathogen .
the single most important contributor to fidelity of most dna polymerases is nucleotide selectivity that is , the propensity with which the polymerase incorporates correctly versus incorrectly base - paired nucleotide [ 33 , 34 , 38 , 4953 ] . for replicative polymerases , nucleotide selectivity has been shown to account for an error rate in the range of > 10 to 10 [ 33 , 34 , 49 , 52 ] .
the structures of a variety of replicative dna polymerases have been solved , including the structures for the a - type polymerases that replicate t7 bacteriophage and mammalian mitochondria ( pol ; ) , and the b - type replicative polymerases of the t4-related bacteriophage rb69 , hsv-1 , and yeast ( saccharomyces cerevisiae ) dna polymerase .
it is clear that the nucleotide - binding pocket is able to accommodate or snuggly fit the correctly paired nucleotide via space and geometry [ 59 , 60 ] .
this promotes a higher ground - state binding affinity of the correct , compared to incorrect , nucleotide .
in addition , evidence points to an induced fit model , whereby the binding of correct nucleotide better promotes the conformational change necessary to form the closed structure required for catalysis [ 34 , 49 , 50 , 54 , 56 , 61 ] . for the bulk of these polymerases , it is this conformational change , rather than the chemical catalytic step , which is rate - limiting for correct nucleotide incorporation under pre - steady - state conditions [ 34 , 39 , 6264 ] .
for incorrect nucleotide incorporation , there may be contributions from conformational and chemical steps as well as from the propensity for rapid dissociation of mispaired dntp from the polymerase .
by contrast , the structure of the active site of the y - family polymerases reveals that the relatively high frequency for mismatch incorporation ( > 10 ) and for bypass of dna lesions can be attributed to a more open active site than that formed by a or b type polymerases [ 6669 ] .
most replicative polymerases possess or are closely associated with a 3 to 5 exo activity , and loss of this inherent or associated activity results in an increased mutation frequency in vitro and in vivo [ 7074 ] .
the contribution of the exo activity to increasing overall fidelity of dna replication varies for different sequence contexts , but is on the order of 10- to 100-fold for most of the replicative polymerases [ 31 , 33 , 51 , 63 , 75 , 76 ] .
the importance of polymerase - associated exo activity in maintaining genomic stability in higher eukaryotes is also confirmed by the increased cancer incidence in transgenic mice containing an exo - deficient polymerase [ 5 , 6 ] and by the premature aging that occurs in transgenic mice containing an exo - deficient pol .
because the exo activity competes with the polymerizing activity for the 3 primer terminus , high - fidelity replication in its presence might be expected to have a real cost in terms of polymerizing speed and/or efficiency .
however , pre - steady - state kinetic experiments have demonstrated that the means by which both rapid polymerization and correct nucleotide incorporation can be maintained reflects the ability of a polymerase to partition the primer terminus to the polymerizing or exo sites as needed [ 15 , 31 , 33 , 34 , 62 , 63 , 77 ] .
the relative efficiencies for polymerization and proofreading during active dna synthesis are influenced by a variety of parameters , including the relative affinities of a matched or mismatched primer terminus for the polymerizing or exo site , the rates of polymerization at matched versus mismatched primer termini , the rates of excision of matched versus mismatched primer termini , and the ability of a primer end to switch between the polymerizing and exo site with or without dissociation of the template from the polymerase .
donlin and coworkers demonstrated that the t7 dna polymerase holoenzyme ( with e. coli thioredoxin processivity factor ) possesses the same binding affinity for matched or mismatched p / t although the t7 pol binds p / t tighter to the polymerization domain than to the exo site .
in addition , the polymerization rate of incorporation of correct nucleotides is fast ( 300/sec ) and the excision rate on ssdna is even faster ( > 700/sec ) [ 33 , 62 ] . however , transfer of the primer to the physically distinct exo site is slower by 10-fold when the dna is matched compared to when it is mismatched .
when a misincorporation event occurs , the polymerization rate for t7 polymerase is slowed , permitting a transfer of the primer strand from the pol to the exo site .
the rapid transfer of the mismatched nucleotide to the exo site permits excision of that nucleotide . for the t7 holoenzyme
, the transfer of the now - matched p / t back to the polymerization site occurs without dissociation .
thus , the kinetic partitioning of the primer between the polymerizing and exo sites , without a rate - limiting dissociation of the holoenzyme from the p / t , permits rapid repair with little cost to overall rate of extension . the structurally similar a - type mitochondrial polymerase ( pol ) possesses an inherently poorer fidelity than the t7 polymerase [ 31 , 63 ] .
compared to t7 polymerase , excision of mismatched dna occurs at a much slower maximum rate ( 9/sec ) . nevertheless , error correction without enzyme dissociation occurs with an efficiency of 80% .
by contrast , another a - type enzyme , klenow fragment of dna polymerase i , has an even slower rate of excision ( 0.003/sec ) , which would favor dissociation when that enzyme stalls at a mismatch [ 15 , 77 ] .
the latter results suggest that proofreading by klenow is a less efficient means for error correction than by either bacteriophage t7 dna polymerase or mammalian pol . the t4 dna polymerase catalytic subunit ( a b - type polymerase ) also incorporates correct nucleotides at a rapid rate ( > 400/sec ) whereas the exo activity excises ssdna at a rate of approximately 100/sec . as for the t7 polymerase ,
transfer of primer from the polymerization to the exo site is slower ( 5-fold for t4 polymerase ) for matched compared to mismatched p / t .
however , because the rate constant for dissociation of the t4 polymerase catalytic subunit from the p / t ( 68/sec ) competes with that for transfer of a mismatched primer to the exo site ( 5/sec ) , direct editing can occur only 40% of the time . therefore , editing by the t4 polymerase catalytic subunit is less efficient than by the t7 dna polymerase holoenzyme [ 33 , 34 ] .
as shown for the t4-like rb69 bacteriophage dna polymerase , the ability of a mispaired end to access the exo site requires a ~40 rotation relative to its position at the polymerase active site [ 56 , 81 ] .
because the template strand is not firmly anchored during this movement to the exo site for klenow enzyme , the dna must diffuse to the exo site , although one - way diffusion could be facilitated by retention of the primer in the thumb domain during the conformational change [ 56 , 82 ] .
a -hairpin within the exo domain of the b - type polymerase encoded by bacteriophage rb69 has been proposed to hold the template in place as the primer terminus is transferred from the polymerizing to the exo active sites .
the analogous hairpin of s. cerevisiae pol interacts extensively with the template strand which could stabilize the enzyme - dna interaction during the conformational transition .
by contrast , the -hairpin of rb69 polymerase does not associate with normal dna and interacts with only a portion of the ssdna template containing an abasic site [ 56 , 58 ] .
this could account for the relative inefficiency by which the rb69-like t4 dna polymerase can edit mismatched dna in a single association event [ 34 , 58 , 84 ] .
it is becoming increasingly clear that the exo activity associated with polymerases increases fidelity by mechanisms in addition to nucleotide editing .
for example , the presence of exo activity also appears to be important for preventing translesion dna synthesis or strand displacement synthesis by a number of polymerases , including those of pol , bacteriophage t4 , and hsv-1 [ 14 , 8589 ] .
this is because the ability of a polymerase to partition the dna primer between the polymerizing and exo sites allows the enzyme to engage in idling turnover that is , successive rounds of excision and incorporation , with or without dissociation whenever it encounters a kinetic barrier to extension .
this idling - behavior increases overall dna replication fidelity because it prevents extension through abasic sites or oxidized nucleotides , such as 8-oxyguanine , which would have a high probability for introducing mutations .
idling turnover by a polymerase also limits strand displacement synthesis . failure to limit strand displacement synthesis by yeast pol during okazaki fragment maturation has been shown to lead to the production of aberrant or improperly processed lagging strand intermediates in vitro and higher mutation frequency in vivo [ 86 , 87 ] .
there has been much disagreement concerning the role of polymerase accessory proteins in maintaining fidelity .
parameters that could be altered by processivity factors include kinetic barriers to extending a mismatch or bypassing a lesion , the ability of the polymerase to partition its activity between the physically distinct exo and pol sites , the relative accessibility of the exo and pol sites , and dissociation of polymerase upon encountering a barrier to extension [ 33 , 72 , 76 , 90 , 91 ] .
proposed that the t4 polymerase processivity factor would enhance fidelity by limiting the dissociation of enzyme from mismatched p / t , thereby increasing the efficiency for direct editing by the enzyme .
however , for several polymerases , an inverse relationship was shown between processivity or dna binding and fidelity , at least under some circumstances [ 9093 ] . for t7 dna polymerase ,
the processivity factor was found to enhance fidelity by retaining the polymerase long enough to edit misincorporated nucleotides .
for t4 dna polymerase , the addition of processivity factors to the wild - type enzyme had no impact on fidelity of dna replication and did not permit lesion bypass .
however the addition of processivity factors to an exo - deficient t4 polymerase did permit lesion bypass with low concentrations of enzyme , which did not permit efficient translesion synthesis in the absence of processivity factors .
proliferating cell nuclear antigen ( pcna ) was also demonstrated to increase misinsertion frequency and to promote the ability of mammalian pol to bypass dna lesions [ 90 , 93 , 94 ] , thereby reducing fidelity .
likewise , the addition of processivity factor to mitochondrial polymerase ( pol ) reduced the incorporation fidelity of both the wild - type and exo - deficient enzyme in gap - filling assays , predominantly by enhancing the efficiency for extending mismatches .
hsv-1 encodes a b - type dna - dependent dna polymerase that is the product of the ul30 gene and is essential for origin - dependent dna synthesis in cell culture and for the production of infectious progeny virus in vivo [ 95100 ] . in vitro
, the hsv-1 dna polymerase is also required together with 5 other viral encoded proteins for leading strand synthesis on model templates .
in addition to a 5 to 3 polymerizing activity , the polymerase catalytic subunit ( pol ) possesses an intrinsic 3 to 5 exo domain [ 57 , 99 , 102 , 103 ] . in infected cells ,
hsv-1 pol forms a stable heterodimer with the product of the ul42 gene ( ul42 ) [ 104106 ] .
the ul42 protein is a double - stranded dna - binding protein that serves as an accessory protein to increase the processivity of the hsv-1 pol catalytic subunit [ 104 , 107 , 108 ] .
the ability of the ul42 processivity subunit to form a stable heterodimer with the hsv-1 pol catalytic subunit resembles the type of arrangement observed for the a - type polymerases , t7 bacteriophage dna polymerase and mitochondrial pol , with their respective processivity factors .
however , the structure of hsv-1 ul30 pol catalytic subunit most closely resembles that for the eukaryotic replicative polymerase , pol [ 57 , 58 ] .
interestingly , the structure of the ul42 processivity factor resembles that for a subunit of the pol processivity factor , pcna [ 109 , 110 ] . however , the two globular domains of hsv-1 ul42 are oriented differently from those of a pcna monomer such that they could not easily form the toroidal structure of the homotrimeric pcna processivity factor .
the co - crystal structure of ul42 with a pol c - terminal peptide suggests a flexible attachment to the unstructured c - terminal tail of hsv-1 pol , similar to what has been observed for other processivity factors with their cognate b - type polymerase [ 5658 , 81 , 82 , 109 ] .
since the ul42 processivity factor does not require energy or other proteins to load it onto dna or to form the heterodimeric holoenzyme [ 104 , 105 , 107 , 111 ] , it is easier to investigate the role of processivity factor in controlling the fidelity of this viral replicative polymerase compared to that of its close homolog , pol . epidemiological studies suggest that hsv-1 dna replication is not as faithful as that of its human host .
for example , mutations occur frequently during hsv-1 replication in vivo , such that many nucleotide polymorphisms can be observed even in epidemiologically related strains of virus [ 112114 ] .
the genetic diversity of viral progeny that results from this poor fidelity is likely to contribute to selection of virus mutants capable of evading natural host immune mechanisms as well as antiviral drugs .
indeed , clinical isolates from humans not exposed to antiviral drugs have been shown to contain a preexisting subpopulation of virus resistant to high concentrations of acyclovir . for
random hsv-1 isolates from japan , the average number of nucleotide differences observed in the 1,131 bp thymidine kinase ( tk ) gene was 3.3 . in another study , the hsv-1 tk gene mutation frequency ( estimated at 5 10 )
was determined by measuring the average frequency of acyclovir - resistant plaques that arose under nonselective growth conditions during a single replication cycle for independent cultures of an acyclovir - sensitive ( wild - type ) laboratory strain of hsv-1 .
examining the role of the 3-5 exo activity in maintaining the fidelity of hsv-1 dna replication in culture has been challenging since it has not been possible to isolate viral mutants by altering conserved residues within either the exo i or exo ii sites [ 117 , 118 ] .
most of the hsv-1 exo ii site pol mutations created by gibbs and coworkers failed to complement the replication of a pol null virus or to synthesize any viral dna in these complementation assays .
biochemical analysis of similar exo ii mutants by another group revealed that these mutations compromised not only the exo activity , but also the extension activity of the polymerase , perhaps accounting for their lethal phenotype .
mutations that map in the conserved exo i residues that are involved in the coordination of the metal ions required for catalysis ( e.g. , d368a and e370a ) also possess little if any exo activity , though their polymerase activities are similar to or greater than that of the wild - type hsv-1 pol [ 75 , 119 ] . nevertheless , the d368a exo i mutation was lethal for virus replication .
it has been suggested that the exo and polymerizing domains of the hsv-1 pol may be fundamentally different and less distinct from each other than those domains for other polymerases .
however , the resolved crystal structure of the hsv-1 pol shows that the organization of the exo domain with respect to the palm , fingers , and thumb subdomains is similar to that shown for s. cereviseae pol [ 57 , 58 ] .
the only exo - deficient hsv-1 polymerases capable of supporting virus replication are those that map to the conserved exo iii site . these exo iii site mutant proteins ( e.g. , y577h , a double mutant y577h / d581a , and y577f ) were somewhat compromised for polymerizing activity , but the 3 to 5 exo activity was reduced from 6- to 50-fold , depending on the mutation [ 116 , 119 ] . transient expression of the y577h and y577h / d581a mutant pol genes complemented the replication of an hsv-1 pol null mutant virus , and viable virus progeny could be isolated when the mutations were introduced into the viral genome .
these viruses displayed a mutator phenotype with mutation frequencies that were 300- and 800-fold higher , respectively , than that for the parental wild - type virus .
the mutator phenotype of exo iii mutant viruses clearly demonstrates an important role for the intrinsic exo activity of the hsv-1 dna polymerase in maintaining fidelity of viral dna replication in culture .
however , the inability of other exo - deficient polymerases to support virus replication , particularly the exo i site mutants with wild - type polymerizing activity , suggests a more complex role for this domain during viral dna replication . pre - steady - state kinetic analysis can provide a better understanding of the complex interactions between the polymerizing and exo functional domains by determining the individual parameters that control correct and incorrect nucleotide incorporation with undamaged template or a template with a noninformative lesion , such as an ap site .
table 1 summarizes the results of several different pre - steady - state kinetic studies of single nucleotide incorporation by various hsv-1 polymerases that is , the wild - type and the exo i site mutant ( d368a ) pols with or without the ul42 processivity factor . for better comparisons , only the apparent kds for dntp are shown since true kd for dntp was determined in only one study .
the rate constants for correct nucleotide incorporation by the wild - type hsv-1 pol in the absence or presence of ul42 processivity factor were not significantly different in two different sequence contexts ( table 1 and ) .
this contrasts with the ability of pcna to increase the rates of polymerization by mammalian pol approximately 3-fold .
for wild - type hsv-1 pol , the rate constant for misincorporation of datp opposite da template ( 106/sec ) was only moderately less than for correct incorporation of dttp ( 157/sec ) into the same p / t ( table 1 ) .
discrimination between the correct and incorrect nucleotide for hsv-1 pol occurs predominantly at the level of ground state binding affinity of dntp , as indicated by a > 20-fold decrease in affinity of datp ( incorrect ) compared to dttp ( correct ) for da - containing template .
although the processivity factor slowed the rate of incorporation of mismatched dntp by the wild - type pol approximately 4-fold , the pol / ul42 complex had an even greater difference in affinity between incorrect and correct dntp compared to the wild - type pol catalytic subunit .
thus , hsv-1 pol , with or without processivity factor , discriminates between correct versus incorrect dntp with similar relative efficiencies ( table 1 ) .
the relative discrimination values shown in table 1 ( 34 and 130 ) differ somewhat from published values , since the latter used the lower true kd ( dntp ) values to estimate a misincorporation frequency of 1 in 300 for both pol and pol / ul42 . this misincorporation frequency is approximately 10 times higher than that reported for the exo - deficient klenow fragment of e. coli dna polymerase i , suggesting that hsv-1 pol is one of the least faithful dna polymerases with intrinsic exo activity .
it is interesting to note that a misincorporation frequency of 1 in 300 is similar to the nucleotide variation within the hsv-1 tk locus ( an average of 3.3 changes for a gene of 1,000 bp ) noted among japanese isolates .
most other studies that have estimated lower hsv-1 mutation frequencies ( between 5 10 and 5 10 ) have relied on the frequencies for isolating mutations in genes that are scored by function , such as acyclovir - resistance or plaque color due to mutation in a lac z locus introduced into the viral genome [ 120 , 121 ] .
such studies naturally underestimate misincorporation frequency because they fail to score silent mutations that do not alter phenotype .
the d368a mutation renders the polymerase completely deficient in exo function but with a pre - steady - state polymerization rate constant for incorporation of correct nucleotide that is approximately 20% higher for the mutant catalytic subunit ( 199/sec ) compared to the wild - type pol on the same p / t ( table 1 ) .
although the relative differences in ground state binding affinity for mismatched versus matched nucleotide were similar for the exo and wild - type pols , the pre - steady - state rate constant for incorporating an incorrect nucleotide by this mutant pol was 23 times lower than that for incorporating a correct one ( table 1 ) .
this results in an overall 600-fold reduced efficiency for incorporation of incorrect compared to correct dntp by the exo pol .
overall , the hsv-1 exo pol misincorporates nucleotides > 5-times less efficiently than does the wild - type pol using the same p / t ( table 1 ) .
thus , the hsv-1 exo pol misincorporation efficiency differs from that of exo - deficient klenow enzyme by a factor of only 2 . as discussed in detail in a subsequent section ,
the lower misincorporation efficiencies observed by the hsv-1 exo pol , compared to the wild - type pol , may reflect a defect in the ability of the enzyme , or enzyme : incorrect dntp ternary complex , to transfer the primer terminus between the polymerizing and exo sites .
the specific impact of the ul42 processivity factor on the efficiency with which the exo - deficient pol can discriminate between incorrect and correct nucleotides for incorporation can not be determined from table 1 .
however , the ground - state binding affinity of the antiviral compound , acyclovir ( acv ) triphosphate , for the exo pol / ul42 complex , is roughly the same as the affinity of dgtp for incorporation opposite a dc templating residue [ 78 , 122 ] ( table 1 ) .
by contrast , the rate constant for incorporation of acv - tp by the exo pol / ul42 complex is considerably slower than the rate constant for incorporation of matched dntp by the exo pol , but similar to that for incorporation of mismatched nucleotide by the exo catalytic subunit ( table 1 ) .
thus , it is likely that the slow rate - limiting step for incorporation of acv - tp by the exo pol / ul42 reflects a slow conformational change and/or chemistry step , as suggested for mismatched dntp incorporation .
the kinetic parameters that govern nucleotide incorporation by the hsv-1 pol opposite an ap site on the template differ from those for either correct or incorrect incorporation with undamaged templates .
for example , for wild - type pol , there is no significant difference in the rate constant for incorporation ( kpol ) of datp opposite the matched dt compared to that for incorporation opposite an ap site ( table 1 ) .
pre - steady - state kinetic experiments also revealed that the productive binding of the hsv-1 pol to a p / t containing an ap site located 1 nucleotide downstream ( + 1 ) from the p / t interface ( true kd ( dna ) = 42.1 7.4 nm ; ) was indistinguishable from that for undamaged p / t ( true kd ( dna ) = 44 3.0 nm ; ) .
these results suggest that the enzyme can not sense the ap site on the template strand ahead of attempts at incorporation .
nevertheless , the ground state binding affinity for datp opposite the noncoding ap site ( 1/kd ) was reduced approximately 5-fold for wild - type pol compared to that for incorporation opposite a matched nucleotide ( table 1 ) . under single turnover conditions in which the wild - type pol is bound to p / t at equilibrium and excision
is initiated by the addition of mgcl2 with high - excess cold dna trap , the kinetics for excision of a mismatched p / t , or a p / t containing da opposite an ap site , approach that for excision of frayed ssdna ends by the wild - type pol / ul42 holoenzyme ( table 2 , [ 64 , 78 ] ) .
the fast burst rate constant for excision of matched p / t by wild - type pol is considerably slower than that for mismatched or a : ap p / ts ( table 2 ) .
in addition , a smaller proportion of matched primer was cleaved , compared to primer opposite a mismatched or ap - containing template .
wild - type pol / ul42 also cleaved a smaller proportion of matched ends compared to frayed ones , and with a smaller burst rate constant ( table 2 ) .
these results indicate that most of the matched p / t is held at equilibrium in the polymerization site with little difference in the relative distribution in the presence ( 12.5% ) versus absence ( 6% ) of processivity factor . because the presence of excess unlabeled dna trap prevents access of labeled p / t to any polymerase that dissociates , the slow burst rate constant for excision , when present , is indicative of the rate by which the primer strand is destabilized and transferred to the exo active site in a single association event ( 2.2/sec for pol and 0.25/sec for pol / ul42 ; table 2 ) . from these data alone , it is difficult to determine whether the differences observed in both fast and slow burst rate constants for cleavage of a da / dt matched p / t by pol , compared to those for cleavage of dg / dc matched p / t by pol / ul42 , reflect a greater thermal stability of the dg / dc base - pair or a significant slowing of excision rate by ul42 .
however , in side - by - side comparisons on the same matched p / t , chaudhuri et al
. demonstrated no more than a 2-fold reduction in fast burst rates for cleavage of matched p / t in the presence versus the absence of ul42 .
although hsv-1 pol excises the 3 nucleotide from mismatched or a : ap p / ts at rates similar to those for ssdna ( unpublished results , but exemplified by the fast rates of excision of frayed ends by pol / ul42 ) , only a portion of the p / ts occupied by the pol are cleaved at the fast burst rate in a single - turnover ( table 2 ) .
since no slow burst rate was observed for wild - type pol with either p / t , the results indicate that the remainder of the p / ts were either not bound to the enzyme or dissociated from it at a rate faster than that required to transfer the 3 primer terminus from the polymerizing to the exo site . in the presence of pol / ul42 , not only
is a large proportion of frayed primer cleaved with a fast burst rate constant , but the remainder that bound initially at the polymerization site ( 27% ; table 2 ) was transferred to the exo active site for cleavage prior to dissociation .
these results suggest that ul42 might increase the overall fidelity of dna synthesis by increasing the probability that a mismatched p / t will be excised prior to its dissociation from wild - type pol during processive synthesis , when most of the primer would be expected to be located at the polymerizing site .
as previously indicated by steady - state kinetic analysis , pre - steady - state kinetic analysis reveals that the excision of acv - tp opposite the matched dc template is extremely slow , with a burst rate constant approximately 2000-fold slower than for the fast burst rate constant for excision of dg on matched template ( table 2 ) .
the excision rate is slower than the rate of transfer from the pol to the exo site and/or the rate of dissociation from the p / t since no slower burst rate was observed .
the association of next correct dntp has been reported to lock the polymerase into a dead - end complex with acv - tp .
however , the comparatively small difference in excision burst rate constants in the presence versus absence of dntp following acv incorporation may suggest that the dntp stabilizes a replicating p / t within the polymerizing site , thereby reducing its rate of transfer from the pol to exo site [ 57 , 78 ] .
taken together , these results suggest the importance of the hsv-1 pol to possess a dynamic ability to switch the p / t between the polymerizing and exo sites for its ability to function properly , and a role for ul42 in preventing dissociation of pol from a mismatched primer terminus during active dna extension .
early steady - state experiments were used to determine the ability of the hsv-1 pol to extend mismatches . despite potent exo activity ,
the wild - type hsv-1 pol was observed to extend mismatches at high concentrations of next correct single nucleotide . however , the efficiency ( vmax / km ) for wild - type pol extension of mismatches with next correct nucleotide was considerably lower than for the exo pol [ 75 , 123 ] .
this was due in large part to cleavage of the mismatched primer terminus by the exo activity of the wild - type pol , resulting in an incorrectly matched p / t for extension with the tested nucleotide . indeed , when the template nucleotide located at position 1 with respect to the mismatched primer terminus was complementary to the incoming nucleotide , efficiency for extending the mismatched p / t was virtually the same as for matched [ 75 , 119 ] .
because dissociation would effectively reduce the vmax , these results demonstrate the effective ability of the wild - type hsv-1 pol to switch the primer to the exo site , cleave the mismatch , switch it back to the polymerizing site , and incorporate new nucleotide , all without dissociating .
it also suggests that with this kinetic partitioning , there is little cost to extension efficiency when proof - reading by the hsv-1 polymerase is required .
nevertheless , steady - state experiments do not provide an accurate measure of the ability of a polymerase to extend uncorrected mismatches .
running - start single - turnover experiments have been used to gain a better understanding of the kinetic barrier for hsv-1 pol to extend mismatches and how the polymerase responds to misincorporation during active polymerization .
the data in have been adapted and included in figure 1 for comparative purposes . in these experiments ,
the terminus of a 5 end - labeled primer was located 3 nucleotides upstream ( 3 ) of a target site that forced misincorporation due to the absence of matched nucleotide in the pool ( figure 1(a ) ) .
critical to these experiments was ( 1 ) a saturating or close to saturating concentration of all other nucleotides , ( 2 ) equilibrium binding of the polymerase to the p / t prior to initiation ( in the presence of edta ) , and ( 3 ) initiation of reactions with mgcl2 and excess dna to trap any polymerase molecules that dissociate from the p / t following initiation . because active polymerization would occur for several nucleotides
, the p / t would be expected to be firmly bound to the polymerase active site for several cycles of processive correct nucleotide incorporations prior to a forced misincorporation event .
surprisingly , three - fourths of the p / t productively engaged by the wild - type pol misincorporated nucleotide at the target position , and two - thirds of those were extended by at least one additional nucleotide prior to dissociation ( accounting for 48% of total
p / t productively bound by the pol , see figure 1(b ) ) .
the presence of a strong pause site suggests that the wild - type pol switches the primer end to the exo site , cleaves the mismatch to form a matched p / t , then rapidly switches back to the pol site for another forced misincorporation event .
repeated cycles of excision and incorporation ( idling ) then ensue in a single association of the pol catalytic subunit with p / t , until the mismatch is successfully extended ( figure 1(b ) ) .
these results indicate that the rate of transfer of the mismatched primer terminus between the polymerizing and exo sites ( one or more times ) is greater than the rate of dissociation of the wild - type pol from the p / t during forced misincorporation . the exo hsv-1 pol also misincorporated and extended mismatches , but the kinetics for misincorporation were markedly slower compared with wild - type pol , with only half of the productively engaged exo pol misincorporating within 2 sec ( figure 1(c ) ) .
the latter results are in excellent agreement with the less efficient ability of the exo pol , compared to the wild - type pol , in incorporating an incorrect nucleotide in standing start experiments ( table 1 ) .
however , a similar proportion of available mismatched p / t was extended by the exo pol , compared with the wild - type pol , albeit at a slower rate .
the near linear kinetics for mismatch extension by the exo pol are not the result of multiple turnovers of enzyme with p / t because of the presence of dna trap .
instead , the absence of a burst likely indicates that the rate - limiting step is the slow rate of primer switching ( 0.24/sec ) from the polymerizing to the exo site and back when the mismatch can not be cleaved .
the impact of the ul42 processivity factor in preventing mismatch extension is clearly observed in these running start experiments .
not only do fewer mismatched p / t accumulate in the presence ( 26% ) versus absence ( 76% ) of ul42 , but only 5.6% of all p / t ( 21% of those that misincorporated ) are extended one nucleotide beyond the mismatch and none were extended further ( figure 1(d ) ; ) . because the rates of incorporation of incorrect nucleotide and excision of mismatches or frayed ends ( tables 1 and 2 , resp . )
do not differ substantially for wild - type hsv-1 pol in the presence or absence of processivity factor , the results suggest that ul42 increases the efficiency and/or rates by which the mismatched / frayed primer terminus is transferred between the polymerizing and exo sites in a single association event during active replication .
similar running - start single - turnover experiments have been performed on p / ts in which the target site on the template was an ap site , located 4 nt downstream of the primer terminus ( figure 1(f ) ) .
the data have been adapted from a previously published report to permit side - by - side comparisons with mismatch extension data .
the wild - type hsv-1 pol extended the primer to the ap target site with more rapid burst kinetics than it did to a misincorporation target ( compare figures 1(g ) and 1(b ) ) .
however , compared to mismatches , ap sites posed a greater kinetic barrier to extension by the wild - type hsv-1 pol , since no lesion bypass was detected ( figure 1(g ) ; ) .
with such a high kinetic barrier , the rate of dissociation of the pol from the damaged p / t exceeded that required for extension , resulting in a smaller percentage ( 30% ) of primer extended to the ap target site ( figure 1(g ) ) compared to that which resulted from misincorporation ( 76% ; figure 1(b ) ) .
the absence of exo activity prevents excision of the residue that is incorporated opposite an ap site and , as observed following misincorporation , this slows the transfer of primer between the exo and polymerizing sites .
although the exo pol was able to bypass ap lesions , bypass synthesis was extremely inefficient ( figure 1(h ) ) .
these results are in agreement with the requirement for exo - deficiency in order for the hsv-1 pol to incorporate nucleotide opposite a cisplatin cross - link .
it was also shown in those studies that neither the wild - type nor exo pol , with or without ul42 processivity subunit , could completely bypass the cisplatin lesion .
however , ul42 did increase the ability of hsv-1 exo pol to incorporate nucleotide opposite the cisplatin lesion .
no studies to date have examined the ability of ul42 to permit ap lesion bypass synthesis .
ap sites have been shown to be present in hsv-1 replicating and virion dna at a frequency of 2.85.9/genome equivalent . given that wild - type pol is unable to bypass these lesions , there must be other mechanisms to permit synthesis through or around ap lesions , such as recombination or repair .
the newly discovered ap and 5-deoxyribose phosphate lyase activities of the hsv-1 pol , both of which are involved in base excision repair , might perform such a task to repair ap lesions .
it is also possible that other viral dna replication components would permit lesion bypass . the kinetic barrier to extending a mismatched p / t prevents most misincorporation events from becoming fixed mutations .
the exo activity of the hsv-1 pol reinforces the kinetic barrier by permitting excision of the mismatched primer terminus when the polymerase stalls .
in reality , the polymerase does not truly stall when it encounters a kinetic barrier , but rather engages in idling at that site through successive rounds of incorporation and excision , even in the absence of the ul42 processivity factor .
the idling activity is made possible by the ability of the polymerase to dynamically switch the p / t from the polymerizing site to the exo site and back .
pre - steady - state kinetic analysis has demonstrated that ul42 increases the processivity of the hsv-1 pol from 1700 to > 5,000 per association event .
ul42 also increases the efficiency of excision of mismatches formed during processive dna synthesis by increasing the rate and/or efficiency of transfer of the mismatched primer between the polymerizing and exo active sites .
this makes ul42 an unusual fidelity factor because it affects neither the rates of polymerization nor the rates of excision .
moreover , ul42 does not promote mismatch extension or lesion bypass , distinguishing it from the functions of the processivity factors of polymerases in the same family , such as t4 dna polymerase and mammalian pol [ 90 , 91 , 94 ] .
mounting evidence suggests that altering the ability of the hsv-1 pol to switch between the exo and pol active sites will have an impact on fidelity .
it is interesting to note that mutations in ul42 that either increase or decrease affinity for dna result in decreased replication fidelity and reduced numbers of viable virus progeny [ 120 , 121 ] .
although classical measures of this idling activity depend on the presence of a functional exo activity , the running - start single - turnover experiments described in figure 1 demonstrate the ability of the hsv-1 polymerase to switch the primer terminus between the exo and pol sites even in the absence of exo catalytic activity .
however , the increased affinity of the exo site for mismatched primer ( ssdna ) , and the corresponding decreased affinity of mismatched dna for the polymerizing site , renders the catalytically inactivated exo i site mutant pol ( d368a ) less efficient in switching behavior and in extending mismatched primers [ 75 , 123 ] .
the fact that the exo i mutant pol is also slower in its ability to incorporate incorrect dntp than the wild - type pol suggests that binding of an incorrectly matched dntp to the hsv-1 pol may destablize the association of the primer terminus with the polymerizing active site .
ul42 slows the rate of switching of the exo pol on mismatched termini during processive synthesis even more ( figure 1(e ) ; and ) .
if the rate of switching is slower than that for dissociation of the polymerase from the p / t , then extension would be disfavored , which could explain why no viable progeny have been isolated with this particular mutation .
mutations outside the exo domain may also impact p / t switching by the hsv-1 pol .
kinetic analysis of hsv-1 pol containing a finger domain mutation ( l774f ) showed significant stalling during normal elongation and a decreased efficiency for extending mismatches [ 125 , 126 ] . when introduced into the pol gene of the virus , this mutation increased fidelity of dna synthesis compared to that of the parental virus , regardless of the presence or absence of an exo iii site mutation [ 125 , 126 ] .
these properties are consistent with enhanced idling - turnover ability and increased primer switching compared to the wild - type pol . for t4 dna polymerase , mutations that increase the switching rate
have also been shown to possess antimutator activity , consistent with the importance of the ability of the pol to efficiently transfer the primer end between the polymerizing and exo active sites to maintain fidelity .
since the t4 switch mutations do not map to the same domain as the hsv-1 l774f mutation , additional studies will be required to ascertain the mechanism by which the hsv-1 finger domain mutant enhances replication fidelity . the ability of the hsv-1 dna polymerase to engage in dynamic switching of p / t between the pol and exo sites when kinetic barriers to extension are encountered is likely to be essential to the viability of virus .
it is interesting to note that part of the effectiveness of the chain - terminator , acyclovir , now appears to be its influence on the ability of the hsv-1 pol to switch the primer terminus between the polymerizing and exo sites . as suggested by hanes et al .
, the addition of dntp to an hsv-1 pol that has incorporated acv may favor retention of the acv - containing p / t at the pol site , making acv less likely to be removed by the exo activity .
we propose that compounds that specifically target the hsv-1 pol exo activity for inactivation , or that significantly inhibit the ability of replicating viral dna to be transferred between the polymerizing and exo sites , would be effective antiviral agents . by holding the primer terminus in the exo site , extension by the polymerase would be slowed and could lead to chain termination and replication failure .
holding the primer in the polymerase active site would be expected to decrease the ability of the polymerase to excise mismatches that are frequently formed by the polymerase and to increase the probability for mismatch extension .
this would lead to the accumulation of a lethal number of mutations during replication . due to the conserved nature of the polymerase among the herpesvirus family members
, it should be possible to target other herpesvirus polymerases in the same way , particularly those for which no effective nontoxic inhibitor has been identified to date .
Output:
| we discuss how the results of presteady - state and steady - state kinetic analysis of the polymerizing and excision activities of herpes simplex virus type 1 ( hsv-1 ) dna polymerase have led to a better understanding of the mechanisms controlling fidelity of this important model replication polymerase . despite a poorer misincorporation frequency compared to other replicative polymerases with intrinsic 3 to 5 exonuclease ( exo ) activity ,
hsv-1 dna replication fidelity is enhanced by a high kinetic barrier to extending a primer / template containing a mismatch or abasic lesion and by the dynamic ability of the polymerase to switch the primer terminus between the exo and polymerizing active sites .
the hsv-1 polymerase with a catalytically inactivated exo activity possesses reduced rates of primer switching and fails to support productive replication , suggesting a novel means to target polymerase for replication inhibition . |
PubmedSumm8882 | ***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: it has a special importance in health economics , and imposes higher costs on the health system compared to the other health system components ( 1 , 2 ) .
hospitals are the main consumer of resources in any health sector thus ; improvement of their efficiency is the main way to decrease the hospital costs ( 3 ) .
thus , providing criteria for evaluation of hospital performance and productivity is important ( 2 , 4 ) . these features are doubled , especially in developing countries , considering their economic structure and extreme vulnerability to deal with fluctuations in currency and commodity markets . in a way , that full response to the needs of consumers in this sector , even in the most advanced countries , seems to be out of reach ( 5 , 6 ) .
hence , the iranian hospitals are no exception from this issue . in this situation , the hospitals managers strategies for reducing the costs and increasing the productivity is necessary ( 7 ) .
productivity is one of the important concepts in assessing the performance of organization over time .
productivity expresses a kind of relationship between the amount of the produced goods or services and the amount of resources , which is consumed in producing goods and services .
therefore , productivity is a measure that shows the relationship between outputs and inputs ( 8) .
productivity indicators show improvement or reduction in performance ( 9 ) . the information obtained from productivity sub - indicators
are used to identify the problems of unites , define the strategies , and in case of need , make change in the staff behaviors ( 10 ) .
several techniques to assessment hospital efficiency and productivity are usually considered either parametric or non - parametric . ( 11 ) .
non - parametric methods such as data envelopment analysis are the most popular ( 12 ) .
this study was performed to determine the productivity rate of hospitals by using data envelopment analysis technique in ahvaz , iran .
this is a cross sectional study in which the panel data were used in a 4 year period from 2007 to 2010 .
the research was implemented in 17 teaching and non - teaching hospitals of ahvaz county , southern iran . as five hospitals did not agree to participate in this study ; and finally 12 hospitals were assessed .
variables were selected based on the experts opinions and previous studies ( 1 , 13 , 14 ) . the set of input and output variables that we have used in this study are similar to those applied in other studies ( 1517 ) .
the input measures included are number of nurses , number of occupied beds and number of physicians .
the output measures included are number of outpatients and inpatients , average of hospital stay , and number of major operations data were collected by studying the medical records and documents of the hospitals retrospectively .
data envelopment analysis technique and the malmquist indices with an input - orientation approach , was used to analyze the data and estimation of productivity .
we selected input - orientation approach and variable returns to scale ( vrs ) model for data analysis . in input - orientation approach , decision - making units ( dmus ) can change their inputs ( 18 , 19 ) . when the productivity and efficiency measurement are based on the input - orientation approach ( minimizing the production factors ) , a value of more than one show productivity decline and a value of less than one show productivity growth ( 1 , 7 ) .
data envelopment analysis technique and the malmquist indices with an input - orientation approach , was used to analyze the data and estimation of productivity .
we selected input - orientation approach and variable returns to scale ( vrs ) model for data analysis . in input - orientation approach , decision - making units ( dmus ) can change their inputs ( 18 , 19 ) . when the productivity and efficiency measurement are based on the input - orientation approach ( minimizing the production factors ) , a value of more than one show productivity decline and a value of less than one show productivity growth ( 1 , 7 ) .
as noted in table 1 , j hospital has the highest value and h hospital has the lowest value of total productivity changes .
therefore , the range of changes of productivity for hospitals was from 0.785 to 1.127 , and j and h hospitals had the best and worst performance respectively .
k hospital had the maximum value of changes in technical , technological , managerial and scale efficiency .
h hospital had the lowest technical and scale efficiency changes , g hospital had the lowest technological efficiency changes and i hospital had the minimum management performance changes .
six hospitals ( 50% ) had a value lower than 1 , which represents an increase in total productivity between 2007 and 2010 .
five hospitals ( 41.66 % ) had a value higher than 1 , which represents a decrease in total productivity and one hospital ( 8.33 % ) had a value equal to 1 which reflects stagnation in total productivity changes . efficiency and total productivity change by hospital type ( teaching and non - teaching hospital ) according to the table 2 ,
the average of total productivity was 1.024 , which reflects a decrease in productivity changes by 2.4% in study period .
the average total productivity change of all factors in the year 2008 was more than 1 , which shows that the level of productivity of hospitals has been decreased in this year .
changes in technological performance had a negative impact on the rate of productivity and had the main role in reducing productivity .
efficiency and productivity change in three years - period ( 200 - 8 - 2010 ) as noted in table 3 , mean of the productivity change had a significant difference among teaching and non - teaching hospitals ( p=0.001 ) in 2009 and had not significant differences in other years .
in general , there was no significant difference in average of productivity changes between teaching and non - teaching hospitals .
the results showed that the productivity of hospitals over the years 2007 - 2010 has increased and had an ascending trend .
however , the average of total productivity was 1.024 , which shows 2.4% reduction ; and changes in technological performance had the highest impact on decrease in value of total productivity .
different values for total factors productivity have been reported in different researches in iran and other countries .
a study in iran showed that just fewer than 60% of all hospitals at were technically efficient and therefore they were non - product because efficiency of units has direct association with productivity trend ( 2 ) .
( 8) in a similar study reported increase in the productivity of 31 regional hospitals in taiwan .
the average of productivity changes in the taiwan s hospitals was ( 0.874 ) was lower than average of productivity changes in our study .
one way to increase technical efficiency is decrease of length of stay and increase of hospital size .
it should be noted productivity change is affected scale efficiency changes , technological performance and managerial performance ( 13 , 15 ) .
( 22 ) reported that the average productivity of the hospitals has declined by 3.3% in ardebil and the technological efficiency changes had the most negative effects on total productivity .
evaluation of the causes of these effects can be helpful in improvement of the total productivity .
technological improvements play an important role in increasing the productivity of larger hospitals ( 23 ) .
findings of our study showed that despite improvement in productivity trend of hospitals , the average of productivity of hospitals not improved ; this result can be used as a warning in order to make better use of existing resources . some hospitals ( a
, b , c , g , h and i ) used resources the more appropriate which can be considered as a model for other hospitals ( d , e , f , i , j , k and l ) . in hospitals
that the main cause of low productivity is changes in technology efficiency , it seems that lack of enough familiarity of managers with the advanced hospital technologies , lack of equipment and inappropriate use of technology in diagnosis , care and treatment , are the main causes ( 22 ) .
second , medical record system is manual and third , dea software has technical limitations .
in the f and k hospitals the main cause of the low productivity is changes in technical efficiency therefore mangers must use inputs ( doctors , nurses and beds ) efficiently and increase the outputs . in hospitals
e that the main cause of low productivity is negative changes of scale efficiency therefore managers must improve the scale efficiency .
finally , according to results of this study , decrease of technological efficiency had the highest negative impact on average of total productivity of hospitals .
therefore , hospital managers and policy makers can use economic of scale methods including : optimizing size of hospitals , increase of production volume and decrease of the length of stay ( by means of discharge process optimizing ) for productivity improvement of hospitals .
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:
| abstractbackgroundthis study aimed to measure the hospital productivity using data envelopment analysis ( dea ) technique and malmquist indices.methodsthis is a cross sectional study in which the panel data were used in a 4 year period from 2007 to 2010 .
the research was implemented in 12 teaching and non - teaching hospitals of ahvaz county .
data envelopment analysis technique and the malmquist indices with an input - orientation approach , was used to analyze the data and estimation of productivity .
data were analyzed using the spss.18 and deap.2 software.resultssix hospitals ( 50% ) had a value lower than 1 , which represents an increase in total productivity and other hospitals were non - productive .
the average of total productivity factor ( tpf ) was 1.024 for all hospitals , which represents a decrease in efficiency by 2.4% from 2007 to 2010 .
the average technical , technologic , scale and managerial efficiency change was 0.989 , 1.008 , 1.028 , and 0.996 respectively .
there was not a significant difference in mean productivity changes among teaching and non - teaching hospitals ( p>0.05 ) ( except in 2009 years).conclusionproductivity rate of hospitals had an increasing trend generally .
however , the total average of productivity was decreased in hospitals . besides , between the several components of total productivity , variation of technological efficiency had the highest impact on reduce of total average of productivity . |
PubmedSumm8883 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: recently , a unique limbic encephalitis that predominantly affects young females and shows various manifestations , including initial psychosis , and subsequent central hypoventilation , intractable seizures , dysautonomia and prominent orofacial dyskinesia , has been noted [ 1 , 2 ] . in patients with this disorder
a new anti - neural antibody for the nr1/nr2 heteromers of the n - methyl - d - aspartate receptor ( nmdar ) has been identified as a disease - specific hallmark , recently adding that the nr1 is possibly a main epitope .
although it is now widely accepted that the presence of ovarian teratoma is an important predisposing factor for the development of anti - nmdar encephalitis [ 4 , 5 ] , the mechanisms that initiate the disease are still incompletely understood .
we here report on a young male patient with anti - nmdar encephalitis which developed during the recovery course of severe guillain - barr syndrome ( gbs ) , and propose that a post - infectious autoimmune mechanism may play an important role in the pathogenesis of anti - nmdar encephalitis .
a 19-year - old man with no history of systemic disease was hospitalized due to muscle weakness and dysesthesia in the extremities following cough and nasal discharge 2 weeks earlier .
neurological examination showed muscle weakness and sensory disturbance in the distal parts of the extremities , and all deep tendon reflexes were absent .
cerebrospinal fluid ( csf ) at 5 days after onset of weakness contained a normal cell count , but the concentration of total protein was elevated ( 52.8 mg / dl ) .
the patient was diagnosed as having gbs and treated with intravenous immunoglobulin ( ivig ) therapy ( 0.4 g / kg / day ) for 5 days . however , the symptoms worsened gradually , he was not able to raise his upper limbs and to walk from the 5th hospital day . furthermore , dysarthria , dysphagia , and dyspnea appeared gradually from the 9th hospital day .
he was transferred to our hospital on the 12th hospital day . on the day of transfer ,
nerve conduction studies showed reduced motor nerve conduction velocities ( right median nerve : 11.3 m / s , normal value > 55 m / s , right tibial nerve : 36.6 m / s , normal value > 45 m / s ) with conduction block ( fig .
1 ) , and sensory nerve action potentials could not be evoked in both nerves .
there was neither anti - gm1 igg antibody nor anti - gq1b igg antibody in the serum .
although mechanical ventilation was necessary from the day of transfer , muscle weakness in the extremities and respiratory function gradually improved after the second course of ivig therapy from the 22nd hospital day for 3 days , and the patient was trained for weaning from mechanical ventilation .
however , he started to experience occasional psychomotor agitation from the 37th hospital day , and generalized tonic convulsive seizures suddenly developed following paralytic ileus and tachycardia on the 42nd hospital day .
since the convulsive seizures did not respond to intravenous administration of diazepam , phenytoin , or midazolam , continuous thiopental infusion was used and mechanical ventilation was continued .
csf showed a slightly increased cell count ( 8/l , mononuclear cells 7 ) , a highly elevated level of total protein ( 446 mg / dl ) , and normal glucose concentration .
brain mri showed high - intensity lesions in the bilateral thalamus and medial temporal lobes on diffusion and flair images ( fig .
he was diagnosed as having some type of autoimmune encephalitis , and intravenous methylprednisolone pulse therapy ( 1,000 mg / day ) for 3 days followed by dexamethasone ( 16 mg / day ) was administered , and used until the 70th hospital day with a gradual dose reduction .
although the generalized convulsive seizures disappeared and the infusion of thiopental was ceased on the 52nd hospital day , orolingual dyskinesia gradually developed . on the brain mri on the 64th hospital day , the abnormal high - intensity lesions in the bilateral thalamus were reduced , while marked atrophy of the bilateral medial temporal lobes was seen ( fig .
2b ) . respiratory failure and autonomic dysfunction that included disturbed bowel movement and abnormal cardiovascular responses gradually improved , and he was released from mechanical ventilation on the 84th hospital day .
however , the patient remained unresponsive to verbal commands and severe orolingual dyskinesia persisted until he was transferred to a local hospital on the 193rd hospital day . during investigation of the causes of the encephalitis , there were no laboratory data suggesting viral encephalitis , including herpes simplex , influenza , varicella zoster , cytomegalovirus , measles , and human herpes virus-6 .
urological examination was normal and no detectable neoplasm was seen on either chest or abdominal ct .
two years after the onset of seizures , his condition was very similar to when he was discharged from our hospital , and repeated examinations showed no appearance of a tumor .
detection of anti - nmdar antibody on the same samples was carried out as follows : cdna encoding nr1 and nr2b was ligated into the expression vectors and transfected into human embryonic kidney ( hek ) 293 cells in the media containing 10 m mk-801 using lipofectamine ( invitrogen ) .
twelve hours after transfection , hek-293 cells were fixed in 4% paraformaldehyde in 0.1 m phosphate - buffered saline ( pbs , ph 7.4 ) for 20 min .
after non - specific binding was blocked with 10% goat serum in pbs , these cells were incubated with patient sera ( 1:40 ) or csf ( 1:2 ) overnight at 4c and then with fitc - conjugated rabbit anti - human igg ( bd biosciences ) for 30 min at room temperature .
slowfade gold anti - fade reagent ( molecular probes ) was applied to the slides and the staining was observed under a fluorescence microscope .
both serum and csf obtained from the 92nd hospital day specifically reacted with hek-293 cells expressing heteromers of nr1/nr2b ( fig .
in our case , encephalitis was shown by abnormal intensity of the bilateral thalamus and medial temporal lobes on brain mri at an early stage .
however , the former thalamic lesions seemed to be edema due to status epilepticus , and the main lesion of this encephalitis was assumed to be in the bilateral medial temporal lobes , because the thalamic lesions rapidly resolved after treatment , whereas the bilateral medial temporal lobes showed progressive atrophy .
moreover , his clinical manifestations consisted of psychiatric symptoms , intractable seizures , dysautonomia and involuntary movements , and anti - nmdar antibody was demonstrated in both serum and csf .
anti - nmdar encephalitis usually affects young females , and an early series of patients with this disease was found to have a high association of ovarian teratoma [ 3 , 4 ] .
thus , the pathogenetic significance of ovarian teratoma in this encephalitis was investigated and it was proposed that , since the ovarian teratomas obtained from diseased patients showed mature- and immature - appearing neurons with expression of nr2b and/or nr2a [ 3 , 4 ] , ectopically expressed nmdars in ovarian teratoma contribute to the production of antibodies to nmdars .
thus , early removal of ovarian teratoma has been recommended for patients with this disease .
however , a recent study on a large number of patients with anti - nmdar encephalitis has shown that this ovarian tumor could not be found in about 40 to 80% of adult patients with the disease [ 1 , 2 , 8 ] , although careful follow - up examinations on the detection of tumors are always required in these patients .
increased recognition of this unique encephalitis has also disclosed that children and adolescents also encounter it [ 9 , 10 ] , although the frequency of associated ovarian teratoma was much lower in children than adults .
additionally , a small number of male cases with anti - nmdar encephalitis were reported , indicating that other causes besides ovarian teratoma can produce encephalitis . in the pathogenesis of anti - nmdar encephalitis ,
the antibody immune response has been shown to be more relevant than cytotoxic t - cell mechanisms and the vast majority of patients with this type of disease have a history of prodromal flu - like symptoms .
it was , therefore , suggested that the preceding flu - like illness leads to the triggering of abnormal antibody production targeting nmdars .
in this situation the presence of ovarian teratoma with a high expression of nmdar epitopes may predispose or exaggerate the production of anti - nmdar antibodies ; these nmdar antibodies then cause a specific , titer - dependent , and reversible decrease in nmdar surface density and synaptic localization , especially in the hippocampus , resulting in learning , memory , and other behavioral deficits seen in patients with anti - nmdar - encephalitis .
immunosuppressive therapy , including corticosteroid , plasma exchange and ivig , has been used for the treatment of this disease .
recently , rituximab , an anti - cd20 monoclonal antibody , is expected to accelerate the recovery of patients with this type of disease .
our young male patient with anti - nmdar encephalitis lacked testicular or mediastinal teratoma , which was previously reported to be of paraneoplastic origin . on the other hand ,
his clinical course was characterized by a preceding attack of gbs : this disease is a representative post - infectious peripheral demyelinating neuropathy with underlying autoimmune abnormalities .
although a causative relationship between gbs and anti - nmdar encephalitis has not been studied , it is likely that gbs - related abnormal immune reactions secondarily caused another autoimmune state with anti - nmdar encephalitis .
although serial examinations of anti - nmdar antibodies in both serum and csf might be useful in clarifying the underlying immune condition of this patient , there were no available samples .
this case report has provided the clinical evidence that a parainfectious autoimmune reaction is an important pathogenetic mechanism in the development of anti - nmdar encephalitis .
Output:
| a 19-year - old man developed rapidly progressive muscle weakness and dysesthesia in the extremities , and dyspnea after a flu - like episode .
nerve conduction studies showed reduced motor nerve conduction velocities with conduction block , and sensory nerve action potentials could not be evoked .
the patient was diagnosed as having guillain - barr syndrome ( gbs ) , and was treated with 2 cycles of intravenous immunoglobulin ( ivig ) therapy and was assisted by mechanical ventilation . during the recovery course of the illness , he experienced several attacks of psychomotor agitation from the 37th hospital day , and generalized tonic convulsive seizures suddenly developed on the 42nd hospital day .
brain mri showed high - intensity lesions in the bilateral thalamus and medial temporal lobes .
the convulsions were controlled by continuous thiopental infusion ( until the 50th hospital day ) and mechanical ventilation ( until the 84th hospital day ) .
intravenous methylprednisolone pulse therapy ( 1,000 mg / day ) for 3 days followed by dexamethasone ( 16 mg / day ) was added .
after relief of convulsive seizures , prominent orolingual dyskinesia appeared , and on mri marked atrophy of the bilateral medial temporal lobes was seen .
anti - n - methyl - d - aspartate receptor ( nmdar ) antibodies in serum and cerebrospinal fluid were positive on the 92nd hospital day .
anti - nmdar encephalitis usually affects young females but a small number of male cases with this disease have been reported .
our male patient was unique in having gbs , a post - infectious autoimmune disease , as a preceding disease , suggesting that anti - nmdar encephalitis itself is caused by a parainfectious autoimmune mechanism . |
PubmedSumm8884 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: malignant lymphoma is the generic term given to tumors of the lymphoid system and these are divided into the following two major categories : hodgkin 's lymphoma and non - hodgkin 's lymphoma ( nhl ) .
nhl usually involves lymph nodes but can also involve extra - nodal sites and can occur in the stomach , skin , lung , salivary glands , and rarely in the mouth .
oral lesions of nhl may develop in the soft tissues or centrally within the jaws .
oral lesions appear as non - tender swellings commonly affecting the vestibule , gingival , or posterior hard palate and develop slowly , mimicking a dental abscess of endodontic or periodontal origin .
the present case report of gingival swelling as the first and only manifestation of extra - nodal follicular nhl also emphasizes the importance of accurate clinical and histologic diagnostic procedures to avoid delayed diagnosis or inappropriate treatment strategies when dealing with unspecific lesions in the oral cavity .
a 46-year old woman was referred to department of periodontics , sjm dental college and hospital , chitradurga , with a painful growth on gums of the posterior teeth of left lower jaw , from a general dentist .
the patient had noticed the sudden appearance of a painless mass about 3 weeks prior to referral . on extra - oral examination , she was non - febrile , without any palpable lymph nodes in the facial region , and she did not mention any recent sudden weight loss .
the patient gave history of hysterectomy one year back and post operative healing was uneventful .
intraoral examination revealed a gingival growth extending from the mandibular left first premolar region to the retro - molar trigone .
the mass was soft to firm and the overlying mucosa was slightly ulcerated and edematous [ figure 1 ] .
there were no palpable lymph nodes of any group in the head and neck region .
a panoramic radiograph revealed slight resorption of the alveolar crest between first and second molar [ figure 2 ] .
clinical diagnoses of pyogenic granuloma and squamous cell carcinoma were given .
the presence of numerous lymphocytes separated by thin fibrous septae with ulcerated epithelium and surface exudation was viewed on microscopic examination , and a repeat biopsy was suggested .
a second incisional biopsy was undertaken from the centre of the lesion to confirm the diagnosis .
histopathology from second biopsy tissue revealed atypical lymphoid cells arranged in diffuse sheets in a delicate connective tissue stroma with areas hemorrhage [ figure 3 ] .
the tumor cells showed indistinct margins having vesicular , hyperchromatic and pleomorphic nuclei with prominent nucleolus and abundant eosinophilic cytoplasm [ figure 4 ] .
based on the histopathological findings of second biopsy and the expert opinion , a final diagnosis of non - hodgkin 's lymphoma was made .
swelling extending from the gingival of left mandibular second premolar region to the retromolar trigone with obliteration of the vestibule panoramic radiograph showing only slight resorption of the alveolar bone in left mandibular molar area photomicrograph showing atypical lymphocytes arranged in sheets with minimal connective tissue stroma ( h and e , 100 ) photomicrograph showing rounded hyperchromatic atypical lymphocytes ( h and e , 250 ) the patient 's general health was examined by a physician to find out involvement of any other site .
investigations like complete hemogram , radiograph , and computed tomography scan were performed and no other site except the oral cavity ( gingival of left posterior teeth ) showed involvement .
she was then referred to kidwai memorial institute of oncology , bangalore , for treatment .
nhls are a group of highly diverse malignancies and have great tendency to affect organs and tissues that do not ordinarily contain lymphoid cells .
the head and neck is the second most common region for extra - nodal lymphoma after gastro - intestinal tract .
the involvement of nhl in the oral cavity is very uncommon accounting for only 0.1 to 5% of the cases reported .
patients often present with nonspecific clinical signs and symptoms like local swelling , pain or discomfort , and ulcer .
the oral nhl may mimic more common benign , oral and dental pathologic conditions such as pyogenic granuloma , periodontal disease , osteomyelitis , and other malignancies.[68 ] many a times , lymphoma presents in the oral cavity as the first identifiable evidence of the disease .
sometimes , these may also present as squamous - cell carcinoma and needs to be considered in the differential diagnosis .
there is considerable evidence that lymphomas at specific sites show a local inflammatory process in the beginning , followed by increased rate of cell division of lymphocytes and thereby increasing the chance of a malignant clone developing .
the prevalence of nhl is increasing among those who are immunocompromised , receiving organ transplants , and those with autoimmune disorders such as sjgren 's syndrome or rheumatoid arthritis .
an increased incidence of nhl has also been recognized in patients suffering from aids and oral lesions of nhl have presented as the first manifestation of aids . until recently
, the rappaport classification has been widely used which was based on the growth pattern of tumor cells ( nodular or diffuse ) , cell type , and degree of cell differentiation .
although the oral involvement of nhl is rare , they are the second most common oral malignant disease after oral squamous cell carcinoma , constituting 2.2% of all malignancies of the head - neck , and 3.5% of intraoral malignancies .
a differential diagnosis was made which included the following conditions : pyogenic granuloma , peripheral giant cell granuloma , squamous - cell carcinoma , and periodontal disease .
due to lack of local factors and good oral hygiene , pyogenic granuloma and periodontal disease were excluded from the diagnosis .
histopathologic findings ruled out peripheral giant cell granuloma and squamous - cell carcinoma . in the present case ,
histopathology of nhl usually shows sheets of chronic inflammatory cells , especially lymphocytes , mimicking an inflammatory reaction .
careful examination by an expert histopathologist is necessary to find out the pleomorphic and atypical lymphoid cells .
primary nhl of the gingiva can mimic other benign or reactive lesions and hence it is necessary to perform a biopsy and microscopic examination in cases where signs and symptoms persist in spite of treatment .
an early biopsy will provide an appropriate diagnosis and may help in avoiding the disease progression , thus improving the prognosis .
Output:
| non - hodgkin 's lymphoma ( nhl ) commonly presents as non - tender , enlarged lymph nodes , accompanied by diffuse symptoms of fatigue and low - grade intermittent fever and it is derived predominantly from the cells of the b lymphocyte series .
nhl cases occur extra - nodally and in 3% of these cases the initial presentation may be in the oral cavity .
though extra - nodal nhl of the oral cavity is a rare finding , patients with oral lesions of nhl commonly present at the dental clinic in the first instance . a careful clinical evaluation supported by histopathological and other laboratory investigations will help in identifying the disease at an early stage , resulting in better prognosis .
any delay in diagnosis has important implications on the morbidity and mortality of the condition . due to the rarity of intraoral nhl ,
we present one such a case with a complaint of tumor - like mass on the gingiva of lower molar region .
the lesion was clinically thought as pyogenic granuloma and later diagnosed as extra nodal nhl of the oral cavity . |
PubmedSumm8885 | ***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: he narrated that when he was in second grade ( age 7 ) , he and a fellow student were irritating his neighbor in the classroom .
the patient mentioned that the point broke off in his thigh and was never extracted .
he complained that the site still hurt intermittently and after all this time , he wanted the lump and the reported pencil point to be removed . examination of the anterior left thigh skin revealed a palpable 0.5-cm subdermal / subcutaneous elliptical lump in the skin .
there was a tinge of black to blue to it as if it had been tattooed .
the patient was explained the indications , risks and benefits of the procedure and he provided consent . a time - out was performed .
firm tan dermal - based soft tissue nodule with associated dark graphite precipitate was removed . in the midst of the removed tissue , a 4-mm cone - shaped pencil ( graphite )
two buried absorbable sutures were placed and three simple interrupted 4 - 0 vicryl sutures were used to close the wound . a triple antibiotic ointment was applied and the wound dressed in sterile fashion .
the patient was put on cephalexin to prevent secondary infection . the surgical wound healed without complications or significant scarring .
the literature reports on hyperpigmented nodules in the skin secondary to a retained pencil core .
hatano et al . in 2000 reported on a pencil core granuloma from a pencil tip injury that had occurred about 30 years prior .
fukunaga et al . in 2011 summarized 9 previously reported cases of pencil core granulomas , the oldest of which was 58 years old .
our case is unique in that we were able to recover the cone - shaped pencil tip and still write with it ( fig .
1 ) . in previous examinations of pencil core granuloma , giant cells and epithelioid cells had been observed .
histologic examination in our case similarly revealed foreign body reaction with abundant entrapped dark black pigment and chronic reparative changes , including dense sclerosis and focal granulation tissue formation ( fig .
furthermore , one report suggested more rapid growth of lesions and greater degree of tissue injury by colored pencils when compared to non - colored graphite pencils . a number of authors have commented on temporal changes in the granuloma , going from a relatively unchanged appearance to a rapid growth phase , ultimately leading to excision . the decision to explore and excise a pencil core granuloma can be thus based on changes in the skin lesion and/or concern for possible malignancy .
Output:
| a pencil core with an intact pencil tip was excised from the thigh of a 60-year - old male 53 years after a puncture wound .
histologic examination of the excised pencil core and the surrounding tissue revealed a foreign body reaction with abundant entrapped dark black pigment and chronic reparative changes , including dense sclerosis and focal granulation tissue formation . |
PubmedSumm8886 | ***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: radiative transfer is unique among parameterization problems for global atmospheric models because the governing equations are deeply grounded in fundamental physics , the approximations ( e.g. , of onedimensional radiative transfer ) applicable across many relevant scales , and the result entirely deterministic . in aerosolfree
clear skies , where scattering is small relative to absorption and emission , the problem is defined by the profile of extinction of the gaseous atmosphere , which is itself determined by the profiles of temperature , pressure , and the concentrations of radiatively active gases .
fluxes of longwave or terrestrial radiation also depend on how the extinction profile is related to the profile of local emission ( which also depends on temperature ) , while for fluxes of shortwave or solar radiation local emission can be neglected , but rayleigh scattering , which increases extinction and singlescattering albedo , changes the problem slightly . for monochromatic problems these calculations are straightforward so that the main challenge for atmospheric models is treating the spectral dependence of radiative fluxes .
the best available information for the spectral variation of radiation in the atmosphere comes from socalled linebyline models with full spectral detail .
when the state of the atmosphere is well characterized , such models are now able to match carefully calibrated observations to within fractions of percent at full spectral resolution [ see , for example , turner et al . , 2004 ;
this is sufficiently accurate , for example , that the very small spectrally dependent signal from a decade 's increase in co2 concentrations can be teased from surface measurements of spectral intensity that are dominated by secular changes in temperature and water vapor [ feldman et al . ,
the absolute accuracy of these models in individual cases is difficult to judge because it is quite difficult to separate errors in the characterization of the atmosphere from errors in the spectral variation of optical thickness ( vertically integrated extinction ) .
estimates from remaining spectrally resolved differences against observations suggest that absolute errors in broadband fluxes ( i.e. , fluxes integrated over all energy emitted by the sun or earth ) are no larger than about 1 w / m [ oreopoulos and mlawer , 2010 ] in the longwave .
comparisons in the shortwave between spectrally resolved measurements and model calculations have been less extensive but suggest that broadband flux errors are somewhat larger .
broadband fluxes are required by dynamical models of the atmosphere to compute heating and cooling rates within the atmosphere and surface fluxes of energy .
the opacity of the cloud and aerosolfree atmosphere ( e.g. , the clear , clean conditions of ghan ) depends strongly enough on temperature and radiatively active gas concentrations that the extinction of the gaseous atmosphere is computed anew at each location and time .
linebyline models are impractically slow for this task because absorption coefficients due to gases vary by many orders of magnitude over very narrow spectral intervals .
computationally efficient parameterizations therefore use techniques such as exponential sum fitting of transmissivities [ hunt and grant , 1969 ; wiscombe and evans , 1977 ] , correlated kdistributions [ lacis and oinas , 1991 ; fu and liou , 1992 ] , or the simplified exchange approximation [ fels and schwarzkopf , 1981 ; schwarzkopf and ramaswamy , 1999 ] to approximate the spectral integral using a relatively small number of quadrature points minimizing some measure of error across a distribution of atmospheric states .
( other simplifications frequently used in parameterizations , such as low angular resolution or the neglect of scattering in the longwave , do not introduce significant errors in aerosolfree clear skies . ) systematic assessments of parameterizations against the reference models on which they are based date back more than two decades [ ellingson and fouquart , 1991 ; cess et al . ,
parameterizations have improved over time such that the best now reproduce linebyline flux calculations in presentday conditions to within about 1 w / m [ oreopoulos et al . , 2012 ] , although a surprisingly large range of error still exists for such a wellunderstood problem .
parameterizations are substantially less accurate with respect to forcing calculations [ collins et al . , 2006 ; forster et al . ,
2011 ] ( i.e. , the change in flux due to a change in atmospheric composition ) in part because the sets of atmospheric states used to develop parameterizations often do not include large variations in composition [ see , e.g. , mlawer et al . , 1997 , section 4 ] . but
changes in radiative flux that arise from increasing levels of greenhouse gases are precisely the radiative forcing that drives climate change .
parameterization errors in estimates of clearsky instantaneous radiative forcing , a purely radiative quantity that might be determined to high precision , are one reason that different models participating in coordinated experiments ( e.g. , the coupled model intercomparison project or cmip ; see taylor et al .
, which describes the recently concluded cmip5 ) may be subject to different instantaneous forcing for the same change in atmospheric composition [ zhang and huang , 2014 ; chung and soden , 2015 ] .
this is especially true for large excursions from presentday conditions such as 4co2 ( carbon dioxide concentrations quadrupled from their preindustrial value ) . despite this concern ,
abrupt 4co2 experiments are widely used to obtain estimates of sensitivity and effective radiative forcing from timeevolving flux imbalance and temperature [ gregory et al . ,
here we examine the accuracy of the greenhouse gas component of a set of parameterizations used in atmospheric models . we consider both fluxes under a range of presentday conditions and the forcing from quadrupled concentrations of carbon dioxide under the same range of conditions .
we focus on parameterizations used in climate models ( roughly , those that participate in cmip experiments ) because these models are often used to understand the response to forcing ; here we seek to identify errors in the forcing itself .
, 2013 ] communities have focused on more processspecific metrics using a different set of models though with broadly similar results . )
we demonstrate below that recent revisions to parameterizations at several modeling centers have reduced error ( at least in our test cases ) but that errors in absorption relative to surface and topofatmosphere fluxes imply biases in presentday model hydrologic cycles and in the hydrologic sensitivity to increasing greenhouse gas concentrations .
we also show that parameterization accuracy often depends on atmospheric state and composition , suggesting that estimates of accuracy at the global scales needed to estimate radiative forcing error require largescale assessments across a wideranging set of conditions .
we report on calculations following a variant of the protocol used by the first phase of the continual intercomparison of radiation codes ( circ ) [ see oreopoulos et al . ,
2012 ] in which broadband fluxes are computed for atmospheric and surface conditions ( temperature , pressure , and greenhouse gas concentrations ) specified in between 55 and 66 layers , roughly comparable to the vertical resolutions used in climate models . in most cases
participants performed the calculations with radiative transfer codes extracted from the host model ( see the recommendation by forster et al . ) , although at least one implemented diagnostic calculations in a singlecolumn version of the full model .
we focus on the treatment of gases by considering four clearsky cases , with precipitable water vapor ranging from 0.32 to 4.85 cm , originally chosen for good agreement between spectral measurements at the surface and reference model calculations using estimates of the overlying atmospheric state .
we further simplify the problem by specifying no aerosols and spectrally uniform surface albedo and emissivity .
we perform two sets of experiments , one under the initially observed atmospheric conditions ( essentially repeating the shortwave case b calculations of oreopoulos et al . ) and a second in which the observed concentrations of co2 have been quadrupled .
fluxes are reported at the top of atmosphere and the surface . atmospheric absorption or emission ( radiative divergence )
many provided results from the current version of their radiation parameterization ; some also provided results from the version used in cmip5 [ taylor et al . , 2012 ] .
calculations made with version 12.2 of the linebyline radiative transfer model ( lblrtm ) model [ clough et al . ,
2005 ] provide the benchmark , as they did for circ ( though circ used a slightly older version ) .
although our assessment does not include every parameterization used by models participating in cmip , several parameterizations are used in more than one model , so that the radiation component is even less diverse than the already interdependent set of models itself [ knutti et al . ,
as with past assessments , we find that reference models agree with one another to within 1 w / m , or to fractions of a percent , for almost all calculations , though this level of agreement is not a measure of uncertainty .
the absolute accuracy of linebyline models , as measured by comparisons of highresolution spectra against observations [ e.g. , delamere et al . , 2010 ; mlawer et al .
, 2012 ; alvarado et al . , 2013 ] , is improving over time . in most cases improvements
are due to refined information about the presence , position , and strength of individual absorption lines or continua .
better spectral information introduces changes in broadband fluxes , illustrated in figure 1 by results from an older version ( 9.4 + ) of lblrtm ( orange squares in this and all subsequent figures ) which has less complete spectroscopy and different models for the water vapor continuum , and agrees less well with spectrally resolved observations , than the more recent version ( 12.2 ) we use as our benchmark .
( broadband fluxes and forcings are far more similar than spectrally resolved differences ; see alvarado et al . .
) more sophisticated treatment of line interactions is also useful : the primary difference between the arts 2.2 ( small black squares ) and arts 2.3 ( large black squares ) is the treatment of line mixing by co2 ( revisions to continua , also present , have a small impact ) .
full names of the radiative transfer codes and the institutions using them is provided in the supporting information .
( left ) errors in topofatmosphere net downward broadband longwave flux under presentday conditions and ( right ) error in forcing from co2 concentrations quadrupled from presentday values for a variety of reference models ( squares , including one highresolution kdistribution model ) and parameterizations used in climate models ( circles ) .
calculations for four atmospheric profiles are ordered by columnintegrated water vapor ranging from 0.32 to 4.85 cm .
histograms along the right edge of each panel show the error by model type ( black for reference models , dark grey for current parameterizations , and light grey for parameterizations used in cmip5 ; normalized across model categories ) in intervals of 1 ( figure 1 , left ) or 0.5 ( figure 1 , right ) w / m ) centered on 0 .
parameterization error is larger but still modest , with error in some parameterizations depending strongly on the water vapor path .
parameterizations that have been updated since cmip5 are more accurate than their predecessors ( compare filled circles and dark grey histogram bars to open circles and light grey bars . ) nonetheless , linebyline model results are almost entirely determined by the underlying spectroscopic data including models for absorption continua .
all the linebyline models in this study use the same continua in the longwave , so spread among the reference models does not reflect true uncertainty . indeed , linebyline models have agreed well with one another for several decades [ e.g. , ridgway and arking , 1991 ] , often to a greater degree than they have agreed with observations .
whatever the underlying uncertainty in linebyline calculations , parameterizations are constructed to reproduce these reference model results across a range of atmospheric conditions . by this measure
parameterization accuracies vary more widely across quantities ( e.g. , topofatmosphere versus surface flux ) , spectral intervals , and atmospheric conditions than do reference models . for topofatmosphere longwave flux and forcing , as one example
, parameterization error is relatively low ( figure 1 ) [ see also oreopoulos et al . ,
2012 ] , but even here errors of 2 w / m ( roughly 1% , depending on the case ) in presentday net flux and 0.5 w / m ( 10% ) in forcing from quadrupled co2 concentrations are common .
figure 1 is meant to be illustrative ; readers interested in details will find an exhaustive set of figures in the supporting information .
revisions to parameterizations since cmip5 have reduced errors , in some cases dramatically , with respect to both flux and forcing ( compare the filled circles and dark grey histogram bars in figure 1 to the open circles and light grey histogram bars ; see also figures s1 and s2 in the supporting information ) . in most cases
the reduced error is due to improved parameterizations of spectroscopy , i.e. , more accurate treatment of how the optical thickness of the gaseous component of the atmosphere depends on temperature , pressure , and composition .
( other changes may be relevant for more complicated atmospheric conditions including aerosols and clouds . )
perhaps more importantly , errors depend to some extent on atmospheric state including the profile of temperature and humidity .
this is evident in how the error in presentday flux in the giss parameterizations ( shown in brown circles ) , and the error in forcing in all models but especially mstrnx(green circles ) , depend on columnintegrated water vapor , which increases from left to right in figure 1 .
as we discuss below , the state dependence of parameterization error makes it hard to extrapolate from relatively few cases , even those constructed to sample , say , latitudinal dependence [ myhre and stordal , 1997 ; forster et al . ,
relationships among errors at the top of atmosphere , surface , and within the atmosphere can have important impacts on the host model : because globally averaged surface radiative fluxes affect the planet 's surface temperature while net radiative cooling controls the global amount of precipitation , radiation parameterization errors can impact presentday energy and water cycles nearly independently . in general , errors in longwave fluxes at the topofatmosphere and surface often partially compensate for one another ( figure 2 , left ) .
for some parameterizations the reasons for this compensation are understood : the gfdl longwave parameterization , for example , includes energy in a narrower spectral interval than do the reference calculations , resulting in smaller upwelling fluxes ( positive error ) at both the surface and top of the atmosphere and hence very small impacts on atmospheric cooling .
errors in surface net downward ( left ) longwave and ( right ) shortwave flux in the present day as a function of errors in net topofatmosphere flux , along with ( diagonal ) isolines of constant error in atmospheric absorption inferred from fluxes at the boundary .
axis tick marks are every 1 w / m and absorption isolines every 5 w / m .
errors in longwave boundary fluxes and radiative divergence are generally within a few w / m , especially for current parameterizations , while errors in shortwave fluxes and absorption are twice as large .
calculations in the shortwave are generally less accurate in absolute terms than in the longwave [ see also oreopoulos et al . ,
2012 ] , though for boundary fluxes the relative errors are similar ( within a few percent ) .
more importantly , shortwave errors at the top of atmosphere tend to be of opposite sign to those at the surface , leading to errors in radiative divergence as large as 10 w / m or 5% even for current parameterizations .
errors for the giss and lmdz cmip5era parameterizations are even more dramatic . in all but
one parameterization shortwave absorption tends to be underestimated , implying a bias toward increased global precipitation in many host models .
the exception is the gfdl parameterization , for which slightly greater solar absorption is consistent with the reference model on which the parameterization is based .
this linebyline model absorbs more than our benchmark due to more recent underlying spectroscopic data and to a different treatment of water vapor continua due to paynter and ramaswamy .
thus , the overestimate of absorption by gfdl relative to our reference is more properly viewed as a legitimate difference than an error .
similarly , the partitioning of forcing errors within and at the boundaries of the atmosphere means that parameterization errors may project differently onto climate ( temperature ) and hydrologic sensitivities to increasing concentrations of greenhouse gases . in the shortwave
most 4 co2 forcing errors , like errors in presentday fluxes , are of opposite sign at the boundaries ( see figure 3 , left ) so that errors in radiative divergence are relatively larger than at the surface or the top of the atmosphere .
this implies that radiation parameterization errors will have larger impacts on hydrologic sensitivity than on climate sensitivity .
the situation is much better in the longwave as shown in figure s3 . in practice relationships between forcing at the boundaries of and within the atmosphere
will be modified by tropospheric and stratospheric adjustments , normally considered as part of the total forcing , that may dampen or amplify one error without affecting others .
( left ) errors in surface net downward shortwave forcing from quadrupled presentday co2 concentrations as a function of error in net topofatmosphere forcing , along with ( diagonal ) isolines of constant error in atmospheric absorption forcing .
axis tick marks are every 1 w / m and absorption isolines every 5 w / m . for many parameterizations errors in topofatmosphere forcing
are smaller than errors in surface forcing , implying errors in absorption forcing with impacts on the host model 's hydrologic cycle .
( right ) error in solar absorption forcing as a function of error in the presentday estimates of solar absorption .
parameterizations have characteristic relationships among presentday and forcing errors that outweigh the impact of atmospheric state .
it is tempting to think of parameterizations as being better or worse depending on some measure of the error in , for example , presentday fluxes , but the size of the error under presentday conditions says nearly nothing about the magnitude of errors in forcing ( figures 3 , right , and s4 ) .
instead , relationships between errors in presentday and 4 co2 conditions are determined more by the parameterization being used than by atmospheric state . to the extent that these results hold on a global scale , it suggests both that presentday biases do not imply errors in forcing ( e.g. , the met office or gfdl parameterizations ) and , conversely , that parameterizations with small errors in the present day may still have significant forcing errors ( e.g. , the ccc and rrtmg parameterizations )
a focus on clear skies may seem narrow given that roughly two thirds of the planet 's surface at any given time is covered by some kind of cloud [ e.g. , stubenrauch et al .
but clearsky errors exist even in cloudy skies ( though they need not add linearly to errors introduced in the treatment of clouds ) , and clouds do not affect forcing directly , so that characterizing the error in aerosolfree clear skies remains a useful starting point for assessing errors in radiative forcing .
in particular , the models to be used in cmip6 [ meehl et al . , 2014 ] are still under construction and the radiation parameterizations are subject to revision before simulations are made and shared .
one goal of intercomparison exercises is to identify errors so they may be fixed ( see discussions in cahalan et al .
, for example ) , and this study has already motivated two changes reflected in our results : spectroscopy was updated in the giss parameterizations , and an important simplification ( the assumption that surface skin and surface air temperature are identical ) was relaxed in the lmdz and cnrm longwave parameterizations after initial calculations demonstrated relatively large errors in two cases .
some , we hope , will expand the range of atmospheres used to train the parameterization to include conditions such as large concentrations of greenhouse gases .
the reference models on which radiation parameterizations are based are themselves moving targets whose results change modestly as knowledge of the underlying spectroscopy improves , especially in the shortwave . all reference models in this study , for example , rely on the hitran ( highresolution transmission ) spectroscopic data ; differences between the 2012 and 2008 versions [ rothman et al . , 2009 , 2013 ] explain half or more ( 1 to 1.5 w / m , depending on the case ) of the difference in absorption calculations with lblrtm ( which uses the older version ) and the gfdl rfm linebyline model . periodic and/or continual assessments of radiation parameterizations help modeling centers from straying too far from current spectroscopic knowledge .
radiation parameterization error is a function of the state of the atmosphere , as is clear from figure 1 .
the set of conditions used in our calculations was originally determined by the availability of highquality observational data with which linebyline models could be validated [ turner et al . , 2004 ] .
we can not extrapolate from these limited results to obtain global estimates of parameterization error in even in aerosol and cloudfree skies .
one goal of the radiative forcing model intercomparison project ( rfmip , http://www.wcrp-climate.org/modelling-wgcm-mip-catalogue/modelling-wgcm-mips/418-wgcm-rfmip ) associated with cmip6 is to provide such globally relevant estimates , under presentday and future conditions and in strongly forced scenarios , by performing offline radiative transfer calculations under a much larger range of atmospheric conditions than is discussed here or in past assessments a set of conditions designed to allow for estimates of global parameterization error .
these calculations will enable the surprisingly large diversity in instantaneous clearsky radiative forcing from 4 co2 [ zhang and huang , 2014 ; chung and soden , 2015 ] , for example , to be decomposed into correctable parameterization errors and legitimate differences in model climatology .
highly accurate calculation of radiative fluxes is of primary interest to the climate modeling community where long freerunning simulations and highly variable greenhouse gas concentrations are the norm .
the range of parameterization errors , especially with respect to forcing , implies that specifying changes in greenhouse gas concentrations ( as in cmip ) does not completely determine the instantaneous clearsky radiative forcing to which each model is subject . in fairness
it is the effective radiative forcing , including modelspecific rapid adjustments [ see , e.g. , sherwood et al . ,
2015 ] and statedependent sensitivities , that is relevant to determining the longterm climate response .
2014 ] will partly mask and may well outweigh the range of parameterization error . but rapid adjustments themselves can be influenced by radiation parameterization error [ ogura et al . , 2014 ] , and , given
the maturity of understanding about radiative transfer , global estimates of parameterization error are a necessary first step in efforts to characterize and assess radiative forcing .
Output:
| abstractthis article reports on the accuracy in aerosol and cloudfree conditions of the radiation parameterizations used in climate models .
accuracy is assessed relative to observationally validated reference models for fluxes under presentday conditions and forcing ( flux changes ) from quadrupled concentrations of carbon dioxide .
agreement among reference models is typically within 1 w / m2 , while parameterized calculations are roughly half as accurate in the longwave and even less accurate , and more variable , in the shortwave .
absorption of shortwave radiation is underestimated by most parameterizations in the present day and has relatively large errors in forcing .
error in presentday conditions is essentially unrelated to error in forcing calculations .
recent revisions to parameterizations have reduced error in most cases .
a dependence on atmospheric conditions , including integrated water vapor , means that global estimates of parameterization error relevant for the radiative forcing of climate change will require much more ambitious calculations . |
PubmedSumm8887 | ***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 recent years , in response to the medical improvements , the field of infection control has progressed by cooperation of the epidemiology with health sciences to decrease risk factors for health care - associated infections ( hals ) ; therefore , interventions to prevent hals should be implemented .
the primary role of an infection - control program is to reduce the risk of nosocomial infection through protecting patients , employees , health care students , and visitors ( 1 ) .
health care - associated infections are reported in 1.7 million cases annually in the united states with approximately 100,000 deaths ( 2 ) .
the functions of a hospital epidemiology program vary from institution to institution , but can be generally divided into the following areas : surveillance , outbreak investigation , education , employee health , the monitoring and management of institutional antibiotic use and antibiotic resistance , the development of infection - control policies and procedures , environmental hygiene , and new - product evaluation .
nearly 60% of the admitted patients receive antibiotics , and antibiotic usage varies widely across hospitals ( 3 ) .
the hospital epidemiology program should monitor the current antimicrobial status and susceptibility profiles on a regular basis to observe the trends in the development of antibiotic resistance .
the results should be adjusted with the antimicrobial agents currently used in the hospital .
the best data are obtained if prophylactic antibiotics are distinguished from antibiotics used for treatment .
efforts should be made to optimize antimicrobial prophylaxis for surgical procedures , optimize selection of the first choice antibiotic and duration of empiric antimicrobial therapy , and improve antimicrobial prescribing practices .
a variety of approaches can be undertaken including educational , administrative , e g formulary restrictions , and direct interventions by a team that manages antimicrobial use in the real time ( 4 ) .
post operation wound infection is a major cause of morbidity , mortality , and health care costs .
a considerable proportion of the millions of operations in the world each year are complicated by a surgical site infection ( ssi ) ( 5 ) .
when an ssi occurs , hospital readmissions and health care services at home increase ( 6 ) .
the use of antibiotics to prevent postoperative infections plays an important role in reducing the incidence of postoperative infections , duration of stay in hospital , cost of treatment , mortality , and helps the patient go back to the normal life more quickly ( 7 ) .
locally published studies ( in farsi ) indicated that antibacterial agents , ranked second after analgesic drugs in iran and the consumption of these drugs in the country shows positive trend over the years . although it was expected that the new antibiotics reduce the number of deaths and the incidence of infectious diseases , in practice they did not ( 8 , 9 ) . indeed , increasing the incidence of infectious diseases caused by bacterial resistance against antibiotics , emerging and re - emerging of infectious diseases , and mortality of nosocomial infections are mostly due to the incorrect use of antibiotics that is a major health problem in the country ( 8 , 10 , 11 ) .
however , despite the effectiveness of prophylactic antimicrobials to prevent ssis , the use of antibiotic prophylaxis is often inappropriate .
previous reports indicated that timing of administration , selection of the antibiotic , and duration of prophylaxis were inappropriate in the great majorities of cases ( 5 , 7 , 12 - 16 ) .
while antibiotic prophylaxis is common in surgical procedures , inappropriate use of antibiotics occurs in 25% to 50% of the general elective surgeries ( 17 ) .
unnecessary use of antibiotics and prolonged antibiotic prophylaxis ( more than 48 hours ) are significantly associated with increased risk of antimicrobial resistant microorganisms ( 7 ) .
to establish strategies for rational use of antibiotics to prevent ssi in hospitals , it is necessary to be aware of the current status of antibiotic use patterns . searching the database of ahvaz university of medical sciences ( published dissertations and articles ) shows that official reports or studies in this field in khuzestan province do not exist ; therefore , the current study aimed to determine the prophylactic antibiotic use patterns in a teaching hospital affiliated to jundishapur university of medical sciences .
simple descriptive study . from april 2011 to march 2012 , this study performed in razi hospital affiliated to ahvaz jundishapur university of medical sciences . according to mangram 's guideline ,
post - surgical wounds are categorized as : class 1 : clean wound ; an uninfected operative wound in which no inflammation is encountered and the respiratory , alimentary , genital , or uninfected urinary tract is not entered .
in addition , clean wounds are primarily closed and , if necessary , drained with closed drainage .
operative incisional wounds that follow non penetrating ( blunt ) trauma should be included in this category if they meet the criteria .
class 2 : clean - contaminated wound ; it is an operative wound in which the respiratory , alimentary , genital or urinary tracts are entered under controlled conditions and without unusual contamination .
specifically , operations involving the biliary tract , appendix , vagina , and oropharynx are included in this category , provided that no evidence of infection or major break in technique is encountered .
in addition , operations with major breaks in sterile technique , e.g. open cardiac massage , or gross spillage from the gastrointestinal tract , and incisions in which no acute purulent inflammation is encountered are included in this category .
class 4 : dirty - infected wound ; that is old traumatic wounds with retained devitalized tissue and those that involve the existing clinical infection or perforated viscera .
this definition suggests that the organisms causing postoperative infection were present in the operative field before the operation ( 18 ) . in the current study , based on the extracted data from medical files , the patients possessing the inclusion criteria were reviewed as cases .
procedure was defined as clean if no inflammation was encountered and the respiratory , alimentary , genital , or infected urinary tract was not entered .
procedure was defined as clean - contaminated if genital , alimentary respiratory or infected urinary tract was entered .
operations involving the appendix , biliary tract , vagina and oropharynx are also included in clean - contaminated procedures .
the procedure was dirty - infected if clinical infection existed or devitalized tissue was observed in the old traumatic wounds .
prophylactic antibiotic was necessary for all clean - contaminated procedures and certain clean procedures , that is the ones in which intravascular / joint prosthetic device was inserted or there were risk factors , i.e. diabetes mellitus , malnutrition , obesity , irradiation history , use of immunosuppressant , or smoking . dirty or contaminated procedures under treatment of antibiotics were not considered prophylaxis .
this criterion was as follows : cefazolin is the selected antibiotic for cardiac , orthopedic , vascular , and neurosurgery operations ; where methicillin resistant staphylococcus aureus ( mrsa ) is suspected to cefazolin , the study shifted to vancomycin and in the case of anaerobic pathogens exist , metronidazole was added .
dose and timing of antibiotic is defined as proper if infusion of one to two grams cefazolin , one gram vancomycin or 500 mg metronidazole started 60 minutes before incision and repeated three to five hours cefazolin , six to eight hours metronidazole , or 12 hours vancomycin after the first dose .
duration of prophylaxis was considered sufficient if lasted less than 24 hours , except 48 hours for cardiac surgery .
patients were studied according to the type of surgery , the department they were admitted in , and the regimen of antibiotic prophylaxis .
all variables were analyzed including demographic characteristics , underlying diseases , type of illness , kind of surgery , received antibiotics , the mode and dose of antibiotic , and the length of treatment .
indications for antibiotic use , proper or inappropriate antibiotics , an antibiotic or combination of antibiotics , dosage , and the length of treatment for each patient were administrated , based on the abovementioned definitions in the textbook of infectious diseases ( 7 ) .
from april 2011 to march 2012 , this study performed in razi hospital affiliated to ahvaz jundishapur university of medical sciences .
according to mangram 's guideline , post - surgical wounds are categorized as : class 1 : clean wound ; an uninfected operative wound in which no inflammation is encountered and the respiratory , alimentary , genital , or uninfected urinary tract is not entered . in addition ,
operative incisional wounds that follow non penetrating ( blunt ) trauma should be included in this category if they meet the criteria .
class 2 : clean - contaminated wound ; it is an operative wound in which the respiratory , alimentary , genital or urinary tracts are entered under controlled conditions and without unusual contamination .
specifically , operations involving the biliary tract , appendix , vagina , and oropharynx are included in this category , provided that no evidence of infection or major break in technique is encountered .
in addition , operations with major breaks in sterile technique , e.g. open cardiac massage , or gross spillage from the gastrointestinal tract , and incisions in which no acute purulent inflammation is encountered are included in this category .
class 4 : dirty - infected wound ; that is old traumatic wounds with retained devitalized tissue and those that involve the existing clinical infection or perforated viscera .
this definition suggests that the organisms causing postoperative infection were present in the operative field before the operation ( 18 ) . in the current study , based on the extracted data from medical files , the patients possessing the inclusion criteria were reviewed as cases
procedure was defined as clean if no inflammation was encountered and the respiratory , alimentary , genital , or infected urinary tract was not entered .
procedure was defined as clean - contaminated if genital , alimentary respiratory or infected urinary tract was entered .
operations involving the appendix , biliary tract , vagina and oropharynx are also included in clean - contaminated procedures .
the procedure was dirty - infected if clinical infection existed or devitalized tissue was observed in the old traumatic wounds .
prophylactic antibiotic was necessary for all clean - contaminated procedures and certain clean procedures , that is the ones in which intravascular / joint prosthetic device was inserted or there were risk factors , i.e. diabetes mellitus , malnutrition , obesity , irradiation history , use of immunosuppressant , or smoking . dirty or contaminated procedures under treatment of antibiotics were not considered prophylaxis .
this criterion was as follows : cefazolin is the selected antibiotic for cardiac , orthopedic , vascular , and neurosurgery operations ; where methicillin resistant staphylococcus aureus ( mrsa ) is suspected to cefazolin , the study shifted to vancomycin and in the case of anaerobic pathogens exist , metronidazole was added .
dose and timing of antibiotic is defined as proper if infusion of one to two grams cefazolin , one gram vancomycin or 500 mg metronidazole started 60 minutes before incision and repeated three to five hours cefazolin , six to eight hours metronidazole , or 12 hours vancomycin after the first dose .
duration of prophylaxis was considered sufficient if lasted less than 24 hours , except 48 hours for cardiac surgery .
patients were studied according to the type of surgery , the department they were admitted in , and the regimen of antibiotic prophylaxis .
all variables were analyzed including demographic characteristics , underlying diseases , type of illness , kind of surgery , received antibiotics , the mode and dose of antibiotic , and the length of treatment .
indications for antibiotic use , proper or inappropriate antibiotics , an antibiotic or combination of antibiotics , dosage , and the length of treatment for each patient were administrated , based on the abovementioned definitions in the textbook of infectious diseases ( 7 ) .
of the total 13763 patients 47.5% and 52.5% were male and female respectively , 8945 procedures were clean , 3440 were clean - contaminated , 963 were contaminated and 412 were dirty .
of the total 8586 patients who took antibiotics for preventive purposes , 4815 ( 56% ) required antimicrobial prophylaxis , and 3771 ( 44% ) patients did not .
unnecessary use of prophylactic antibiotics was observed in 3771 ( 44% ) patients . of the total 4815 medical procedures requiring antimicrobial prophylaxis , all received it . of the 4815 patients who received perioperative prophylaxis , 4182 ( 86.9% ) cases
received it appropriately , and 633 ( 13.1% ) received it inappropriately , 397 ( 8.2% ) cases received inappropriate dosage , and 457 ( 9.5% ) cases received antibiotic longer than 24 hours .
cefazolin , vancomycin , gentamicin , and metronidazole were the most commonly used drugs for prophylactic purposes .
the frequency of patients who received cefazolin in the departments of obstetrics , general surgery , and orthopedics was 4261 , 2457 , and 2322 , respectively .
the frequency of patients who received vancomycin in the departments of obstetrics , general surgery , and orthopedics was 2025,820 , and 705 , respectively .
the number of patients who received gentamicin in the departments of obstetrics , general surgery and orthopedics was 1152 , 2300 , and 1025 respectively , and the number patients who received metronidazole in the departments of obstetrics and general surgery was 512 and 1750 , respectively . the frequency of patients who received these antibiotics is shown in figure 1 .
antimicrobial selection , cefazolin , vancomycin , and metronidazole , was appropriate in most of the cases except for gentamicin .
comparison of the hospital departments for prophylaxis and unnecessary prophylaxis are shown in tables 2 and 3 .
comparison of the hospital departments for incorrect antibiotic regimen , inappropriate dosage of antibiotic , and the length of treatment are shown in table 4 .
the most unnecessary antibiotic use was observed in general surgery ward and the most inappropriate antibiotic regimen , wrong dosage , and length of antibiotics were observed in obstetrics ward .
of the six infection prevention measures , three core measures contain recommendations regarding the selection of prophylactic antibiotics , timing of administration , and duration of therapy ( 12 ) . in the current study ,
for most of the patients undergoing clean - contaminated surgeries , gastrointestinal , orthopedic , and gynecologic , infection control committee recommended an antibiotic regimen including the first generation cephalosporin such as cefazolin or vancomycin , when mrsa infection is suspected ; with or without metronidazole , if anaerobic pathogens were likely , as the choice antibiotic regimen to prevent post operation infections .
results of the current study revealed that the current patterns of using antibiotics to prevent surgical infections in razi hospital were not favorable . in total , approximately 45% of antibiotics were prescribed without indication and were unnecessary .
approximately 13% ( 8.2% to 13% ) of the indicated antibiotic prophylaxis was inappropriate at least in antibiotic regimen , dose , or duration of antibiotic administration . in spite of hospital infection control recommendations ,
the application of prophylactic antimicrobials to prevent ssis and use of antibiotic prophylaxis were often inappropriate .
published studies indicate that the antibiotic regimen selection , timing of administration , dose of antibiotic and duration of prophylaxis in majority of the cases is inappropriate ( 5 , 7 , 12 - 16 ) .
for example it is administered when not required , not administered when required , or not administered properly ( 7 , 15 ) .
in contrast to the findings of other studies , however , the prescription of antibiotics in iranian hospitals is irrational , it is not higher than those of the other regions of the world , but it is still unacceptable .
the infection control committee in razi hospital has not distributed a guideline for surgical prophylaxis based on the standard documents and original researches conducted by microbiology department of the university regarding the most common isolated organisms and susceptibility patterns .
it seems advisable that surgeons consult with infectious diseases specialist before administration of antibiotics for prophylaxis for surgical procedures in special clinical situations ( 19 ) the present study found that approximately 42% of the studied patients received appropriate antimicrobial prophylaxis .
prophylaxis was inappropriately performed in 13% of 4,815 patients requiring prophylaxis . in the current study ,
3771 ( about 44% ) patients received preoperative antibiotic , but they did not need it .
thus , the most common wrong activities of surgical prophylaxis in razi hospital appear to be excessive use of antibiotics .
this finding is consistent with reports from developing countries as well as iran ( 16 , 20 , 21 ) , but in contrast to developed country where the most common error in the surgical prophylaxis practice is omission of antibiotics rather than their excessive use ( 15 ) .
the current study also found that all of the patients under study received antibiotics on time .
as a routine in the hospital , initiation of prophylaxis is at the time of anesthesia induction .
this finding is similar to that of the studies performed in other areas ( 15 , 16 ) .
however , six different drugs or drug combinations were used ; cefazolin , cefazolin plus gentamicin , vancomycin , vancomycin plus gentamycin , cefazolin plus metronidazole , and vancomycin plus metronidazole .
this problem is similar to that of a study previously performed ( 16 , 22 ) .
surgeons ` unawareness to consult with infectious disease specialists and lack of certain guidelines of antibiotics use for prophylaxis in the hospital may be discussed for these differences . in the current study ,
the rate of longer duration of administration of antibiotics was 9.5% , which ranged from 2.2% in general surgery department to 13.6% in gynecology department .
this finding was inconsistent with that of vaisbrud et al . with 91% ( 15 ) .
after unnecessary use of antibiotics and selection of antibiotics , the most commonly detected error was too long postoperative administration of antibiotics .
majority of iranian surgeons insist on the need for prolonged postoperative use of antibiotic therapy to prevent post - operative infections . it is known well that prolonged use of post - operative antimicrobials not only does not provide additional benefit , but also affects emerging the bacterial resistance ( 7 ) .
the current study had limitations such as retrospective design , restriction to just one hospital , and only three surgery departments . since the condition of all hospitals affiliated to jundishapur university is similar from the study purposes view point ; therefore , restriction to a hospital could not result in significant bias . in conclusion
however , 44% of those who received prophylaxis did not need it . in patients receiving antibiotics ,
the most common mistakes were antibiotic selection followed by prolonged prophylaxis ( > 24 hours ) , and excess dose of antibiotics . feeding this information back to surgeons and establishing pre - operative prophylaxis guidelines as a routine activity of infection control teams could improve nosocomial infection control program .
Output:
| background : despite the effectiveness of prophylactic antimicrobials to prevent surgical site infection the use of antibiotic prophylaxis is often inappropriate.objectives:the current study aimed to determine the pattern of prophylactic antibiotic use in a teaching hospital affiliated to jundishapur university of medical sciences , ahvaz , iran.patients and methods : the current descriptive study included 8586 patients who received prophylactic antibiotics before surgery from april 2011 to march 2012 , in razi hospital affiliated to jundishapur university of medical sciences .
indications for antibiotic use , proper or inappropriate antibiotics , an antibiotic or combination of antibiotics , dosage and length of treatment for each patient based on the infectious disease textbook ( mandel 's principle and practice of infectious diseases ) definitions were administrated.results:of the total 8586 patients who took antibiotics for preventive purposes , 4815 ( 56% ) required antimicrobial prophylaxis , and 3771 ( 44% ) patients did not .
of the 4815 patients who received prophylaxis , 86.9% received it appropriately , 13.1% received it inappropriately ; 8.2% received inappropriate dosage , and 9.5% received antibiotic longer than 24 hours.conclusions:the current study revealed that 44% of those who received prophylaxis did not need it .
in the patients who received antibiotics , the most common mistakes were antibiotic selection followed by prolonged prophylaxis ( > 24 hours ) and excess dose . |
PubmedSumm8888 | ***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 - traumatic stress disorder ( ptsd ) represents arguably the most salient example of how fear and stress shape the mind .
because controlled prospective studies can not be conducted on humans , it is necessary to use an animal model to help elucidate the etiology of ptsd and explore the associated neurological changes ( cohen et al . , 2010 ) .
a suitable animal model should utilize stressors that emulate as closely as possible the relevant stressors in humans ; the behavioral , physiological , and neurological responses elicited in the animal must reflect clinical symptomatology ; and pharmacological agents known to affect symptoms in human patients should correct , with equal efficacy , comparable symptoms in the animal ( rosen and schulkin , 1998 ; roseboom et al . , 2007 ; stam , 2007 ; armario et al .
, 2008 ; masini et al . , 2009 ; mitra et al . , 2009 ; cohen et al . ,
many researchers have adopted utilizing exposure to a predator ( e.g. , showing a rat a cat ; adamec and shallow , 1993 ) , or predator odor , as a stressor , in exploring the animal model of ptsd ( cohen et al .
predator exposure was initially seized upon for practical reasons as this permits the researcher to utilize a ( 1 ) psychological stressor , that is ( 2 ) life - threatening , but ( 3 ) does not involve pain ; all consistent with the etiology of ptsd in humans ( adamec and shallow , 1993 ; roseboom et al .
takahashi et al . , 2008 ; staples et al . , 2009 ; cohen et al . , 2010 ; mackenzie et al
. , 2010 ) . of greatest importance with respect to understanding ptsd , the hallmark of which is the long - lasting or transformational
change in the patient in response to a trauma ( yehuda and bierer , 2009 ) , predator exposure has been demonstrated to have long - lasting effects on : anxiety - like behaviors , glucocorticoid levels , dendritic morphology , gene expression , and the release of the neuropeptide corticotrophin - releasing hormone ( crh ) in the amygdala ( the region of the brain most frequently linked to fear ) , as well as many other phenomena associated with ptsd ( adamec and shallow , 1993 ; schulkin et al . , 2005 ;
, 2008 ; campeau et al . , 2008 ; rosen et al . , 2008 ;
predator exposure early in life has also been shown to increase vulnerability to developing subsequent long - term behavioral disruptions when exposed to a predator in adulthood ( cohen et al . , 2006 ) , consistent with the growing evidence that individual variation in susceptibility to ptsd is influenced by early - life experiences ( yehuda and bierer , 2009 ) .
researchers studying the predator model of ptsd have increasingly begun to suggest that predator exposure offers an additional advantage in attempting to understand ptsd , because long - lasting predator - induced fear and stress is ethologically and ecologically relevant , and represents a valid experience applicable to animals in their natural environment ( roseboom et al . , 2007 ;
cantor , 2009 ; staples et al . , 2009 ; cohen et al . , 2010 )
independently , wildlife ecologists have begun to arrive at a similar conclusion , following a line of inquiry that began in the 1990s ( creel and christianson , 2008 ) .
traditionally , the view of both wildlife ecologists and comparative endocrinologists has been that predator - induced fear and stress is necessarily acute and transitory : the prey detects a predator ; freezes , flees , or fights ; survives or does not ; the event is over ; the animal returns to going about its business ; homeostasis is restored ( schulkin , 2003 ; sheriff et al . , 2009 ) .
according to this traditional view , lasting effects are necessarily maladaptive and pathological : since the evolutionary function of predator - induced fear and stress is to ensure immediate survival , any further or lasting effect on fitness ( i.e. , darwinian fitness ) , such as an effect on subsequent reproduction , must be maladaptive ; and since the function of the stress axis is to maintain homeostasis , chronic stress must be pathological ( lupien et al . , 2009 ; rodrigues et al .
, the many lasting effects of predator exposure documented by researchers exploring the predator model of ptsd must be an artifact .
the most parsimonious explanation being given this perspective that such lasting effects stem from the unnatural conditions of captivity , i.e. , it is not the fact of predator exposure but the fact the predator is inescapable that must explain these effects , since the animal can not flee from the predator as it naturally would ( creel et al . , 2009 ; jngren et al . , 2010 ) .
we propose that the traditional view in wildlife ecology and comparative endocrinology , that the effects of predators on free - living animals are necessarily transitory , is no longer tenable , since the results from a growing number of experimental and observational field studies show that predator - induced fear and stress has long - lasting effects on animals in the wild ( creel and christianson , 2008 ; hawlena and schmitz , 2010 ) , comparable to those documented by investigators addressing the predator model of ptsd . for animals in the wild that are in peril every moment of every day of being torn limb from limb by any number of predators , responses resembling ptsd in humans may result from necessary trade - offs to stay alive , that are fully adaptive , because dead animals do not reproduce .
we suggest that for both , researchers studying the predator model of ptsd , and ecologists , conducting collaborative studies on predator - induced fear and stress on animals in the wild would be of enormous benefit . for investigators addressing the predator model of ptsd
, the extremity of the stressors faced by animals in the wild , in a real world context , would appear to much better emulate the circumstances leading to ptsd in humans .
for ecologists , building upon the progress that has been made in understanding ptsd in the lab provides the most expedient means of addressing the mechanisms underlying predator - induced fear and stress effects in the field .
we briefly review approaches taken to studying ptsd in the lab that appear translatable to the field ; and then describe recent field studies on songbirds and snowshoe hares showing that , predator - induced fear and stress affects reproduction in animals in the wild , and the physiological responses involved appear comparable to those documented in response to predator exposure in the lab .
behavioral responses to predator exposure in the lab include avoidance , reduced activity and increased vigilance ( blanchard and blanchard , 1989 ; stam , 2007 ; armario et al . , 2008 ; takahashi et al . , 2008 ) , and similar responses to predator exposure have been exhaustively documented in the field since at least darwin 's time ( caro , 2005 ) .
predator exposure in the lab results in changes in plasma glucocorticoid levels ( blanchard et al . , 1998 ;
2009 ) and the same has been shown in both birds and mammals in the field ( hawlena and schmitz , 2010 ) .
measuring glucocorticoid metabolites in feces provides a new , non - invasive means of assessing glucocorticoid responses to predator exposure that is particularly useful in field studies ( sheriff et al . , 2009 , 2010 ) .
studying the neurological effects of predator - induced fear and stress in animals in the wild will likely rely primarily on destructive sampling .
though effects on live animals could be studied using pharmacological methods or neuroimaging , there are practical difficulties translating these approaches to the field .
the suitability of using predator exposure in exploring the animal model of ptsd has been validated , in part , by the numerous studies showing that pharmacological agents known to affect symptoms of ptsd in human patients also correct comparable symptoms in animals exposed to predators ( cohen et al . , 2006 , 2010 ;
. some of these pharmacological agents can be administered in food ( e.g. , antalarmin ; zoumakis et al . , 2006 ; armario et al . ,
2008 ) , which is of practical advantage for use with free - living animals since it is then not necessary to capture the subject to administer the drug .
the principal constraint on using pharmacological agents on animals in the wild is almost certain to be the cost of the drugs , since the intrinsically greater error variation associated with studying any phenomenon in the field necessitates a larger sample size than that required in the lab .
a number of recent neuroimaging studies using magnetic resonance imaging ( mri ) have evaluated the neurological effects of exposure to predator odor in lab rats ( e.g. , chen et al .
mri has also been used to assess neuroactivity in response to other stimuli in mice and songbirds ( van der linden et al . , 2007 ) .
neuroimaging holds enormous promise as a technique for studying effects on animals in the wild because , being non - destructive , subjects could be returned to the field to determine if differences in brain activity predicted their subsequent behavior and reproduction .
however , though mri is non - destructive it is necessarily invasive and may be very injurious depending upon the method used ( e.g. , the manganese used in manganese - enhanced mri is potentially toxic ; silva et al . , 2004 ) .
at a minimum , neuroimaging requires restraining the subject 's head in a scanner for a protracted period . to measure effects in conscious animals requires acclimation to being restrained in this manner , which takes several days in laboratory animals ( king et al . , 2005 ) , and may be unachievable in many wild - caught animals . even if anesthetized during the procedure , the trauma of capturing a wild animal and transporting it to wherever the scanner is might render the results uninterpretable ( van der linden et al . , 2007 ) . nonetheless , we strongly recommend that using neuroimaging to study effects on animals in the wild should at least be attempted . because animals in the wild are generally challenging to capture , and limited in number , it is critical to maximize the information extracted from every animal euthanized .
moreover , because free - living animals must be captured , the conditions of capture will vary , meaning the rate at which tissue can be obtained will vary , and the circumstances will often be less than ideal .
measures that respond to an acute trauma or perturbation , such as the trauma of capture , will be largely unsuitable . several new approaches to measuring neurological effects , developed in the lab , nonetheless appear amenable to use on animals in the wild , even given these constraints .
immunohistochemistry has been used to map the expression of genes in response to predator exposure in various brain regions that appear central to the phenomenon of fear ( such as the medial amygdala ) .
whereas a number of lab studies have mapped the expression of the immediate - early gene c - fos , in response to predator exposure ( dielenberg et al . , 2001 ; roseboom et al . , 2007 ; campeau et al . , 2008 ) , c - fos is rapidly expressed ( within < 1 h ; armario et al . , 2008 ) and
rapidly down - regulated ( staples et al . , 2009 ) , which is problematic for use in the field .
two recent studies ( staples et al . , 2009 ; mackenzie et al . , 2010 ) have mapped the expression of fosb and its protein products fosb/fosb , as an alternative to mapping c - fos .
fosb can persist in the brain for weeks after chronic stimulus exposure ( mcclung et al . , 2004 ) , and staples et al .
( 2009 ) reported that fosb/fosb expression remained elevated 7 days after repeated predator exposure , making this a much more suitable marker for use in field studies .
global gene expression has been assessed in response to predator exposure using cdna microarrays ( gene chips ) in rats and chickens .
( 2007 ) euthanized rats 3 h after predator exposure , and found increased crh - binding protein gene expression in the amygdala , consistent with previous studies ( schulkin et al . , 2005 ) .
( 2010 ) euthanized chickens 2 week after predator exposure and identified 13 significantly differentially expressed genes in the midbrain .
roseboom et al.s ( 2007 ) findings confirm that cdna microarrays can be used to identify the expression of genes expected to be upregulated in response to fear , and jngren et al.s ( 2010 ) study shows that this approach can be used to detect long - lasting effects , even in non - mammalian subjects .
quantifying dendritic morphology appears ideally suited for indentifying individual variation in susceptibility to predator - induced fear and stress in field studies , and may be useful in evaluating predator - induced changes in neural architecture .
( 2009 ) evaluated behavioral differences in subjects 2 weeks after predator exposure and found differences in the architecture of the neurons in the basolateral amygdala .
total dendritic length , dendritic extent , and total branch points were all greater in individuals that continued to demonstrate anxiety - like behaviors as compared to those that no longer showed anxiety - like symptoms .
though the design of mitra et al.s ( 2009 ) study did not allow them to determine whether these differences in dendritic morphology were pre - existing or induced by predator exposure , mitra and sapolsky ( 2008 ) reported changes in dendritic morphology in response to a single day of stress , suggesting that predator - induced fear could indeed induce such changes in neural architecture .
yehuda and bierer ( 2009 ) recently reviewed the potential role of epigenetic changes in the etiology of individual differences in susceptibility to ptsd .
epigenetic modifications involve long- lasting , often environmentally induced , changes in gene expression and function , that can be inter - generationally transmissible ( i.e. , heritable ) , though the dna sequence itself remains unchanged ( champagne and curley , 2009 ; yehuda and bierer , 2009 ) .
several lines of evidence point to epigenetic changes as potentially being involved in predisposing individuals to ptsd , including the association of ptsd risk with maternal ptsd , the relevance of childhood adversity to the development of ptsd , and recent evidence of a relationship between childhood abuse , dna methylation ( in gene promoters , an epigenetic marker of gene silencing ) and suicide ( mcgowan et al . , 2008 , 2009 ; yehuda and bierer , 2009 ) . as noted above , cohen et al .
( 2006 ) reported that early - life predator exposure increased vulnerability to behavioral disruptions in response to exposure in adulthood , though there have been no studies looking specifically at predator - induced epigenetic changes . in the aforementioned suicide study
, subjects had been dead an average of 24 h before sampling , suggesting that changes in dna methylation ought to be detectable in the brains of animals in the wild collected under less than ideal field conditions , as recently corroborated by pilsner et al .
( 2010 ) in a study that examined dna methylation in the brains of polar bears shot by aboriginal hunters in eastern greenland .
evolutionarily , the function of staying alive is to reproduce , i.e. , to transmit genes to the next generation . for ecologists
ecological factors such as food and parasites , with obvious long - lasting effects ( malnutrition and disease ) , have always been considered to be those most likely to affect reproduction , because reproduction ( giving birth and rearing young ) is a slow process .
traditionally , predators have not been thought to affect reproduction because predator - induced fear and stress has been considered to be far too acute and transitory .
behavioral ( e.g. , kotler , 1992 ) and physiological ( e.g. , boonstra et al . ,
1998 ) studies began , in the 1990s , to suggest that predator - induced fear and stress could have lasting effects on animals in the wild , but because of the logistical challenges involved the critical experiments necessary to demonstrate effects on reproduction have only very recently been conducted .
free - living animals can , and do , simply flee or avoid , a predator in a cage , predator models , or predator odor stations ( e.g. , stankowich and blumstein , 2005 ) . because sound travels , and thus occupies space , field studies often use playbacks of recorded predator calls and sounds to investigate effects of predator exposure . moreover , for organisms that rely more on sound and sight than smell , such as birds and humans , auditory stimuli are generally more meaningful than olfactory ones ( jarvis , 2004 ) , and acoustic cues may frequently be more alarming than visual ones ( cohen et al . , 2010 ) .
only one study to date on a bird or a mammal has , to our knowledge , exposed free - living prey to increased predator cues in the field , and demonstrated a resulting effect on the number of offspring produced per year .
( submitted ) used an array of speakers spaced over several hectares to expose nesting female song sparrows to playbacks of either predator calls and sounds , or non - threatening calls and sounds .
females exposed to elevated predation threat produced almost 40% fewer offspring than controls ( 3.8 0.4 vs. 6.0 0.4 , mean se ) , over the 4-month breeding season , because they laid fewer eggs , fewer of their eggs hatched , and more of their chicks starved to death .
these effects on reproduction were most likely mediated in part by predator - threat - induced changes in glucocorticoid levels , because work on the same study populations has demonstrated lasting effects on glucocorticoid levels associated with variation in predator abundance ( clinchy et al . , 2004 , 2011 ) , and the probability of suffering nest predation ( travers et al . , 2010 ) .
sheriff et al . ( 2009 ) recently reported correlative results suggesting that predator exposure affects glucocorticoid levels and reproduction in free - living snowshoe hares , consistent with the results from zanette et al.s ( submitted ) experiment . to corroborate their findings , sheriff et al .
( 2009 ) presented a live predator ( a trained dog ) to pregnant hares housed in 4 m 4 m outdoor pens , and demonstrated that predator - exposed females had dramatically elevated fecal glucocorticoid metabolite ( fcm ) levels , and were significantly less likely to give birth to live young . in a subsequent study on snowshoe hares , sheriff et al .
( 2010 ) showed that predator exposure may have very long - lasting effects on animals in the wild , extending from one generation to the next .
sheriff et al . ( 2010 ) reported that at a population level , predator exposure , mean maternal fcm levels , and mean juvenile fcm levels , were all correlated , suggesting that predator - induced glucocorticoid changes in mother hares affect their offspring 's glucocorticoid levels . to corroborate these findings , sheriff et al .
( 2010 ) measured fcm levels in pregnant hares , housed in 4 m 4 m outdoor pens , and demonstrated that each mother 's fcm level was highly correlated with her offspring 's glucocorticoid responses to a hormonal challenge , when the latter was 28 days old .
thus , in animals in the wild , maternal or early - life exposure to predators may increase responsiveness to predators later in life , consistent with cohen et al.s ( 2006 ) lab results demonstrating that early - life predator exposure increases vulnerability to behavioral disruptions when exposed to a predator in adulthood .
life - long maternal effects on the glucocorticoid responsiveness of their offspring , resembling the results shown by sheriff et al .
( 2010 ) , have been well - studied in relation to stress effects on maternal care in laboratory rodents , and have been shown to be associated with dna methylation of genes affecting glucocorticoid receptor function in the hippocampus ( weaver et al . , 2004 ; kappeler and meaney , 2010 ) . in an example of the kind of collaboration between neuroscientists and ecologists we are herein hoping to encourage , mcgowan and boonstra are currently examining the brains of juvenile snowshoe hares , collected in the field , whose mothers were subject to naturally varying levels of predator exposure , to test if maternal predator exposure affects dna methylation in their offspring 's hippocampus in a manner similar to the way in which childhood abuse evidently affects dna methylation in humans , as shown in the aforementioned suicide study ( mcgowan et al . ,
calisi and bentley ( 2009 ) recently proposed that studying neurobiology and behavior in semi - natural settings may provide a means to merge lab and field approaches .
our focus here is on the lasting effects of predator - induced fear and stress on neurobiology and ecology . as noted above , the principal challenge in studying such lasting ecological effects concerns space , and this applies equally to studying such effects in a semi - natural setting
the subject must have the same amount of space available as it would if it were free - living , to flee or avoid a predator , otherwise any effects seen could be attributed to the unnatural conditions of captivity ( creel et al . ,
sheriff et al.s ( 2009 , 2010 ) exposure of caged hares to a predator , for example , can not be considered definitive , for this reason ( clinchy et al . , 2011 ) . moreover , since , as noted above , the ecological currency that matters is reproduction , the subject must be able to reproduce as it naturally would .
very large ( e.g. , several hundred square meter ) outdoor enclosures may fulfill these requirements when studying very small animals ( e.g. , mice or songbirds ) , whereas housing an animal in a somewhat larger cage than usual in an animal care building ( e.g. , blanchard and blanchard , 1989 ; choi and kim , 2010 ) does not meet these criteria .
the scope for future collaborations between neuroscientists and ecologists will almost certainly involve studying many more species than just sparrows and hares .
as further field experiments on the effects of predator exposure on reproduction are conducted , we have no doubt such effects will be found to be common .
effects on components of reproductive success have already been documented in experiments on several other species .
( 2006 ) reported effects of predator call playbacks on the number of eggs laid by siberian jays , and fontaine and martin ( 2006 ) found that where predators were removed songbirds laid heavier eggs .
( 2000 ) similarly showed that where predators were removed the proportion of arctic ground squirrel females weaning young was increased .
lasting behavioral and physiological effects pointing to likely effects on reproduction have been shown in an even larger number of species ( creel and christianson , 2008 ; hawlena and schmitz , 2010 ) .
what effect such predator - induced fear and stress has in shaping the minds of free - living birds and mammals is a question that is almost completely unexplored , presenting a wide - open field of study replete with opportunities for new discoveries .
numerous laboratory experiments have shown that predator - induced fear and stress has lasting neurological effects , and wildlife ecologists have begun demonstrating that predator - induced fear and stress has lasting effects on reproduction in free - living animals in the field .
we propose that the next two critical questions to answer are : ( 1 ) whether predator - induced fear and stress has lasting neurological effects on free - living animals , and if so ; ( 2 ) which of the effects seen in the lab appear most frequently in wild animals in the field . the insights neuroscientists have to offer ecologists in exploring the effects of predator - induced fear and stress on the minds of wild animals in the field include , where to begin , and what to measure .
the insights ecologists , in turn , have to offer researchers studying the predator model of ptsd include , establishing which effects seen in the lab are observed in the greatest number of species and circumstances , and which are most biologically meaningful as gaged by their association with effects on reproduction .
we suggest that if , as the predator model assumes , ptsd in humans has evolutionary precursors , then it is virtually certain that collaborations between neuroscientists and ecologists will greatly enhance our understanding of the etiology of ptsd and the associated neurological changes .
the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
Output:
| that the fear and stress of life - threatening experiences can leave an indelible trace on the brain is most clearly exemplified by post - traumatic stress disorder ( ptsd ) .
many researchers studying the animal model of ptsd have adopted utilizing exposure to a predator as a life - threatening psychological stressor , to emulate the experience in humans , and the resulting body of literature has demonstrated numerous long - lasting neurological effects paralleling those in ptsd patients . even though much more extreme , predator - induced fear and stress in animals in the wild was , until the 1990s , not thought to have any lasting effects , whereas recent experiments have demonstrated that the effects on free - living animals are sufficiently long - lasting to even affect reproduction , though the lasting neurological effects remain unexplored .
we suggest neuroscientists and ecologists both have much to gain from collaborating in studying the neurological effects of predator - induced fear and stress in animals in the wild .
we outline the approaches taken in the lab that appear most readily translatable to the field , and detail the advantages that studying animals in the wild can offer researchers investigating the predator model of ptsd . |
PubmedSumm8889 | ***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: cataract is the leading cause of blindness in the world with blindness from cataract being particularly common in low - income countries .
there are 39 million people reported to be blind worldwide.1 age - related cataract is responsible for 51% of world blindness , which represents about 20 million people.2 according to the national blindness survey conducted in nigeria in 20052007 , out of the 25,061,000 adults above the age of 40 years , cataract was responsible for 42.9% magnitude of blindness.3 the corneal endothelium plays an important role in maintaining corneal transparency .
the numerical density of corneal endothelium is highest at birth ( 3,000 cells / mm ) and declines slowly but steadily thereafter.4 a minimal numerical density of 400500 cells / mm is required to sustain the pumping activity of the endothelium .
the cells of the endothelium do not regenerate , but they stretch to compensate for dead cells which reduce the overall cell density of the endothelium with consequent impact on fluid regulation . if the endothelium can no longer maintain a proper fluid balance , stromal swelling will occur , leading to loss of transparency with resultant impaired vision .
interest has therefore developed in the assessment of endothelial damage either by cell counts or indirectly by measuring corneal thickness postoperatively .
many studies have been conducted in more developed settings among diverse races to determine how long it takes for the cornea to return to its preoperative thickness value after cataract surgery .
this , therefore , leaves some uncertainties as to whether the findings from these studies apply to the african population .
this study , therefore , aimed to determine changes in central corneal thickness ( cct ) in patients after cataract surgery at lagos university teaching hospital ( luth ) and to assess the length of time it takes for the cornea to return to its preoperative thickness value .
this is a prospective , hospital - based open within - patient controlled study carried out in the ophthalmology clinic in luth between november 2012 and july 2013 .
the sample size of 160 subjects for the study was determined using the statistical formula by schlesselman.5 while making provision for attrition rate of 20% , a total number of 192 approximated to 200 participants ( 400 eyes ) were selected by consecutive sampling method .
this was made up of 200 eyes that had cataract surgeries ( cases ) and 200 contralateral eyes that did not undergo cataract surgeries ( controls ) .
consecutive patients aged 18 years and above enrolled for small incision cataract surgery ( sics ) with intraocular lens implantation performed by the same surgeon ( ota ) formed the study patients .
all the consenting patients underwent dilatation with topical gutt tropicamide and phenylephrine and were prepped with 5% povidone iodine solutions .
all manual sicss as described previously by venkatesh et al6,7 were done under local anesthesia ( peribulbar , retrobulbar , and rarely topical ) .
after a limited conjunctival peritomy and light wetfield cautery , superior self - sealing sclerocorneal tunnel incision of 6.07.0 mm was created with a crescent blade , starting 1.52.0 mm behind the limbus .
this incision was widened to approximately 9.0 mm as it advanced into the clear cornea .
a large capsulorrhexis or rarely can - opening capsulotomy ( 6.07.0 mm ) was performed with a cystotome followed by hydrodissection .
a 3.0 mm keratome blade was used to open the internal lip of the tunnel incision .
the nucleus was prolapsed into the anterior chamber using a sinskey hook and extracted in one piece using the viscoelastic or the irrigating simcoe cannula at the mouth of the tunnel incision .
cortical cleanup was performed with the simcoe irrigating aspirating cannula using ringer s lactate or 0.9% normal saline solution .
after implantation of a 6.00 mm diameter optic poly(methylmethacrylate ) posterior chamber intraocular lens into the capsular bag , the side port was hydrated , and the anterior chamber was pressurized with the wound integrity intact and left unsutured in most cases .
excluded from the study were patients with corneal opacity and endothelial defect such as leukoma , staphyloma , dystrophy , or corneal guttata , those with any preexisting ocular disease other than cataract , and those with traumatic or complicated cataract .
other excluded patients were those who have had refractive surgeries , those with only one eye , those with operative complications such as vitreous loss , and those who declined participation in the study .
structured questionnaires were administered to eligible and consenting patients by the authors after detailed explanation of the study and the procedures .
they were also informed of the few possible side effects that can occur during examination such as peppery sensation from application of anesthetic eye drops .
relevant data obtained include the following : the biodata ; eye to be operated ; cct measurements a day before cataract surgery ; and cct measurements a day after surgery , and at 2 weeks , 4 weeks , 8 weeks , and 12 weeks after surgery .
corneal thickness measurements were done by one of the authors ( oaa ) on each participant using the ultrasonic suoer ophthalmic a scan pachymeter sw 100 ( model number gi 090760982 sn/0037cp ) in the mornings of every visit . for each eye ,
data entry and analysis were done using statistical package for social sciences spss version 18 .
frequencies , means , and standard deviations were generated to observe pattern of variable distribution among respondents .
comparison was done using the variable means of cct using paired t - test and pearson correlation .
the analysis was considered to show statistically significant association when the p - value is < 0.05 .
a total of 200 consecutive consenting patients with 400 eyes were analyzed in this study .
only 12 ( 6.0% ) of the patients were below 50 years , while 141 ( 70.5% ) were between the ages of 50 years and 69 years .
the largest proportion , 157 ( 78.5% ) , were of the yoruba tribe ( table 1 ) .
almost half of the patients , 94 ( 47.0% ) , had bilateral mature cataract ; 111 ( 55.5% ) had their left eyes operated .
the preoperative intraocular pressure in most patients , 164 ( 82.0% ) , was within the normal range in both the operated and unoperated eyes .
the mean baseline cct of patients a day before surgery in the operated eye was 520.620.3 m . this increased by 76.9 m ( 597.930.4 m ) a day after surgery . by 2 weeks
, the mean cct reduced to 555.224.7 m , and at 12 weeks , it was 525.119.7 m .
these differences were found to be statistically significant ( p<0.05 ) ( table 2 ) .
the mean cct , however , reduced closest to the preoperative value with a mean of 525.119.5 m at 8 weeks after surgery was performed ( figure 1 ) .
the mean baseline cct of patients a day before surgery in the unoperated eye was 521.019.7 m ; this increased by 6.6 m ( 529.521.3 m ) a day after surgery , and by 2 weeks , it has reduced to 524.921.4 m .
these differences were found to be statistically significant ( p<0.05 ) ( table 3 ) . at 4 weeks , the mean cct ( 522.7 m ) was closest to the preoperative value , while at 12 weeks , the mean cct was 523.120.3 m ( figure 1 ) .
most of the patients were elderly , reemphasizing the aging process as the commonest etiology of uncomplicated cataract in the study population .
there were more males in this study pointing to the fact that women still have poor access to eye health services often with their influencing factors such as economic , geographic , cultural , social , and sex issues as reported by mganaga et al.8 the largest proportion are yorubas , and this is not unconnected with the location of study center in the south - western part of nigeria where the predominant ethnic group is the yorubas .
bilateral mature cataracts being the commonest in this finding showed the burden of binocular - blinding cataracts in this population .
the mean preoperative cct in the operated eye ( ccto ) was similar to those documented by bolz et al9 but in contrast to the findings of salvi et al and ventura et al.10,11 this difference could have been due to the type of instrument used in measurements of corneal thickness .
several investigations had shown a consistent overestimation of corneal thickness with optical systems compared with ultrasound measurements.12 however , reported measurements of cct determined by ultrasonic pachymetry exhibited greater fluctuations than those estimated by optical low - coherence reflectometry pachymetry.11 moreover , these contrasting studies were done in the euroid population with relatively thicker corneas compared to the predominantly negroid population of native africans in this study.13 cataract surgery induced an increase in mean corneal thickness on the first day ; this is in contrast to salvi et al10 study done in the white population .
however , this increase was reduced at 2 weeks with a further decrease till eighth week .
this study showed that the difference in corneal thickness between pre- and postoperative values in the operated eye was statistically significant .
this is in agreement with jacob s study14 that reported that maximal increase occurred within 24 hours following cataract surgery . also , the study showed similarity with bolz et al,9 ventura et al,11 and cheng et al15 studies where increase followed by gradual decreases in corneal thickness was recorded following cataract surgery .
interestingly , there was a change in the corneal thickness value post - cataract surgery in the unoperated eye by an increase of 1.26% on day 1 followed by reduction at 2 weeks .
a slight increase was then recorded again at 8 weeks with subsequent reduction by 12 weeks .
this study showed a statistical significance in the difference in corneal thickness between pre- and postoperative values up to 2 weeks in the unoperated eye .
this is in contrast with salvi et al10 study where there was just a very small insignificant difference from preoperative values .
the mechanism of increases in the corneal thickness value in the unoperated eye as found in this study is unclear , since no surgery which could pose a risk to the eye was performed on these eyes .
however , it has been postulated that once the body is exposed to injury or trauma , all body cells become sensitized by the inflammatory mediators which are system and tissue specific , such that a fresh insult to any parts of the body stimulates an exaggerated inflammatory response in that affected area as demonstrated in an animal model.16 it is noteworthy that el - hirazi et al17 described a similar consensual inflammation of unknown etiology following ocular surgery in the unoperated eye attributable to phacoemulsification and trabeculectomy in the consensual eye using kowa laser flare meter and laser cell counter .
the amount of inflammation in the nonoperated eyes of 60 patients studied returned to the preoperative levels by day 28 .
similarly , table 3 shows the return of the cct to the preoperative state occurring between the second week and fourth week in this study .
there is no gain saying the plausible roles of an exaggerated inflammatory response in this phenomenon following controlled trauma in the contralateral eye , and more studies will be needed to explain the etiopathogenesis of this unexplained transient cct changes . in this study , it was found that the mean cct in the operated eye returned closest to the preoperative values by eighth week postoperatively and remained same till 12 weeks .
this is not in agreement with the study done by jacob,14 which reported attainment of preoperative value by 4 weeks ( 28 days ) ; this wide disparity may be due to the phacoemulsification technique used here , which is different from the technique used in this study
. however , this study may be similar to ventura et al study , in which there was restoration of preoperative thickness value by 3 months.11 this study could not be compared to olsen and eriksen study18 and kohlhaas et al study19 where preoperative corneal thickness values were reached by 6 months and 12 months , respectively , as our study patients were only followed up for 3 months .
the limitations of study are the time constraints , which do not allow prolonged follow - up as a basis for comparison of findings with other similar studies that had longer study follow - up duration , the lack of correlation of endothelial cell counts using specular microscopy with cct measured by ultrasound pachymetry , and nonavailability of balanced salt solution for anterior chamber irrigation and aspiration for this study .
this study revealed that there was a transient increase in corneal thickness following cataract surgery with subsequent progressive decrease as the postoperative day progresses till 12th week .
overall , it took 8 weeks for the corneal thickness in the operated eye to return closest to its preoperative value .
the unoperated eye also showed a transient increase in corneal thickness , which was found to be statistically significant till the fourth week .
it is therefore recommended that conscious and adequate measures should be taken to reduce manipulation on the cornea during cataract surgery in order to achieve relatively reduced cct and endothelial cell loss with immediate postoperative patient s satisfaction , and to improve patient s vision and quality of life .
a further research on the possibility of increasing postoperative cct in an unoperated eye as found in this study following surgery in the contralateral eye can be explored with a view to unraveling the mechanism behind it .
postoperative refraction may be delayed until eighth week after manual sics in view of the recovery time for the cct to return to its preoperative values in this study .
earlier refraction at 4 weeks may not be stable and reproducible following this procedure in our patients .
Output:
| aimto determine changes in post - cataract surgery central corneal thickness ( cct ) at lagos university teaching hospital by assessing the time it takes for the cornea to return to its preoperative thickness value.methodsthis study is a prospective , hospital - based open within - patient controlled study with the unoperated eye controlling for the operated one.resultstwo hundred patients with 400 eyes were analyzed , with bilateral mature cataract in 47.0% .
all the patients had manual small incision cataract surgery with posterior chamber intraocular lens implant .
there is an increase in mean baseline cct from 520.620.3 m by 76.9 m ( 597.930.4 m ) 24 hours after cataract surgery followed by relative reduction in the mean cct to 555.224.7 m and 525.119.7 m at 2 weeks and 12 weeks , respectively .
increase in mean cct in the unoperated and contralateral eyes were recorded in this study.conclusionthere was a transient increase in corneal thickness following cataract surgery with subsequent decrease to preoperative thickness by 12th and fourth week in the operated and unoperated eyes , respectively .
corneal manipulations during cataract surgery must be minimal to reduce visual rehabilitation time to barest minimum .
postoperative refraction will be better at eighth week to 12th week considering the time it takes for the cct to return to its stable preoperative values . |
PubmedSumm8890 | ***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 european hedgehog ( erinaceus europaeus ) is one of the two species of hedgehogs living in catalonia ( north - eastern spain ) . in the area of study , this species is frequent in deciduous or semideciduous forests , in holm - oak woods and also in human - related habitats such as gardens , parks , and fields . due to their distribution and behaviour ,
many hedgehogs are found in the wild and brought to wildlife rehabilitation centres in europe [ 1 , 2 ] .
several potential zoonotic agents have been reported in hedgehogs , mostly bacteria such as salmonella spp .
[ 3 , 4 ] , tick - borne diseases , [ 5 , 6 ] and also fungi .
erinacei is the most common causative agent of ringworm in wild hedgehogs and 25% of carriers have been documented in a survey from england .
the skin is the largest mammalian organ and represents a complex microbial ecosystem with bacteria , viruses , protozoa , and fungi in direct contact with the environment .
the potential association of the alterations of the skin mycobiota with disease has been well established in human medicine .
erinacei has been isolated in zoophilic dermatophytoses in humans [ 11 , 12 ] and an outbreak of ringworm in caretakers of wild european hedgehogs was reported in germany .
there are several studies of mycobiota carried out with samples from domestic animals , like cats and dogs . in all these studies ,
the most frequently isolated fungal genera were classified as saprophytes ( mainly aspergillus , alternaria , penicillium , and cladosporium spp . )
but in cats two pathogenic genera ( microsporum and trichophyton ) have been also described . since there is scarce information about the mycobiota in wild hedgehogs , the aim of this study was to describe this mycobiota , with special attention to dermatophytes , in wild hedgehogs admitted at a wildlife rehabilitation centre in catalonia ( spain ) .
all wild european hedgehogs admitted at the wildlife rehabilitation centre of torreferrussa ( catalonia , north - east spain , 319-09 e and 4251-4031 n ) from june 2009 to august 2010 were included in the study .
animals were anesthetized with isoflurane ( forane , abbott ) after chamber or mask induction , and one to three spines and hair were removed with a sterile mosquito forceps .
the forceps were sterilized by flaming immediately before the sampling of each body part .
thus , protocols , amendments , and other resources were done according to the guidelines approved by the government of catalonia .
samples were cultured in sabouraud dextrose agar ( sda ) with antibiotics and dermatophyte test medium ( dtm ) plates .
each plate was divided in two parts , one from the dorsal spine and the other from the lumbar one .
samples were inoculated on duplicate plates of sda ( difco ) with chloramphenicol ( 400 ppm ) and dermatophyte selective medium prepared according to taplin 's dtm formula ( biolife ) .
taxonomic identification of all the different mycelial colonies was based on macroscopic and microscopic studies .
the observation was made from fragments of the colony prepared freshly by adding blue lactophenol .
the strains were observed under light microscope . according to the fungal structures observed , identification of strains at genus level was performed .
the identification of yeasts was performed by staining with methylene blue and using the api 20c system .
the following data were recorded : age , sex , date of admission , cause of hospitalization , main diagnosis , and location where hedgehogs were found .
age was categorized as juveniles or adults , according to their body weight and the date of admission .
data analysis was carried out using spss version 15.0 statistical software ( chicago , illinois , usa ) .
differences were evaluated by the test for qualitative variables , and their 95% cis were calculated .
kruskall - wallis test with the percentiles 25% and 75% was applied as a nonparametric test .
the causes of admission and demographic characteristics of these animals are summarized in table 1 .
no cases of ringworm were diagnosed and no dermatophyte isolation was obtained in any of the cultures . moreover ,
the majority of the saprophytic species that grew on sda medium were also detected at the dtm . in some strains of the genera cladosporium , penicillium , and aspergillus a colour change
the prevalence of the different fungal genera isolated from the wild hedgehog is summarized in table 2 .
the most prevalent genus were cladosporium ( 79.1% ) , penicillium ( 74.7% ) , alternaria ( 64.8% ) , and rhizopus ( 63.7% ) .
no significant differences were observed in the prevalence of genera among the different anatomical regions ( cranial and caudal spines or fur ) .
only two genus , rhizopus and trichoderma were more frequently found in spines than in fur and 4 species ( aphanocladium spp .
as regards the season of the year , we found lower prevalence of aspergillus ( p = 0,035 ; = 8,633 ) and arthrinium ( p = 0,043 ; = 8,173 ) in the spring and higher frequencies of fusarium ( p = 0,015 ; = 10,533 ) in the autumn .
the number of species isolated from the different body areas was similar : cranial ( median = 3 ; p25 = 2 ; p75 = 5 ) ; caudal ( median = 3 ; p25 = 2 ; p75 = 5 ) , and fur ( median = 3 ; p25 = 1 ; p75 = 4 ) .
moreover , no statistical differences were observed between prevalence of fungal species and the cause of admission , the clinical signs , or the sex . by contrast , the prevalence of acremonium was significantly higher in young animals ( 70% , 26/37 ) than in adults ( 30% , 11/37 ) ( p = 0,019 ; = 5,915 ) .
this work provides the first description of the normal mycobiota of the integument of wild european hedgehog in a region of spain .
interestingly , a large variety of saprophytic fungi were isolated in these animals , although no dermatophytes were found .
hedgehogs are one of the most common wild mammals attended at the different rehabilitation centres in europe , due to their abundance and their vicinity to humans
. moreover , the reduced body size and relatively tameness of these animals are factors that favour their capture and handling .
erinacei has been reported in wild european hedgehogs , clinically characterized by crusty lesions , alopecia , and loss of spines , mainly affecting the head area . in britain ,
morris and english reported a prevalence of 19.8% ( 39/203 ) of t. mentagrophytes var .
erinacei in hair samples in a survey which included both alive and dead animals . in their study , many of infected cases carried the fungus without lesions .
thus , the potential role of wild european hedgehogs as a source of human infection and its public health significance have been emphasized in different reports [ 18 , 19 ] .
different species of dermatophytes have been commonly reported in healthy mammals with different prevalence levels depending on the animal species ; for instance , 4% of cats , 8.1% of dogs , 8.8% of goats , and 12.2% of sheep were positive to dermatophytes .
by contrast , in some animal species , such as in dromedary camels , it has not been possible to find dermatophytes .
the majority of the fungal species isolated in this work are ubiquitous and most of the genera match with those reported in human toes and in the hair of other mammalian species . in the toes of humans
these genera included yeasts such as candida albicans , rhodotorula rubra , torulopsis glabra , and trichosporon cutaneum ; dermatophytes such as microsporum gypseum and trichophyton rubrum ; opportunistic fungi that can live in skin such as rhizopus stolonifer , trichosporon cutaneum , fusarium spp , scopulariopsis brevicaulis , curvularia spp , alternaria alternata , paecilomyces spp , aspergillus flavus , and penicillium spp .
other authors reported t. mentagrophytes and t. rubrum as the most common dermatophytes in a study carried out in 360 human patients . among nondermatophytes
the order of decreased incidence was scopulariopsis brevicaulis , acremonium roseum , aspergillus spp , and fusarium spp .
on the other hand , frequencies of saprobe genera higher than 50% have been described in dogs of the same geographical area ( catalonia ) of our study by cabaes et al .
moreover , chaetomium and trichoderma are known for their cellulolytic activity , so their presence may be related to the natural environment in which the wild hedgehogs live .
there are evidences in the literature that pet [ 26 , 27 ] and wild hedgehogs can be the source of pathogenic fungal infections in humans . the absence of trichophyton sp . in hedgehogs of this study
all examined animals were wild hedgehogs sampled the first day of the admission and no clinical signs indicative of ringworm were observed in any of the animals ; likely , they had no time to suffer immunodepression due to the capture - associated stress and , in consequence , no time for spreading any subclinical infection in case of wild reservoirs . moreover , the total number of saprophytic fungal genera isolated in this work was higher than those published by others [ 19 , 28 ] .
the presence of saprophytic species has been considered as an indicator of transient integument contamination from soil or environment .
this high prevalence of saprophyte mycobiota could interfere with the growth of other pathogenic species , like dermatophytes if they are in a lower proportion .
more sensitive techniques , like pcr , could help in determine this role in wild reservoirs .
nonetheless , in the present study , the mycotic culture was conducted in two different mediums ( dtm and sda ) , and in three different anatomical locations , corroborating the absence of these pathogens in all the cultures .
the following genera : acremonium , alternaria , aspergillus , mucor , rhizopus , absidia , alternaria , fusarium , and penicillium , detected in integument of the hedgehogs of our study , have been reported as opportunistic pathogens in immunocompromised humans and animals , causing cutaneous or systemic mycoses .
however , those genera are considered ubiquitous and the potential role of the hedgehogs as carriers or reservoirs could be considered as negligible . although no cases of mycoses have been observed in our study population , the potential risk in primary or secondary immunodepressed hedgehogs should be considered .
neosartorya hiratsukae , an ascomycete in which the conidial state resembles aspergillus fumigatus , was described in a captive exotic african pygmy hedgehog .
our study provides the first description of the integument mycobiota of wild european hedgehogs in spain , showing a large number of saprophyte species in both spines and fur and the absence of dermatophytes .
further larger studies are necessary to elucidate the relevancy of the seasonal and age group differences observed .
Output:
| there are some reports about the risk of manipulating wild hedgehogs since they can be reservoirs of potential zoonotic agents like dermatophytes .
the aim of this study was to describe the integument mycobiota , with special attention to dermatophytes of wild european hedgehogs .
samples from spines and fur were cultured separately in sabouraud dextrose agar ( sda ) with antibiotic and dermatophyte test medium ( dtm ) plates .
nineteen different fungal genera were isolated from 91 cultures of 102 hedgehogs .
the most prevalent genera were cladosporium ( 79.1% ) , penicillium ( 74.7% ) , alternaria ( 64.8% ) , and rhizopus ( 63.7% ) . a lower prevalence of aspergillus ( p = 0,035 ; 2 = 8,633 ) and arthrinium ( p = 0,043 ; 2 = 8,173 ) was isolated during the spring time and higher frequencies of fusarium ( p = 0,015 ; 2 = 10,533 ) during the autumn .
the prevalence of acremonium was significantly higher in young animals ( 70% , 26/37 ) than in adults ( 30% , 11/37 ) ( p = 0,019 ; 2 = 5,915 ) .
moreover , the majority of the saprophytic species that grew at the sda culture were also detected at the dtm .
finally , no cases of ringworm were diagnosed and no dermatophytes spp . were isolated .
concluding , this study provides the first description of fungal mycobiota of the integument of wild european hedgehogs in spain , showing a large number of saprophytic species and the absence of dermatophytes . |
PubmedSumm8891 | ***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: alterations in the six essential functions defining the neoplastic gene expression pattern collectively dictate malignant growth .
escape , circumvention of programmed cell death , unlimited replicative potential , sustained angiogenesis , and local and metastatic invasiveness .
targeted therapeutics currently being used are directed against derivatives of amplified genes and/or overexpressed protein kinases in malignant cells involving one or more of these core functions .
fifteen molecular targeting therapies ( herceptin , tykerb , gleevec , tasigna , rituxan , bexxar , avastin , tarceva , iressa , vectibix , erbitux , velcade , sutent , nexavar and sprycel ) have already been approved by the us food & drug administration ( fda ) for cancer treatment .
cancer functions through a robust network with both adaptive pliability and functional redundancy , which ( with the exception of chelates such as bexxar ) buffers the effect of any single gene / target modification on the malignant process [ with some rare exceptions , such as chronic myeloid leukaemia ( cml ) ] .
for example , a number of agents targeting epidermal growth factor receptor ( egfr ) have entered the clinic ( tarceva , iressa , vectibix , and erbitux ) primarily for use in epithelial tumors .
it has recently been shown that egfr inhibition will induce upregulation of insulin - like growth factor 1 receptor ( igf-1r ) resulting in a regulatory shift of akt from the egfr pathway to the igf pathway .
mathematical analyses of targeting strategies ( such as antivirals and targeted therapies ) of a variety of biological systems suggest that a disruption of at least three key biorelevant nodes will result in network disarray .
these data include modelling resistance in cml , hiv viral escape following rna interference ( rnai ) therapeutics , and the effectiveness of rnai at targeting coxsackie virus .
many are undergoing preclinical and clinical testing with a variety of target specific agents ( monoclonal antibodies , small molecules , antisense constructs , ribozymes and rnai technology ) .
unfortunately , given the potential for targeted therapeutic development and the availability of technology to assess genomic networks relevant to cancer - cell function , there is a discrepancy between the ability to identify presumptive targets and their actual biological relevance and integrated target sensitivity ( the converse of robustness ) .
the necessity to more effectively interrogate and quantify system functions , which would enable the pursuit of predictable , biorelevant , low - morbidity personalized therapeutics , has also become more glaring . based on our understanding of spatial distribution , kinetics , and post - translational modifications , proteins
are thought to be the direct effectors of cellular behavior rather than their dna and intermediary mrna templates .
proteins assemble themselves into complex small - world networks composed of functional modules with key regulatory hubs and interconnecting , informational ,
this protein - network based approach has recently been used in the analysis of breast cancer metastases .
we believe that characterization of these interactions and in silico prediction of outcomes from the reasoned and deliberate disruption of these events will provide the basis for defining novel and more effective target - complexes for drug therapy .
gene mutation , gene loss , and gene duplication or amplification can result in absent , defective or overexpressed proteins .
although correlations of genomic patterns with survival have been demonstrated in a variety of cancers , it remains undetermined which of these anomalies are pathogenic and which are not .
yet , we believe using new technologies , it is feasible to reduce the finite but unwieldy number of overexpressed proteins in malignant tissue into a manageable subset of candidate target - complexes against which potentially effective multi - target therapies can be constructed .
newer technology platforms , such as yeast two - hybrid screens , forward - phase and reverse - phase protein arrays , and protein chips , combined with emerging bioinformatic analytic technologies , help define how proteins interact with each other and will enable us to elucidate and simulate functional modules within networks , regulatory motifs and informational cross - talk linkages .
the field of microarray technology has also rapidly evolved . over the last 5 years , it has become possible to simultaneously analyze integrity and/or expression level of hundreds of thousands of genes within days .
microarray technology can be used to examine the integrity of genome and gene expression levels ; genomic dna analysis identifies the genes that have been mutated , deleted or amplified , whereas rna analysis reveals differences in transcription and rna processing .
brown and botstein first reported the utilization of microarray technology to examine gene expression patterns in human malignancy in 1999 .
however , testing of clinical samples in the past generally utilized admixed tissue containing endothelial cells , stromal tissue , and hematopoietic cells , in addition to cancer cells . as a consequence , many of the reported gene expression patterns of malignant cells are likely to be confounded by these less than homogenous specimens .
this potentially confounding factor is now being addressed with the routine implementation of laser capture microdissection ( lcm ) . with this technique ,
malignant cells can be selectively dissected and captured so that only a morphologically homogeneous population of cells is investigated . however , only a relatively small amount of material is retrieved with the lcm process , so the captured rna requires amplification . as a result , an unbalanced amplification of transcripts can lead to misinterpretation of cancer gene expression levels .
gene transcript levels often show poor correlation with protein levels , and clearly can not predict post - transcriptional regulatory changes ( for example , splicing ) and post - translational modifications ( for example , phosphorylation , sulphation , and glycosylation ) of the encoded proteins .
proteomic technologies such as two - dimensional difference gel electrophoresis ( 2d - dige ) , bead capture , micro - enzyme - linked immunosorbent assays ( micro - elisa ) , and liquid chromatography aligned with tandem mass spectroscopy , are currently employed for drug discovery and biomarker identification .
recent technologies quantifying mrna and protein signalling patterns have in fact been successfully used to demonstrate that a finite number of genes are unique to each individual cancer and that their identification visualizes critical pathways or networks which can be utilized for therapeutic targeting .
early trials in primates indicate that its safety and potency ( as measured by knockdown of mrna and protein levels ) is far greater than small molecules or antisense constructs targeting the same gene products .
with these tools a mere step away from the bedside , the challenge is now to identify a systems - dependent target - complex as the network 's fragile site ( its achilles ' heel ) so as to allow for the production of a therapy that disarms the malignant
hostile takeover. therapeutic targeting based on unique individual dynamic genomic / proteomic constructs , differentially expressed , as opposed to traditional non - discriminative chemotherapy agents , can now be envisioned .
it is probable that future rnai - based gene therapy for cancer can be prescribed based on the integrated mrna proteomic expression profile of each individual 's tumors .
the accumulation of data from fresh tissue obtained from the patient 's tumors ( preferably , primary and metastatic sites ) , the employment of lcm with refined amplification technology , and the incorporation of quantitative genomic / proteomic methodologies together with sophisticated modelling techniques provide a means for automated construction of probabilistic network models based on real - world clinical data .
this will enable the rapid discovery and characterization of tumor - specific oncogenic pathways that are responsive to each individual patient 's needs within a realistic time frame .
advances in genomic sequencing technology , developed through the human genome project , and high throughput snp ( single nucleotide polymorphism ) analysis have resulted in the elucidation of consensus coding sequences in a variety of human tumor types allowing for an increased depth of understanding of intratumoral interactions such as synergy between amplified and mutated genes in breast cancer [ for example , tgf ( transforming growth factor beta ) , wnt ( wingless - type pathways ) , and fgf ( fibroblast growth factor ) ] .
quantitative molecular profiling promises to change the way oncology is practiced by enabling us to : ( 1 ) reformat tumor classification using biomolecular parameters ; ( 2 ) individualize therapeutics ; and ( 3 ) establish early assessment of therapeutic efficacy using biorelevant markers rather than volume - based endpoints .
furthermore , it will also enable a systems biological approach to the understanding of the malignant process using mathematical methods capable of virtualizing intracellular signalling pathways , intercellular communications , and cellular - environmental interactions .
jn declares that he is co - founder of gradalis , inc , a rna interference development company .
Output:
| cancer - cell survival , growth and metastatic potential are directed by dominant molecular signalling patterns , the components of which have been shown to be qualitatively different from their normal tissue counterparts .
these signalling patterns can now be further distinguished by quantitative assessment , either at a single point in time or at intervals .
this commentary will focus on the emergence of proteomic analysis which , in conjunction with the genomic expression data , is an evolving technology that one day will enable personalized therapeutic strategies that are differentially targeted against cancer . |
PubmedSumm8892 | ***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: isolation of different isolates of a. dactyloides was done with slight modification ( bandyopadhyay and singh , 2000 ) using the method described by duddington ( 1955 ) from different locations : varanasi , ghazipur , mirzapur , chunar ( uttar pradesh ) and ranchi ( jharkhand ) , india .
different isolates were purified and maintained on maize meal agar medium ( maize-20 g ; agar-20 g ; distilled water-1000 ml ) .
further single spore culture of each isolate was made by the method given by singh et al .
cultures of each isolate were maintained on maize meal agar medium by regular subculturing at an interval of 15 days .
the effect of urea , dap and muriate of potash on the spore germination of five isolates of a. dactyloides was studied by the method described by jackson ( 1958 ) for soil fungistasis .
soil samples were taken from vegetable research farm , banaras hindu university , varanasi , india and passed through a 2 mm mesh sieve .
urea , dap and muriate of potash were separately mixed in the soil at the rate of 1% , 0.5% and 0.1% .
50~60 g of soil of each concentration were taken in 90 mm petri dishes and soil was watered near full water holding capacity by addition of distilled water .
water agar blocks ( 10 mm size , 3 mm thickness ) were placed on whatman 's filter paper disc ( 20 mm size ) lying on the surface of soil at five places in the petri dishes and incubated at room temperature ( 25~30 ) for 24 h to allow the diffusates to reach in the agar blocks .
five agar blocks were taken for inoculation of spores of five isolates of a. dactyloides . for unamended soil ( control )
after incubation period , spore suspension of each isolate was made separately by harvesting the spores from 15 days old culuture .
a small drop of water containing 75~100 spores of each isolate were inoculated separately on each agar block and incubated for 24 h at room temperature for observations .
data on spore germination , direct trap formation and trap formation on spore germ tube was taken .
for each treatment three petri dishes were taken as replicates . in order to find out the effect of neem cake amendments in soil on the spore germination of five isolates of a. dactyloides and trapping of soil nematodes by the fungus ,
soil was collected from vegetable research farm , banaras hindu university , varanasi , india .
neem cake was thoroughly mixed in the soil at the rate of 0.5% and placed in pots for decomposition .
50~60 g soil from amended and unamended soils was placed into petri dishes and soil was wet to near full water holding capacity with distilled water .
five water agar blocks were placed directly on the surface of soil in petri dishes at different places and incubated at room temperature for 24 h. after incubation spores of different isolates of a. dactyloides were inoculated on agar block as per method described earlier and the inoculated petri dishes were further incubated for 24 or 48 hours for observations .
data on spore germination , direct trap formation and trap formation on germ tube were recorded .
the experiments on spore germination were conducted on 1 day , 15 day and 30 day after amendment .
isolation of different isolates of a. dactyloides was done with slight modification ( bandyopadhyay and singh , 2000 ) using the method described by duddington ( 1955 ) from different locations : varanasi , ghazipur , mirzapur , chunar ( uttar pradesh ) and ranchi ( jharkhand ) , india .
different isolates were purified and maintained on maize meal agar medium ( maize-20 g ; agar-20 g ; distilled water-1000 ml ) .
further single spore culture of each isolate was made by the method given by singh et al .
cultures of each isolate were maintained on maize meal agar medium by regular subculturing at an interval of 15 days .
the effect of urea , dap and muriate of potash on the spore germination of five isolates of a. dactyloides was studied by the method described by jackson ( 1958 ) for soil fungistasis .
soil samples were taken from vegetable research farm , banaras hindu university , varanasi , india and passed through a 2 mm mesh sieve .
urea , dap and muriate of potash were separately mixed in the soil at the rate of 1% , 0.5% and 0.1% .
50~60 g of soil of each concentration were taken in 90 mm petri dishes and soil was watered near full water holding capacity by addition of distilled water .
water agar blocks ( 10 mm size , 3 mm thickness ) were placed on whatman 's filter paper disc ( 20 mm size ) lying on the surface of soil at five places in the petri dishes and incubated at room temperature ( 25~30 ) for 24 h to allow the diffusates to reach in the agar blocks .
five agar blocks were taken for inoculation of spores of five isolates of a. dactyloides . for unamended soil ( control )
after incubation period , spore suspension of each isolate was made separately by harvesting the spores from 15 days old culuture .
a small drop of water containing 75~100 spores of each isolate were inoculated separately on each agar block and incubated for 24 h at room temperature for observations .
data on spore germination , direct trap formation and trap formation on spore germ tube was taken . for each treatment three petri dishes
in order to find out the effect of neem cake amendments in soil on the spore germination of five isolates of a. dactyloides and trapping of soil nematodes by the fungus , soil was collected from vegetable research farm , banaras hindu university , varanasi , india .
neem cake was thoroughly mixed in the soil at the rate of 0.5% and placed in pots for decomposition .
50~60 g soil from amended and unamended soils was placed into petri dishes and soil was wet to near full water holding capacity with distilled water .
five water agar blocks were placed directly on the surface of soil in petri dishes at different places and incubated at room temperature for 24 h. after incubation spores of different isolates of a. dactyloides were inoculated on agar block as per method described earlier and the inoculated petri dishes were further incubated for 24 or 48 hours for observations .
data on spore germination , direct trap formation and trap formation on germ tube were recorded .
the experiments on spore germination were conducted on 1 day , 15 day and 30 day after amendment .
in agar blocks placed over unamended soil ( control ) directly or on filter papers , the conidia of a. dactyloides largely germinated by direct traps ( fig .
there was no difference in the germination of spores by direct traps whether the spores placed on agar blocks directly on the soil or on the filter papers .
the percentage of spore germination in both the situations were almost similar ( table 1 ) .
however application of urea at the concentration of 1.0% , 0.5% and 0.1% completely inhibited the germination of spores of all the isolates of a. dactyloides ( table 2 ) .
similarly diammonium phosphate ( dap ) also checked the germination of spores or direct trap formation at 1% concentration .
however , in the soil amended with 0.5% dap , 61~83.3% spores germinated by direct trap while very low percentage of spores ( 0~1.7% ) germinated by germ tube ( fig .
the level of trap formation on germ tube was also very low in all the isolates . at 0.1% concentration of dap , the germination of spores by direct rings ranged between 66.7 to 92.2% irrespective of the isolates .
microconidia of isolates b also recorded direct ring formation at 0.1% concentration of dap in soil .
application of muriate of potash also showed adverse effect on the spore germination or ring formation at all the concentrations . in observations recorded after 24 h of incubation only scant germination of spores by germ tube
was recorded at 0.5% and 1% concentration of muriate of potash . however , at 0.1% concentration , the germination of spores by germ tube increased conspicuously and very low percentage of spores germinated by direct rings . when the same agar blocks were observed after 48 h , the germination of spores by direct trap increased conspicuously with the decreasing concentrations of this fertilizer .
soil freshly amended with neem cake at the rate of 0.5% completely checked the germination of spores by germ tube and direct trap ( table 3 ) .
after , 15 days of amendment , germination of spores only by germ tube was recorded in all the isolates , however , the percentage of germinated spores was very low in all the isolates .
irrespective of isolates , the germination rate of spores ranged between 1.6% and 2.6% in 24 h. the microconidia of isolate b , however , failed to germinate . when the observation was taken after 48 h , fairly higher percentage of spores germinated by direct rings , indicating that germination was delayed .
1a ) ranged between 3.8 to 8.9% , while constricting rings on germ tubes ( fig .
after one month of amendment , 91~94% of spores germinated by direct rings in 24 h. microconidia of isolate
the level of germination of spores by germ tube was very low ranging from 1.34 to 3.9% only . from the observations it is evident that after 24 h of amendment of neem cake there was neither spore germination nor nematode trapping
. however after 15 days of incubation of amended soil , few nematodes were attracted on agar blocks incubated for 24 h without any capturing . when the same blocks were observed after 48 h of incubation ,
this clearly indicated that even after 15 days of incubation of amended soil the toxic substances of neem cake had its effect although it was reduced .
however after 30 days of amendment , fairly higher number of nematodes were attracted and captured . in the corresponding controls ,
i.e. , unamended soil after 1 , 15 and 30 days the germination of spores by direct trap were almost similar as given in table 1 .
in general , soils amended with higher concentrations of fertilizers reduced spore germination of all the isolates of a. dactyloides ( table 2 ) . inhibition of germination of spores by urea at the concentrations used may be attributed to direct toxicity of urea on the spores . however , dap at 0.5% and 0.1% concentrations caused little inhibition on the germination of spores of almost all the isolates .
muriate of potash also reduced germination of spores as well as direct ring formation on conidia . from the observations it is very clear that application of fertilizers would reduce the population of nematode trapping fungi in the soil , which might be playing important role in reducing the population of nematodes . in soils ,
top - dressed with the fertilizers , the concentration of these fertilizers might be fairly high on the soil surface , which would be detrimental to sensitive fungi like a. dactyloides .
it is also possible that excessive use of these fertilizers may slowly reduce the population of sensitive nematode trapping fungi in the soil .
inhibition of germination of conidia of a. dactyloides in soil duly amended with 0.5% neem cake may be attributed to the toxic principle present in the neem cake .
( 1980 ) on the spore germination of some pathogenic fungi by neem plant extract .
the toxicity of neem cake was also reported on second stage juveniles of heterodera cajani by singh and singh ( 1997 ) . however , in observations after 15 days , the toxic effect of neem cake was considerably reduced which was evident from the observations on germination or trap formation after 48 hours of spore inoculation . this change in toxicity
may be attributed to biodegradation of neem toxic factor in soil , which was completely eliminated after 30 days of application of neem cake .
it was interesting to note that a large number of soil nematode migrated to the top of the agar block containing the spores of a. dactyloides , which may be attributed to attraction of nematode to fungal traps ( table 3 ) .
further most of the nematodes were captured and killed on the agar block ( fig .
1d ) and the developing hypha from the spore cell produced few to many traps on the hyphae ( fig .
it is concluded that mass culture of a. dactyloides should be applied only after 15 days of neem cake application to make the biocontrol agent more effective .
it has been observed that the population of saprophytic nematodes increases several folds after neem cake amendment ( data not shown ) , which can serve as pabulum for the fungus and increase the population of a. dactyloides .
Output:
| application of fertilizers such as urea , diammonium phosphate ( dap ) and muriate of potash in soil adversely affected the spore germination of arthrobotrys dactyloides .
amendment of soil with urea at the concentrations of 1.0% , 0.5% and 0.1% completely inhibited spore germination and direct trap formation on the conidium , whereas muriate of potash delayed and reduced the spore germination even at the lowest concentration .
dap also inhibited spore germination at 1.0% concentration , while at lower concentration the percentage of spore germination was reduced .
application of neem cake at the concentration of 0.5% also inhibited spore germination after 24 h of amendment .
the inhibitory effect of neem cake was reduced after 15 days of amendment , while after 30 days after amendment the inhibitory effect was completely lost and the spore germinated by direct trap as in unamended soil .
nematodes were not attracted to ungerminated spores after 24 h of amendment .
after 15 days of amendment nematodes were attracted to agar blocks containing fewer germinated spores after 24 h of incubation but after 48 h of incubation large number of nematodes were attracted and trapped by the germinated spores with direct traps .
after 30 days of amendment , larger number of nematodes were attracted and trapped by direct traps . |
PubmedSumm8893 | ***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: glycemia and diabetes are rising globally accounting 347 million people worldwide . the study of type 2 diabetes ( t2d ) has been stimulated due to its growing pandemic and intricate physiopathology , in search of better ways of prevention and treatment of the t2d and its associated complications . among the several studies to explain the different causative factors and their roles in the onset and maintenance of the t2d and pancreatic islet dysfunctions , the formation of the advanced glycation end products ( ages ) has gained significant importance . for example
, it has been reported that patients with diabetes present increased serum concentrations of ages compared with nondiabetic patients .
, these molecules can increase their intracellular concentrations through the autooxidation of glucose resulting in glyoxal that can undergo a final fragmentation producing the methylglyoxal .
glyoxal and methylglyoxal interact with amino groups of intracellular and extracellular proteins to produce the ages .
in addition to the prevailing formation of ages under physiological conditions and their increase under conditions of hyperglycemia and oxidative stress , these products are also introduced in the organism by means of exogenous sources , such as tobacco and diet .
the diet is considered the main exogenous source of ages and is associated with the development of several pathologies such as diabetes .
food preparation methods using high temperatures ( frying , roasting , and grilling ) potentialize the production of ages present in the diets ; moreover , high - fat foods are the main contributors to the formation of ages in the diets . thus , both the endogenous and exogenous ages influence the installation and progression of pathologies like t2d .
glucose is responsible for the triggering of insulin release while the secretagogues may amplify or inhibit the release depending on their interactions .
recent studies have shown that ages long - term exposure may impair the beta - cell function by inducing apoptosis or decreasing the insulin secretion [ 13 , 14 ] .
however , the specific sites of interactions of the ages on the different pathways of insulin secretion remain to be elucidated .
our current study highlights the acute effect of incubation of a precursor of ages , methylglyoxal ( mg ) , on the insulin secretion triggered by glucose and modulated by different secretagogues .
our findings revealed that mg exerts a dual role on the insulin secretion depending on both glucose concentration and the type of secretagogue .
the experiments were conducted in accordance with the european communities council directive of 1986 ( 86/609/eec ) and approved by the french departmental direction of veterinary services committee .
ten adult wistar rats were purchased from harlan laboratories ( gannat , france ) and housed two per cage .
the animal facility rooms were maintained on a dark / light schedule ( 12 h/12 h , light on at 08 h ) and controlled temperature ( 22 2c ) .
animals were maintained with free access to food ( regular rat chow diet ) and tap water . after a week of acclimation ,
8 ml of hanks buffered saline solution ( hbss ; ( mm ) : nacl , 136.9 ; kcl , 5.4 ; mgso47h2o , 0.81 ; na2hpo4 , 0.34 ; kh2po4 , 0.44 ; cacl22h2o , 1.26 ; nahco3 , 4.16 ; glucose , 0.06 ; bsa , 15 ) ; and ( ( v / v ; 95% o2 + 5% co2 , mixed)/10 min , ph 7.4 ) containing ( ( w / v ) 0.1% collagenase type xi , 5% bsa and 0.6% n-(2-hydroxyethylpiperazine)-n-(2-ethanesulfonic acid ; hepes ) ; sigma - aldrich ) was injected into the rats ' common bile duct .
the pancreas was washed with hbss and the islets were hand - picked with the aid of a stereomicroscope . to adapt the pancreatic islets
, they were preincubated for 60 min in 1 ml of normal krebs - ringer solution ( ( mm ) : nacl , 115 ; nahco3 , 24 ; kcl , 1.6 ; mgcl6h2o , 1 ; cacl22h2o , 1 ; bsa , 15 ; ph 7.4 ) containing 5.6 mmol / l glucose .
this solution was gassed with ( v / v ) 95% o2 c5% co2 ( mixed ) to maintain ph 7.4 .
after the preincubation , groups of 4 islets were incubated with different concentrations of glucose ( 5.6 , 8.3 , and 16.7 mm ) for an additional 60 min . to study the different amplifying / inhibiting pathways of insulin secretion ,
islets were incubated ( after the preincubation period ) for further 60 min with 8.3 mm of glucose plus 10 m of acetylcholine in the presence of 10 m of neostigmine to avoid the acetylcholinesterase action ; or 16.7 mm of glucose plus 1 m of epinephrine ; or 5.6 mm of glucose plus 40 mm of k ; or 8.3 mm of glucose plus 10 m of forskolin ; or 5.6 mm of glucose plus 10 mm of leucine .
doses were tested before or chosen from the literature to the optimal induction / inhibition of the insulin secretion .
the supernatants from the incubations were collected and stored for posterior insulin measurements using a radioimmunoassay method .
data are presented as mean standard error of the mean ( s.e.m . ) .
student 's t - test was performed using graphpad prism version 6.01 for windows ( graphpad software , la jolla , ca , usa ) .
to study the effect of mg on insulin release triggered by different concentrations of glucose , cells were incubated with 5.6 mm , 8.3 mm , and 16.7 mm of glucose in presence or absence of mg ( 10 mm ) .
as shown in figure 1 , at basal glucose concentration , mg induced an increase of 91% ( p < 0.01 ) in the glucose - stimulated insulin secretion ( gsis ) .
however , at 8.3 and 16.7 mm of glucose , the insulin secretion in presence of mg was reduced by 71% and 42% ( p < 0.01 ) , respectively .
secondly , we studied the effect of mg on islets insulin secretion in presence of different secretagogues .
results shown in figures 2 and 3 have been expressed as a percentage from the respective basal glucose concentration . in presence of 8.3 mm of glucose , acetylcholine amplified the insulin secretion by 160% ( p < 0.001 ) , and the presence of mg decreased the acetylcholine - increased insulin secretion by 27% ( p < 0.001 ) , compared with 8.3 mm of glucose . in presence of 16.7 mm of glucose , epinephrine decreased the insulin secretion by 76% ( p < 0.001 ) and the addition of mg resulted in a slight decrease ( 67% compared with 16.7 mm of glucose , p < 0.001 ) of the epinephrine - induced inhibition of gsis . in figure 3 , the gsis was increased by 85% ( p < 0.001 ) in presence of k and 5.6 mm of glucose , and the addition of mg induced by
177% ( p < 0.001 ) the insulin secretion compared with 5.6 mm of glucose .
forskolin induced by 89% ( p < 0.001 ) the insulin secretion in presence of 8.3 mm of glucose , while the addition of mg resulted in further increase of around 3-fold ( p < 0.001 ) . finally , in presence of 5.6 mm of glucose , leucine increased the insulin secretion by 85% ( p < 0.001 ) , while in presence of mg this leucine - induced increase of insulin secretion was of 32% ( p < 0.05 ) compared with 5.6 mm of glucose .
our study provides evidence to support the hypothesis that mg affects the insulin secretion in a dual manner .
we have shown that short exposure of a low concentration of mg leads to an imbalance of insulin secretion at both basal and high glucose concentrations as well as in the presence of acetylcholine , epinephrine , potassium , leucine , and forskolin .
these results indicate that different pathways are involved in ages regulation of insulin secretion and that their mode of action is dependent either on glucose concentration or on the nature of secretagogue applied in the cells . in agreement with a previous study ,
our findings support the idea of a dual effect of ages in the regulation of insulin secretion .
it is internalized by glucose transporters 2 ( glut2 ) present in the beta - cell surface . briefly , within the cells , the glucose is metabolized by oxidative glycolysis , which leads to a rise of the atp - to - adp ratio .
the increased levels of atp result in the closure of atp - sensitive potassium channels , which leads to a depolarization of the membrane and subsequent opening of voltage - dependent calcium channels and the influx of calcium resulting in the rise of cytoplasmic - free calcium concentration and activation of the exocytotic machinery .
the incubation of isolated islets with glucose stimulates the insulin secretion in a concentration - dependent manner .
interestingly , when the islets were incubated with basal concentration of glucose and ages , the insulin release was increased . on the other hand , islets incubated with higher glucose concentrations and ages exhibited a great inhibition of the insulin release .
these data indicate a possible interaction of age in a dual manner on the regulation of glucose - stimulated insulin secretion ( gsis ) . this age regulation could be related to the metabolic state of the cell .
a previous study has shown that mg exerts a major damaging effect on ins-1e cells impairing both insulin action and secretion , which includes impairment of the insulin - induced phosphorylation of the insulin receptor ( irs ) and activation of the glycogen synthase kinase 3 ( gsk-3 ) with its reduced phosphorylation response to insulin . to further investigate the age action on insulin secretion
the blocking of the katp by high extracellular potassium concentration led to increased insulin secretion even in low levels of glucose , as seen in the literature and in our results .
furthermore , the addition of ages induced even higher secretion in combination with extracellular potassium .
an amplifying pathway augments insulin secretion without a reduced katp permeability ( katp independent pathway ) , indicating that glucose controls the insulin secretion by other additional pathways [ 9 , 20 , 21 ] .
acetylcholine is one potent modulator of gsis through its action on cholinergic muscarinic receptors present throughout the insulin secreting cells . when incubated with glucose and acetylcholine ,
otherwise , when these cells received also the age compound , they exhibited a rough decrease in insulin secretion , even lower than the secretion exhibited by islets only in presence of glucose . in agreement with previous studies , it seems that ages activate pathways of beta - cell damage , through generation of mitochondrial superoxide , which can lead to an impairment of insulin secretion [ 17 , 22 ] .
the cholinergic muscarinic receptors are classified as g protein coupled receptors ( gpcr ) and are regulated by phosphorylation following acetylcholine stimulation .
these receptors couple with various downstream pathways such as the increase or decrease in cyclic amp ( camp ) levels and stimulation of phospholipase c ( plc ) with the formation of ip3 [ 23 , 24 ] . in the same line ,
the adrenergic receptors are also formed of gpcr , but are targets of the catecholamines , and islets incubated with epinephrine presented a great inhibition of gsis . on the other hand , the addition of ages caused a slight decrease in the epinephrine - induced inhibition of insulin release . to further explore the involvement of ages and camp levels
, we activated the adenyl cyclase ( ac ) with forskolin , which resulted in increased insulin secretion when islets were incubated with only 8.3 mm of glucose . adding the ages to
it is evident that ages may have a cross - talk interaction with the ac downstream pathway .
whether the ages are acting or not in those downstream pathways remains to be further studied .
leucine is known to stimulate insulin release in normal beta - cells by two mechanisms .
firstly , by degradation through transamination pathway producing -ketoisocaproate , a metabolite which is a potent secretagogue allowing stimulation of insulin secretion through subsequent mitochondrial oxidation . secondly , by the allosteric activation of glutamate dehydrogenase resulting in increased glutaminolysis , which also stimulates mitochondrial oxidation . both mechanisms lead to an increase of the metabolic flux rate through the citric acid cycle , which increases the atp production [ 2628 ] .
our findings show that insulin release was increased in a basal concentration of glucose in presence of leucine ; however , in the presence of ages this leucine - increased insulin secretion is blocked and is similar to the secretion levels from the control situation ( 5.6 mm of glucose ) .
this latter result provides an insight that ages may be acting directly in the mitochondria , which is in agreement with a previous study supporting the idea that ages impair the secretion of pancreatic beta - cells at least in part through oxidative stress mechanisms .
impaired mitochondrial function is also reported both in vivo and in vitro as a cause of insulin secretory dysfunction resulting from ages treatment [ 14 , 15 ] .
another study has pointed out that the effects of ages , in a low concentration for longer exposure period , are mainly caused through a reduction in the expression of the malate dehydrogenase ( mdh1/2 ) gene , which plays an important role within the mitochondria . beyond the oxidative stress ,
ages are also formed in presence of hyperglycemia , but they still can be obtained from the diet [ 68 , 31 ] .
ages bind to their receptors for age ( rage ) resulting in a downstream signaling activation , generation of intracellular oxygen free radicals , and the activation of gene expression [ 22 , 32 ] that could be involved in the inhibition of leucine - potentiated insulin release .
altogether , we provide several evidences that ages might regulate the insulin secretion through specific and different pathways within the pancreatic islets , which remain to be revealed .
recent findings together with our data bring up the idea that ages can effectively inhibit or stimulate insulin secretion pathways .
in addition to their chronically deleterious long - term effects in beta - cells , the ages acute effects described in the present work may participate in the onset of diabetes .
Output:
| aim .
chronic diseases are the leading cause of death worldwide .
advanced glycation end products , known as ages , are a major risk factor for diabetes onset and maintenance .
methylglyoxal ( mg ) , a highly reactive metabolite of glucose , is a precursor for the generation of endogenous ages
. methods . in this current study
we incubated in vitro pancreatic islets from adult rats in absence or presence of mg ( 10 mol / l ) with different concentrations of glucose and different metabolic components ( acetylcholine , epinephrine , potassium , forskolin , and leucine ) .
results .
different effects of mg on insulin secretion were evidenced . in basal glucose stimulation
( 5.6 mm ) , mg induced a significant ( p < 0.05 ) increase of insulin secretion . by contrast ,
in higher glucose concentrations ( 8.3 mm and 16.7 mm ) , mg significantly inhibited insulin secretion ( p < 0.05 ) . in the presence of potassium , forskolin , and epinephrine , mg enhanced insulin secretion ( p < 0.05 ) , while when it was incubated with acetylcholine and leucine , mg resulted in a decrease of insulin secretion ( p < 0.05 ) . conclusion .
we suggest that mg modulates the secretion activity of beta - cell depending on its level of stimulation by other metabolic factors .
these results provide insights on a dual acute effect of mg on the pancreatic cells . |
PubmedSumm8894 | ***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: previous studies focused on retraining muscle coordination patterns in which the optimal
ratios between the gluteus maximus ( gm ) and the erector spinae ( es ) are assumed to be
essential1,2,3 .
bridging exercises are
associated with a risk of dominant hamstring ( ham ) and es activities as compensation for gm
weakness3 .
various studies have
indicated that specific lumbar stabilizing exercises combined with other therapies can
prevent unwanted movement error1 , 4 .
the practice of pointing or positioning
tasks improves performance of trunk movement in persons with back pathologies2 .
thus , to prevent excessive movement of the lumbar and thoracic
spine , therapists often ask patients to stabilize the spine via therapist hands or abdominal
drawing - in maneuver ( adim)5 .
no previous
studies have used visual biofeedback with a laser pointer on the pelvic belt for lumbar
stabilization exercises as therapy for individuals with low back pain . to our knowledge
,
this study is the first to evaluate the effect of trajectory exercises using a laser pointer
on gm muscle activity during a bridging exercise .
we created an instrument that enabled
trajectory exercises with a laser pointer on a pelvic strap to prevent unwanted movement of
the lumbar spine .
in addition , this instrument can aid repositioning accuracy of the trunk
during selfbridging exercises .
the purpose of this study was to investigate activities of
the hip extensors and es during bridging exercises by using a raiser pointer on the pelvic
belt .
twelve non - specific subjects with low back pain ( age , 23 to 33 years ) volunteered for this
study .
the inclusion criteria were patients with non - specific low back pain for > 3 months
and the willingness and ability to participate in the task safely . the study purpose and
methods
were explained to all the subjects , who provided their informed consent according to
the principles of the declaration of helsinki before participation .
subjects performed the
same bridging exercise twice and maintained each position for 5-s under two conditions :
using instruments a laser pointer ( lpt ) and without an lpt .
bridging exercise performed
without ilp was followed by bridging exercises with lpt to minimize the carry over or
learning effect4 .
both knees were flexed at 90 , the feet were placed hip - width apart
while resting on the floor , and the toes were faced forward . the arms were crossed over the
chest to minimize arm support .
each subject was instructed to lift the pelvis comfortably at a self - selected
speed while maintaining the trunk , pelvis , and thigh in a straight line and holding the
bridging position for 5 s. bridging with lpt followed the same procedure as bridging without
lpt , with the exception of the application of laser pointer trajectory for visual
biofeedback .
a white board and laser pointer attached on the pelvic strap were prepared for
visual biofeedback .
the white board , which was 50 cm long and 70 cm wide , was attached to
both parallel bar .
a vertical line of 30-cm length through the cranial direction was drawn
in the center of the board .
further , the start and end markers of the vertical line were
displayed in both ends . a plastic cylinder , 7.5 cm long and 2.5 cm in diameter , designed to
focus a 0.5 cm diameter laser pointer was attached to a pelvic strap .
kinematic data from
the hip and knee joints were acquired using video analysis system control .
a strap with a
laser attached for visual biofeedback was worn on each subject s lower back ( positioned
above the asis ) .
subjects performed bridging exercises while attempting to control the red
ray from the laser - pointer such that it moved along the vertical line ( length 30 cm ) to the
cranial direction until the end marker was drawn on the board .
emg data were collected using
biopac mp100wsw ( biopac systems , inc , goleta , ca ) . for normalization ,
two surface electrodes with an
interelectrode distance of 2 cm were positioned on the gm , medial ham , and es bilaterally .
trunk muscles ( es , gm , and ham ) activities with and without trajectory exercises using a
laser pointer were analyzed using spss statistics ver .
the
significance between the two conditions was tested using paired t - tests , with significance
at p<0.05 .
compared to the group with the laser pointer , the emg signal amplitude was significantly
higher for the gm in the group that performed bridging exercises with visual biofeedback
using a laser pointer ( 28.6 18.0% versus 21.3 12.9% ) , and was significantly lower in the
es ( 26.8 15.1% versus 43.1 16.8% ) ( p < 0.05 ) .
however , there were no significant
differences in the activities of the ham between the groups with ( 53.3 52.3% ) and without
( 41.7 32.3% ) laser pointer use ( p > 0.05 ) . for bridging exercise with visual
biofeedback using laser pointer ,
the gm / es ratios were significantly higher in the group
with laser pointer use than in the group without ( p<0.05 ) .
this study is the first to evaluate the effect of trajectory exercise using the laser beam
on gm activity during bridging exercises .
gm activity increased significantly during
bridging with visual biofeedback using the laser pointer , supporting the research
hypothesis . on the other hand
a possible explanation is that performing trajectory exercises with the
laser beam during bridging exercises can prevent excessive anterior pelvic tilt .
weakness of
the gm and dominant activity of the es due to low back pain may contribute to excessive back
spine hyperextension during bridging exercises7 .
thus , moving a raiser pointer on the pelvic strap along the
quantified cranial direction during bridging exercises could be a good strategy for clbp
when anterior pelvic tilt and lumbar lordosis motion are minimized . in terms of muscle
ratios ,
gm / es ratios were significantly higher when a laser pointer was used than when one
was not used . based on these studies , synergistic trunk extensors such as
the gm and es can
affect one another during bridging , increasing gm activity and reducing es activity .
these
results also suggest that using a raiser pointer during bridging exercise promotes
activation of the hip extensors , while reducing activation of the es .
previous evidence suggests that patients
with chronic low back pain exhibit deficits in trunk proprioception and motor control2 , 7 .
these deficits can affect and compromise segmental spinal stability and eventually lead to
articular damage and subsequent chronic pain2 .
we consider that applying visual biofeedback using a laser pointer
during bridging facilitated gm activity in advance before the initiation of the bridging
movement , consequently increasing gm activity .
Output:
| [ purpose ] the purpose of this study was to investigate activities of the hip extensors
and erector spinae during bridging exercise by using instruments with a laser pointer on
the pelvic belt .
[ subjects ] twelve subjects ( age , 23 to 33 years ) with non - specific low
back pain volunteered for this study . [ methods ] subjects performed bridging exercises with
and without trajectory exercises by using a laser pointer fixed to a pelvic strap .
the
erector spinae , gluteus maximus and hamstring activities with and without trajectory
exercises using a laser pointer were recorded on using electromyography .
[ results ]
compared to the without laser pointer group , the group that underwent bridging with
trajectory exercises using a laser pointer had significantly higher gluteus maximus
activity and significantly lower erector spinae activity .
significantly higher gluteus
maximus / erector spinae activity ratios were observed when performing trajectory exercises
using a laser pointer during bridging exercises . [ conclusion ]
this result suggests that
trajectory exercises using a laser pointer during a bridging exercise would be effective
for improving gluteus maximus activity . |
PubmedSumm8895 | ***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: muscular dystrophies with an autosomal recessive mode of inheritance comprise of a genetically heterogeneous group of disorders . among these
, miyoshi myopathy ( mm ) is an early - adult onset , autosomal recessive form of distal muscular dystrophy , characterized by predominant involvement in the calf muscles and highly elevated serum creatine kinase ( ck ) levels ( 1 ) .
mm has been known to be caused by mutations in the dysferlin gene ( dysf ) on chromosome 2p13 ( 2 ) .
mutations in the same gene were also identified in patients with limb - girdle muscular dystrophy type 2b ( lgmd2b ) ( 3 ) , and distal anterior compartment myopathy ( 4 ) .
these diseases caused by mutations in dysf are known by the term ' dysferlinopathy ' .
although mm patients and their mutations in the dysf gene have been found from all over the world , only a few cases have been reported in korea ( 5 - 8 ) .
considering that there have been many reports of mm among japanese population ( 9 ) , the incidence of mm might be underestimated in korea since both countries are geographically and ethnically related with each other ( 10,11 ) . in the present study
, we performed clinical and genetic analysis of three korean patients with mm and found that all patients had compound heterozygous mutations in the dysf gene .
three unrelated and non - consanguineous patients with clinical features of mm were evaluated ( table 1 ) .
all the patients experienced early adulthood onset of slowly progressive muscle weakness , which preferentially involved muscles in the lower extremities .
patients 1 and 2 had a history of steroid medication under the presumptive diagnosis of polymyositis according to the muscle biopsies and both showed transient responses .
the genomic dna was extracted from the peripheral blood leukocytes using a wizard genomic dna purification kit according to the manufacturer 's instructions ( promega , madison , wi , u.s.a . ) .
all the coding exons as well as the flanking introns of the dysf gene were amplified using the primer sets designed by the authors ( primer sets available on request ) .
a polymerase chain reaction was performed with a thermal cycler ( model 9700 , applied biosystems , foster city , ca , u.s.a . ) using the following conditions : 32 cycles of denaturation at 94 for 30 sec , annealing at 60 for 30 sec , and extension at 72 for 30 sec .
after the amplicon ( 5 l ) treatment with 10 u shrimp alkaline phosphatase and 2 u exonuclease i ( usb corp . ,
cleveland , oh , u.s.a . ) , direct sequencing was performed with the bigdye terminator cycle sequencing ready reaction kit ( applied biosystems ) using a abi prism 3,100 genetic analyzer ( applied biosystems ) .
three unrelated and non - consanguineous patients with clinical features of mm were evaluated ( table 1 ) .
all the patients experienced early adulthood onset of slowly progressive muscle weakness , which preferentially involved muscles in the lower extremities .
patients 1 and 2 had a history of steroid medication under the presumptive diagnosis of polymyositis according to the muscle biopsies and both showed transient responses .
the genomic dna was extracted from the peripheral blood leukocytes using a wizard genomic dna purification kit according to the manufacturer 's instructions ( promega , madison , wi , u.s.a . ) .
all the coding exons as well as the flanking introns of the dysf gene were amplified using the primer sets designed by the authors ( primer sets available on request ) .
a polymerase chain reaction was performed with a thermal cycler ( model 9700 , applied biosystems , foster city , ca , u.s.a . ) using the following conditions : 32 cycles of denaturation at 94 for 30 sec , annealing at 60 for 30 sec , and extension at 72 for 30 sec .
after the amplicon ( 5 l ) treatment with 10 u shrimp alkaline phosphatase and 2 u exonuclease i ( usb corp . , cleveland , oh , u.s.a . ) ,
direct sequencing was performed with the bigdye terminator cycle sequencing ready reaction kit ( applied biosystems ) using a abi prism 3,100 genetic analyzer ( applied biosystems ) .
patient 1 was a 45 yr - old male patient who had presented with progressive weakness in both lower extremities for the previous 17 yr .
he noticed difficulty in running and atrophy of the lower leg muscles at 27 yr of age . the muscle weakness and atrophy progressed .
a neurological examination showed bilateral motor weakness and symmetric atrophy of the entire lower extremity muscles , which were more severe on the distal part than on the proximal part . marked atrophy of the lower leg muscles with
relatively spared pelvic girdle and upper thigh muscles resulted in a stalk - leg appearance .
he had been diagnosed of having a polymyositis at the age of 28 yr as a result of a muscle biopsy of the medial gastrocnemius showing myopathic changes with inflammatory cell infiltration .
his 43 yr - old younger sister was affected in the same way in her early thirties and found it difficult to walk up and downhills . since then , the muscle weakness worsened so that walking was still possible but only for short distances using a cane .
she also had difficulty in holding her baby due to extended weakness of her upper extremity muscles .
patient 2 was a 30 yr - old female who presented with difficulty in stair walking and pain in her low back and knee .
difficulty in climbing stairs developed at 26 yr of age and this difficulty in walking gradually worsened so that she could not climb stairs without the support of her upper extremities .
a neurological examination showed atrophy of both calf muscles , decreased strength of the lower extremity muscles , and an absent tendon reflex .
she could not stand on her tip - toe , but standing on her heels was possible .
the emg revealed the myopathic changes in gastrocnemius , rectus femoris , and biceps brachii muscles .
a muscle biopsy without immunohistochemial stain from the biceps brachii suggested a diagnosis of inflammatory myopathy .
magnetic resonance imaging of her lower leg disclosed symmetric fatty degeneration and decreased muscle volume of the posterior compartment muscles in both lower legs .
the anterior and lateral compartment muscles had either a normal or a relatively normal signal intensity and morphology .
patient 3 was a 37-yr - old man with quadriparesis who first became aware of periodic weakness in his lower extremities at the age of 18 yr .
he noticed difficulties in standing and climbing stairs at the age of 21 and could not walk by himself by the age of 33 .
an examination at the age of 37 showed incomplete quadriparesis and he could walk with a four - point crutch .
his older sister developed lower extremity weakness and atrophy at the age of 18 yr and could not walk by the age of 36 .
direct sequencing analysis identified five heterozygous mutations in the dysf gene including three novel mutations ( fig .
patient 1 and his sister had compound heterozygous mutations of a novel c to t transition ( c.2494c > t ) in exon 24 resulting in a nonsense mutation ( gln832x ) along with a previously reported missense mutation ( c.2997g > t ; trp999cys ) .
the gln832x mutation was also found in the patient 2 with a novel missense mutation ( c.2974c > t ; trp992arg ) .
patient 3 had two mutations including a novel a to t transversion ( c.3307a > t ) in exon 30 , which resulted in a nonsense mutation ( lys1103x ) , and a previously reported insertion mutation ( c.4200dupc ) in exon 39 resulting in a frame shift mutation ( ile1401hisfsx8 ) .
three novel mutations ( gln832x , trp992arg , and lys1103x ) were not detected in 100 control chromosomes .
patient 1 was a 45 yr - old male patient who had presented with progressive weakness in both lower extremities for the previous 17 yr .
he noticed difficulty in running and atrophy of the lower leg muscles at 27 yr of age . the muscle weakness and atrophy progressed .
a neurological examination showed bilateral motor weakness and symmetric atrophy of the entire lower extremity muscles , which were more severe on the distal part than on the proximal part . marked atrophy of the lower leg muscles with
relatively spared pelvic girdle and upper thigh muscles resulted in a stalk - leg appearance .
he had been diagnosed of having a polymyositis at the age of 28 yr as a result of a muscle biopsy of the medial gastrocnemius showing myopathic changes with inflammatory cell infiltration .
his 43 yr - old younger sister was affected in the same way in her early thirties and found it difficult to walk up and downhills . since then , the muscle weakness worsened so that walking was still possible but only for short distances using a cane .
she also had difficulty in holding her baby due to extended weakness of her upper extremity muscles .
patient 2 was a 30 yr - old female who presented with difficulty in stair walking and pain in her low back and knee .
difficulty in climbing stairs developed at 26 yr of age and this difficulty in walking gradually worsened so that she could not climb stairs without the support of her upper extremities .
a neurological examination showed atrophy of both calf muscles , decreased strength of the lower extremity muscles , and an absent tendon reflex .
she could not stand on her tip - toe , but standing on her heels was possible .
the emg revealed the myopathic changes in gastrocnemius , rectus femoris , and biceps brachii muscles .
a muscle biopsy without immunohistochemial stain from the biceps brachii suggested a diagnosis of inflammatory myopathy .
magnetic resonance imaging of her lower leg disclosed symmetric fatty degeneration and decreased muscle volume of the posterior compartment muscles in both lower legs .
the anterior and lateral compartment muscles had either a normal or a relatively normal signal intensity and morphology .
patient 3 was a 37-yr - old man with quadriparesis who first became aware of periodic weakness in his lower extremities at the age of 18 yr .
he noticed difficulties in standing and climbing stairs at the age of 21 and could not walk by himself by the age of 33 .
an examination at the age of 37 showed incomplete quadriparesis and he could walk with a four - point crutch .
his older sister developed lower extremity weakness and atrophy at the age of 18 yr and could not walk by the age of 36 .
direct sequencing analysis identified five heterozygous mutations in the dysf gene including three novel mutations ( fig .
patient 1 and his sister had compound heterozygous mutations of a novel c to t transition ( c.2494c > t ) in exon 24 resulting in a nonsense mutation ( gln832x ) along with a previously reported missense mutation ( c.2997g > t ; trp999cys ) .
the gln832x mutation was also found in the patient 2 with a novel missense mutation ( c.2974c > t ; trp992arg ) .
patient 3 had two mutations including a novel a to t transversion ( c.3307a > t ) in exon 30 , which resulted in a nonsense mutation ( lys1103x ) , and a previously reported insertion mutation ( c.4200dupc ) in exon 39 resulting in a frame shift mutation ( ile1401hisfsx8 ) .
three novel mutations ( gln832x , trp992arg , and lys1103x ) were not detected in 100 control chromosomes .
this study identified five different mutations in three korean mm patients , and all patients had compound heterozygous mutation in the dysf gene .
the c.2997g > t ( trp999cys ) mutation is reported to be one of the most frequent mutations found in japanese mm patients , and has been associated with a significantly later onset and a relatively mild form of mm ( 9 ) .
the age at onset in patient 2 with the c.2997g > t mutation was delayed compared with the other patients , but was earlier than the mean age at onset reported elsewhere ( 9 ) . the c.4200dupc mutation ( ile1401hisfsx8 ) , which was found in two patients with mm or lgmd2b , appeared in the dysferlin sequence variations in the leiden muscular dystrophy pages .
the c.2494c > t ( gln832x ) mutation was novel and was found in 2 unrelated patients , which might be due to a possible founder effect in the korean population .
however , it will be necessary to perform haplotype analysis and collect more data on mm patients in korea to address this issue . some patients with mm
can be easily misdiagnosed as having an inflammatory myopathy because inflammation is frequently observed in patients with mm and the inflammatory changes found in patients with mm are indistinguishable from those observed in patients with inflammatory myopathy ( 12 ) .
indeed , two patients in this study had previously been suspected of having a form of inflammatory myopathy based on the muscle biopsy findings .
( 13 ) reported that the presence of inflammation is not an exclusion criterion in muscular dystrophy related to a dysferlin deficiency , while the muscle biopsies of mm or lgmd2b patients generally demonstrates signs of a dystrophy with a dysferlin deficiency .
it is possible that some mm patients have been erroneously diagnosed with polymyositis based on the absence of dystrophic features and the presence of inflammation in the muscle biopsies .
therefore , mm should be considered when making a differential diagnosis of patients exhibiting distal myopathy and muscular inflammation on muscle biopsies , and dysf gene analysis should also be considered .
Output:
| miyoshi myopathy ( mm ) is an autosomal recessive distal muscular dystrophy caused by mutations in the dysferlin gene ( dysf ) on chromosome 2p13 .
although mm patients and their mutations in the dysf gene have been found from all over the world , there is only one report of genetically confirmed case of mm in korea .
recently , we encountered three unrelated korean patients with mm and two of them have previously been considered as having a type of inflammatory myopathy .
the clinical and laboratory evaluation showed typical features of muscle involvement in mm in all patients but one patient initially had moderate proximal muscle involvement and another showed incomplete quadriparesis with rapid progression .
direct sequencing analysis of the dysf gene revealed that each patient had compound heterozygous mutations ( gln832x and trp992arg , gln832x and trp999cys , and lys1103x and ile1401hisfsx8 , respectively ) among which three were novel .
although mm has been thought to be quite rare in korea , it should be considered in a differential diagnosis of patients exhibiting distal myopathy . |
PubmedSumm8896 | ***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:
pancreatic islet transplantation is a physiologically advantageous and minimally invasive procedure for the treatment of type 1 diabetes mellitus ( 1 ) .
the success rate of islet transplantation has been improved by transplanting a higher mean islet mass prepared from two to four donor pancreases and using glucocorticoid - free immunosuppressants ( 1 , 2 ) . however , a shortage of donors and the use of potentially islet - toxic immunosuppressants are the main hurdles to successful islet transplantation .
few data are available on islet isolation from the pancreas of asian people , and most of the guidelines on islet isolation techniques are based on the procedures used on western subjects .
reports on allogeneic islet transplantation alone in the korean population are lacking . according to data from the korean network for organ sharing
, 10 cases of allogeneic islet transplantation have been performed , and most were islet - after - kidney transplantations ( 3 ) .
several autologous islet transplantations have been reported ( 4 ) , but islet isolation was performed using a living - donor pancreas and an inadequate quantity of isolated islets was not a limitation to performing the transplantation . here , we report on a case of allogeneic islet transplantation alone , using a marginal dose from a single - donor pancreas in a korean patient with type 1 diabetes mellitus .
a 59-yr - old woman who had been diagnosed with type 1 diabetes mellitus for 25 yr , suffered from recurrent severe hypoglycemia and hypoglycemic unawareness since october 2011 .
her body weight was 52 kg and her body mass index ( bmi ) was 20.31 kg / m .
fasting and postprandial serum c - peptide concentrations were 0.07 ng / ml and 0.23 ng / ml , respectively .
she had visited the emergency room twice complaining of decreased consciousness related to severe hypoglycemia ( < 50 mg / dl ) in the previous year .
she did not experience hypoglycemic symptoms until her blood glucose level decreased to 50 mg / dl .
her total insulin requirement was 34 u / day , and her glycated hemoglobin ( hba1c ) level ranged from 7.8% to 9.6% with a mean value of 8.54% in the preceding 2 yr . the estimated glomerular filtration rate ( egfr ) was 91.67 ml / min/1.73 m and albumin to creatinine ratio ( acr ) was 16.45 mg / g .
the pancreas was procured from a 49-yr - old brain - death donor with a bmi of 23.13 kg / m .
the organ was transported in chilled histidine - tryptophan - ketoglutarate solution and transferred to the good manufacturing practice facility .
the pancreas was distended by controlled ductal perfusion with liberase human islet enzyme ( roche diagnostics , indianapolis , usa ) and digested mechanically in a ricordi chamber .
pancreatic tissue density was tested before purification using a cobe 2991 cell processor ( gambro bct inc . , lakewood , co , usa ) to predict the pancreatic tissue density .
prepurification gradient tests were performed using a ficoll ( biochrom , berlin , germany)-based standard gradient ( 1.100 - 1.077
louis , mo , usa)-based gradient-1 ( 1.100 - 1.085 - 1.060 g / cm ) and optiprep - based gradient-2 ( 1.090 - 1.075 - 1.050 g / cm ) .
the tests showed little differences in the density and produced a single layer of islet - acinar cell mixture .
by contrast , a gradient test using optiprep - based gradient-3 ( 1.080 - 1.065 - 1.040 g / cm ) produced two distinct layers of the different cell types .
the total amount of purified islets was 216,500 islet equivalents ( ieq ) ( 4,163 ieq / recipient body weight in kg ) , which is the minimally adequate quantity for transplantation ( 5 ) .
the purity of the isolated islets was 79.6% , and the islet viability was > 90% .
glucose stimulated insulin secretion of isolated islet was tested in vitro and showed an insulin concentration of 10.1 u / ml at low ( 2.8 mm ) glucose media and 17.1 u / ml at high ( 16.8 mm ) glucose media during 1 hr each .
the patient was sedated and a percutaneous transhepatic approach was used to access to the portal vein under fluoroscopic guidance .
doppler ultrasonography of the portal vein was performed within 24 hr after transplantation , and no definite evidence of flow disturbance was observed .
the immunosuppressive regimen was based on that previously described in the edmonton protocol ( 5 ) . instead of daclizumab
, basiliximab was given intravenously at a dose of 20 mg 2 hr before islet transplantation and 4 days after transplantation .
sirolimus was administered administered once daily to achieve a target trough therapeutic range of 12 - 15 ng / ml for the first 3 months , after which the target trough range was planned to be lowered to 7 - 12 ng / ml .
tacrolimus was administered twice daily and adjusted to achieve a target trough level of 3 - 6 ng / ml .
one month after transplantation , the dosage of sirolimus was reduced because of systemic mucositis and leukopenia , and this dosage was maintained at the trough level of 5 - 9 ng / ml .
the islet transplantation protocol was approved by the institutional review board of the catholic university of korea ( no .
after islet transplantation , the patient 's insulin requirement decreased to 22 u / day , which was about 65% of the previous requirement ( fig .
fasting and postprandial c - peptide concentrations improved to 0.25 ng / ml and 0.44 ng / ml , respectively , at 2 months after transplantation . the hba1c level improved to 7.3% at 3 months after transplantation .
self - monitored blood glucose concentration was measured four times a day ( before each meal and at bedtime ) , and the results showed marked improvement in the frequencies of both hypoglycemia and extreme hyperglycemia after transplantation ( fig .
2 ) . before transplantation , she experienced severe hypoglycemia ( < 50 mg / dl ) on average twice a month .
however , she did not experience further severe hypoglycemia and became aware of hypoglycemia at a glucose concentration of 70 mg / dl .
we calculated the glycemic risk assessment diabetes equation ( grade ) score to assess the glycemic variability and the percentage contribution of hypoglycemia events , before and at 3 and 9 months after the transplantation ( 6 ) .
also the average daily risk range ( adrr ) index was calculated ; the values are stratified into three categories : low risk < 20 ; moderate risk , 20-40 ; and high risk > 40 ( 7 , 8) . before the transplantation ,
the grade score was 10.31 with 28.5% of hypoglycemia ( < 70 mg / dl ) events , and improved to grade score of 7.94 with 2.4% of hypoglycemia events and 5.99 with 2.1% of hypoglycemia events at 3 and 9 months after the transplantation , respectively .
similarly , the adrr index was 26.88 before the transplantation and improved to 17.56 and 14.60 at 3 and 9 months after transplantation , respectively .
currently ( about 9 months after the transplantation ) , her hba1c is 7.8% , and fasting and postprandial c - peptide concentrations are 0.20 and 0.43 ng / ml , respectively .
there is no evidence of leukopenia and her renal function is in normal range with an egfr of 106.04 ml / min/1.73 m.
a 59-yr - old woman who had been diagnosed with type 1 diabetes mellitus for 25 yr , suffered from recurrent severe hypoglycemia and hypoglycemic unawareness since october 2011 .
her body weight was 52 kg and her body mass index ( bmi ) was 20.31 kg / m .
fasting and postprandial serum c - peptide concentrations were 0.07 ng / ml and 0.23 ng / ml , respectively .
she had visited the emergency room twice complaining of decreased consciousness related to severe hypoglycemia ( < 50 mg / dl ) in the previous year .
she did not experience hypoglycemic symptoms until her blood glucose level decreased to 50 mg / dl .
her total insulin requirement was 34 u / day , and her glycated hemoglobin ( hba1c ) level ranged from 7.8% to 9.6% with a mean value of 8.54% in the preceding 2 yr . the estimated glomerular filtration rate ( egfr ) was 91.67 ml / min/1.73 m and albumin to creatinine ratio ( acr ) was 16.45 mg / g .
the pancreas was procured from a 49-yr - old brain - death donor with a bmi of 23.13 kg / m .
the organ was transported in chilled histidine - tryptophan - ketoglutarate solution and transferred to the good manufacturing practice facility .
the pancreas was distended by controlled ductal perfusion with liberase human islet enzyme ( roche diagnostics , indianapolis , usa ) and digested mechanically in a ricordi chamber .
pancreatic tissue density was tested before purification using a cobe 2991 cell processor ( gambro bct inc . ,
prepurification gradient tests were performed using a ficoll ( biochrom , berlin , germany)-based standard gradient ( 1.100 - 1.077
louis , mo , usa)-based gradient-1 ( 1.100 - 1.085 - 1.060 g / cm ) and optiprep - based gradient-2 ( 1.090 - 1.075 - 1.050 g / cm ) .
the tests showed little differences in the density and produced a single layer of islet - acinar cell mixture .
by contrast , a gradient test using optiprep - based gradient-3 ( 1.080 - 1.065 - 1.040 g / cm ) produced two distinct layers of the different cell types .
the total amount of purified islets was 216,500 islet equivalents ( ieq ) ( 4,163 ieq / recipient body weight in kg ) , which is the minimally adequate quantity for transplantation ( 5 ) .
the purity of the isolated islets was 79.6% , and the islet viability was > 90% .
glucose stimulated insulin secretion of isolated islet was tested in vitro and showed an insulin concentration of 10.1 u / ml at low ( 2.8 mm ) glucose media and 17.1 u / ml at high ( 16.8 mm ) glucose media during 1 hr each .
the islet transplantation was performed in november 2013 . the patient was sedated and a percutaneous transhepatic approach was used to access to the portal vein under fluoroscopic guidance .
doppler ultrasonography of the portal vein was performed within 24 hr after transplantation , and no definite evidence of flow disturbance was observed .
the immunosuppressive regimen was based on that previously described in the edmonton protocol ( 5 ) . instead of daclizumab
, basiliximab was given intravenously at a dose of 20 mg 2 hr before islet transplantation and 4 days after transplantation .
sirolimus was administered administered once daily to achieve a target trough therapeutic range of 12 - 15 ng / ml for the first 3 months , after which the target trough range was planned to be lowered to 7 - 12 ng / ml .
tacrolimus was administered twice daily and adjusted to achieve a target trough level of 3 - 6 ng / ml .
one month after transplantation , the dosage of sirolimus was reduced because of systemic mucositis and leukopenia , and this dosage was maintained at the trough level of 5 - 9 ng / ml .
the islet transplantation protocol was approved by the institutional review board of the catholic university of korea ( no .
after islet transplantation , the patient 's insulin requirement decreased to 22 u / day , which was about 65% of the previous requirement ( fig .
fasting and postprandial c - peptide concentrations improved to 0.25 ng / ml and 0.44 ng / ml , respectively , at 2 months after transplantation . the hba1c level improved to 7.3% at 3 months after transplantation .
self - monitored blood glucose concentration was measured four times a day ( before each meal and at bedtime ) , and the results showed marked improvement in the frequencies of both hypoglycemia and extreme hyperglycemia after transplantation ( fig .
2 ) . before transplantation , she experienced severe hypoglycemia ( < 50 mg / dl ) on average twice a month .
however , she did not experience further severe hypoglycemia and became aware of hypoglycemia at a glucose concentration of 70 mg / dl .
we calculated the glycemic risk assessment diabetes equation ( grade ) score to assess the glycemic variability and the percentage contribution of hypoglycemia events , before and at 3 and 9 months after the transplantation ( 6 ) .
also the average daily risk range ( adrr ) index was calculated ; the values are stratified into three categories : low risk < 20 ; moderate risk , 20-40 ; and high risk > 40 ( 7 , 8) . before the transplantation ,
the grade score was 10.31 with 28.5% of hypoglycemia ( < 70 mg / dl ) events , and improved to grade score of 7.94 with 2.4% of hypoglycemia events and 5.99 with 2.1% of hypoglycemia events at 3 and 9 months after the transplantation , respectively .
similarly , the adrr index was 26.88 before the transplantation and improved to 17.56 and 14.60 at 3 and 9 months after transplantation , respectively .
currently ( about 9 months after the transplantation ) , her hba1c is 7.8% , and fasting and postprandial c - peptide concentrations are 0.20 and 0.43 ng / ml , respectively .
there is no evidence of leukopenia and her renal function is in normal range with an egfr of 106.04 ml / min/1.73 m.
to our knowledge , this is the first reported case on allogeneic islet transplantation alone in korea .
although insulin independence was not achieved , the patient showed stabilized blood glucose concentration , reduced insulin dosage and reversal of hypoglycemic unawareness , even with a marginal dose of islets and reduced immunosuppressant .
there are only a few reports on islet transplantation in asian subjects . according to the collaborative islet transplantation registry ,
centers from north america , europe and australia are registered , but none from asian countries ( 9 ) . when islets are purified with a cobe
however , this method does not appropriately adjust for interpancreatic variations in exocrine and islet tissue density , which is influenced by donor characteristics , the secretory status of exocrine cells , and the islet isolation procedure ( 10 ) .
predicting pancreatic tissue density using prepurification density tests may improve the islet isolation yield , as we performed in this case . hering et al .
( 11 ) reported on allogeneic islet transplantation using marginal dose islets ( average of 7,271 ieq / kg ) from a single donor pancreas along with potent induction immunotherapy ( antithymocyte globulin , daclizumab and etanercept ) .
however , our patient underwent islet transplantation with only a marginal quantity of islets ( 4,163 ieq / kg ) with reduced immunosuppressant . in conclusion , this is the first reported case on successful islet transplantation alone in a korean patient with type 1 diabetes .
although insulin independence was not achieved , the patient showed stabilized blood glucose concentration , reduced insulin dosage and reversal of hypoglycemic unawareness , even with a marginal dose of islets and reduced immunosuppressant .
Output:
| pancreatic islet transplantation is a physiologically advantageous and minimally invasive procedure for the treatment of type 1 diabetes mellitus . here
, we describe the first reported case of successful allogeneic islet transplantation alone , using single - donor , marginal - dose islets in a korean patient .
a 59-yr - old patient with type 1 diabetes mellitus , who suffered from recurrent severe hypoglycemia , received 4,163 islet equivalents / kg from a single brain - death donor .
isolated islets were infused intraportally without any complications .
the immunosuppressive regimen was based on the edmonton protocol , but the maintenance dosage was reduced because of mucositis and leukopenia . although insulin independence was not achieved , the patient showed stabilized blood glucose concentration , reduced insulin dosage and reversal of hypoglycemic unawareness , even with marginal dose of islets and reduced immunosuppressant .
islet transplantation may successfully improve endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus.graphical abstract |
PubmedSumm8897 | ***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: behavioral and neurophysiological data were collected from two exotropic juvenile rhesus ( macaca mulatta ) monkeys ( 6 years , 910 kg ) .
strabismus was previously induced by optical prism - rearing of infant monkeys . during the prism - rearing paradigm ,
infant monkeys wore a helmet like device that housed a horizontally oriented fresnel prism in front of one eye and a vertically oriented fresnel prism ( 20 prism diopter ) in front of the other eye , starting from day 1 after birth to 4 months of age , after which they were allowed unrestricted vision .
disruption of binocular vision due to prism - viewing during this initial period leads to strabismus as it is the critical period for development of eye alignment , stereopsis , and binocular sensitivity .
all procedures were carried out in accordance with national institutes of health guidelines and were approved by the university of houston institutional animal care and use committee .
prior to commencement of experiments associated with this study , each juvenile monkey ( 4 years of age ) underwent surgical procedures carried out under aseptic conditions under isoflurane anesthesia ( 1.25%2.5% ) . in the first surgery ,
a head stabilization post was implanted to restrict head movements during the experiments . in subsequent procedures ,
scleral search coils were implanted in both eyes , using the technique of judge et al . , to record binocular eye movements . after collecting baseline data ,
strabismus correction surgery was performed by an expert strabismus surgeon ( also one of the study authors ) on the left eye only of m1 and right eye only of m2 and consisted of lateral rectus recession ( weakening the lateral rectus muscle ) and medial rectus resection ( strengthening the medial rectus muscle ) to improve their strabismus angle .
we specifically chose to operate on only one eye , because we wanted to use the fellow eye as a control .
the goal of data acquisition and analysis was to perform a longitudinal evaluation of eye alignment and eye movements following strabismus correction surgery .
therefore , binocular eye movement data were collected as the animals performed central and eccentric fixation , saccades ( 15 horizontal and vertical target locations ) , and smooth pursuit ( 0.3 hz , 15 ) tasks under monocular left eye or right eye viewing conditions .
alignment data were collected at five time points : before surgical treatment ( pre ) , the day after surgical treatment ( p1d ) , 1 week after treatment ( p1w ) , 1 month after treatment ( p1 m ) , and 6 months after treatment ( p6 m ) .
saccade and smooth - pursuit data were analyzed at pre , p1w , p1 m , and p6 m because there were not enough experimental trials collected at p1d .
binocular data were collected using the magnetic search coil technique ( primelec industries , regensdorf , switzerland ) .
eye coils were calibrated at the beginning of each experiment by rewarding the animal with small amounts of juice as they looked at a series of targets projected along the horizontal or vertical meridian on a screen at distance of 57 cm .
calibration of each eye was performed independently during monocular viewing forced by occluding one or the other eye using liquid crystal shutter goggles ( citizen fine devices , nagano , japan ) that were under computer control .
visual stimuli were generated using the bits # visual stimulus generator ( cambridge research systems , cambridge , united kingdom ) and psychtoolbox 3 operated under computer control and presented using a depthq projector running at a 120-hz frame rate ( lightspeed design , inc . , bellevue , wa , usa ) .
the target and binocular eye position signals were passed through anti - aliasing filters with a cutoff of 400 hz before digitization at 2.79 khz with 12-bit precision ( alphalab snr system ; alpha - omega engineering , nazareth , israel ) .
were additionally calibrated offline and filtered using a software finite impulse response ( fir ) low - pass filter with a cutoff of 80 hz prior to further analysis . analysis of eye movement data was partially automated using custom scripts written in matlab ( mathworks , natick , ma , usa ) . for saccade data , the computer displayed target position , binocular eye position , eye velocity , and eye acceleration traces of a single saccade trial .
velocity and acceleration signals were generated by digital differentiation of the position signal using a central difference algorithm .
the investigator viewed the traces and decided whether the saccade trial was to be accepted or rejected .
trials that were rejected were usually those in which the animal was not fixating prior to the target step , the saccade did not appear to be directed toward the target , or the saccade did not occur within 400 ms of the target step .
once a decision to accept the trial was made , mean and sd of control eye acceleration prior to the saccade were calculated over a 70-ms fixation period .
saccade onset was automatically determined by the software as the first time point at which eye acceleration was greater than 5 sds away from the control eye acceleration , and saccade offset was determined as the last time point at which eye deceleration was less than 5 sds away from the same mean eye acceleration .
although detection of saccade onset and offset was automated , the investigator visually examined the velocity and acceleration traces of every saccade and had the option of either accepting or changing the computer selection , although this was not typical .
once the saccade was identified , saccade metric parameters ( amplitude and peak velocity ) for each eye were calculated .
main sequence plots of horizontal saccade peak velocity versus horizontal saccade amplitude were fitted with the following exponential rise to maximum equation :
where amp = horizontal saccade amplitude , pv = horizontal saccade peak velocity , a = constant determining exponential rise , and pvmax = asymptotic peak velocity .
for sinusoidal smooth - pursuit analysis
then smooth - pursuit gain ( ratio of peak eye velocity to peak target velocity ) was calculated separately for nasalward and temporalward movements . to assess fixation stability , 10 seconds of eye movement data from both the eyes were analyzed as the monkey maintained monocular fixation at a stationary straight - ahead target .
fixation stability was quantified by calculating the bivariate contour ellipse area ( bcea ) , a metric that quantifies the area of the region over which eye positions are dispersed during attempted fixation .
the bcea encompassing 68.2% of fixation points was calculated using the following equation :
,
where x = sd of horizontal eye position , y = sd of vertical eye position , 2.291 is the value ( 2 df ) corresponding to a probability of 0.68 , and p is the pearson product moment correlation coefficient of horizontal and vertical eye positions .
for statistical analysis , the kruskal - wallis 1-way anova on ranks
was performed , and if significant , post hoc testing was performed using dunn 's method .
behavioral and neurophysiological data were collected from two exotropic juvenile rhesus ( macaca mulatta ) monkeys ( 6 years , 910 kg ) .
strabismus was previously induced by optical prism - rearing of infant monkeys . during the prism - rearing paradigm ,
infant monkeys wore a helmet like device that housed a horizontally oriented fresnel prism in front of one eye and a vertically oriented fresnel prism ( 20 prism diopter ) in front of the other eye , starting from day 1 after birth to 4 months of age , after which they were allowed unrestricted vision .
disruption of binocular vision due to prism - viewing during this initial period leads to strabismus as it is the critical period for development of eye alignment , stereopsis , and binocular sensitivity .
all procedures were carried out in accordance with national institutes of health guidelines and were approved by the university of houston institutional animal care and use committee . prior to commencement of experiments associated with this study , each juvenile monkey ( 4 years of age ) underwent surgical procedures carried out under aseptic conditions under isoflurane anesthesia ( 1.25%2.5% ) . in the first surgery , a head stabilization post was implanted to restrict head movements during the experiments . in subsequent procedures ,
scleral search coils were implanted in both eyes , using the technique of judge et al . , to record binocular eye movements . after collecting baseline data
strabismus correction surgery was performed by an expert strabismus surgeon ( also one of the study authors ) on the left eye only of m1 and right eye only of m2 and consisted of lateral rectus recession ( weakening the lateral rectus muscle ) and medial rectus resection ( strengthening the medial rectus muscle ) to improve their strabismus angle .
we specifically chose to operate on only one eye , because we wanted to use the fellow eye as a control .
the goal of data acquisition and analysis was to perform a longitudinal evaluation of eye alignment and eye movements following strabismus correction surgery .
therefore , binocular eye movement data were collected as the animals performed central and eccentric fixation , saccades ( 15 horizontal and vertical target locations ) , and smooth pursuit ( 0.3 hz , 15 ) tasks under monocular left eye or right eye viewing conditions .
alignment data were collected at five time points : before surgical treatment ( pre ) , the day after surgical treatment ( p1d ) , 1 week after treatment ( p1w ) , 1 month after treatment ( p1 m ) , and 6 months after treatment ( p6 m ) .
saccade and smooth - pursuit data were analyzed at pre , p1w , p1 m , and p6 m because there were not enough experimental trials collected at p1d .
binocular data were collected using the magnetic search coil technique ( primelec industries , regensdorf , switzerland ) .
eye coils were calibrated at the beginning of each experiment by rewarding the animal with small amounts of juice as they looked at a series of targets projected along the horizontal or vertical meridian on a screen at distance of 57 cm .
calibration of each eye was performed independently during monocular viewing forced by occluding one or the other eye using liquid crystal shutter goggles ( citizen fine devices , nagano , japan ) that were under computer control .
visual stimuli were generated using the bits # visual stimulus generator ( cambridge research systems , cambridge , united kingdom ) and psychtoolbox 3 operated under computer control and presented using a depthq projector running at a 120-hz frame rate ( lightspeed design , inc . ,
the target and binocular eye position signals were passed through anti - aliasing filters with a cutoff of 400 hz before digitization at 2.79 khz with 12-bit precision ( alphalab snr system ; alpha - omega engineering , nazareth , israel ) .
all eye movement data were additionally calibrated offline and filtered using a software finite impulse response ( fir ) low - pass filter with a cutoff of 80 hz prior to further analysis .
analysis of eye movement data was partially automated using custom scripts written in matlab ( mathworks , natick , ma , usa ) . for saccade data , the computer displayed target position , binocular eye position , eye velocity , and eye acceleration traces of a single saccade trial .
velocity and acceleration signals were generated by digital differentiation of the position signal using a central difference algorithm .
the investigator viewed the traces and decided whether the saccade trial was to be accepted or rejected .
trials that were rejected were usually those in which the animal was not fixating prior to the target step , the saccade did not appear to be directed toward the target , or the saccade did not occur within 400 ms of the target step .
once a decision to accept the trial was made , mean and sd of control eye acceleration prior to the saccade were calculated over a 70-ms fixation period .
saccade onset was automatically determined by the software as the first time point at which eye acceleration was greater than 5 sds away from the control eye acceleration , and saccade offset was determined as the last time point at which eye deceleration was less than 5 sds away from the same mean eye acceleration .
although detection of saccade onset and offset was automated , the investigator visually examined the velocity and acceleration traces of every saccade and had the option of either accepting or changing the computer selection , although this was not typical .
once the saccade was identified , saccade metric parameters ( amplitude and peak velocity ) for each eye were calculated .
main sequence plots of horizontal saccade peak velocity versus horizontal saccade amplitude were fitted with the following exponential rise to maximum equation :
where amp = horizontal saccade amplitude , pv = horizontal saccade peak velocity , a = constant determining exponential rise , and pvmax = asymptotic peak velocity .
for sinusoidal smooth - pursuit analysis
then smooth - pursuit gain ( ratio of peak eye velocity to peak target velocity ) was calculated separately for nasalward and temporalward movements . to assess fixation stability , 10 seconds of eye movement data from both the eyes were analyzed as the monkey maintained monocular fixation at a stationary straight - ahead target .
fixation stability was quantified by calculating the bivariate contour ellipse area ( bcea ) , a metric that quantifies the area of the region over which eye positions are dispersed during attempted fixation . therefore , a smaller value for bcea is indicative of greater fixation stability .
the bcea encompassing 68.2% of fixation points was calculated using the following equation :
,
where x = sd of horizontal eye position , y = sd of vertical eye position , 2.291 is the value ( 2 df ) corresponding to a probability of 0.68 , and p is the pearson product moment correlation coefficient of horizontal and vertical eye positions
.
for statistical analysis , the kruskal - wallis 1-way anova on ranks was performed , and if significant , post hoc testing was performed using dunn 's method .
prior to treatment , both monkeys had an exotropia whose magnitude depended on the eye of fixation , a likely indicator for dissociated horizontal deviation .
m1 had an exotropia of 27 under left eye viewing ( lev ) conditions and 30 under right eye viewing ( rev ) conditions .
m2 had an exotropia of 37 under lev conditions and 30 during rev . immediately after surgery ( p1d ) ,
exotropia in m1 reduced to 10 ( lev ) and 11 ( rev ) and exotropia in m2 reduced to 9 ( lev ) and 12 ( rev ) . the initial decrease in strabismus angle after the surgery was followed by a gradual reversal toward presurgical exotropia by the end of 6 months .
figure 1 is a hess plot showing alignment at different time points as the animals fixated a series of targets along the horizontal and vertical meridian . by 6 months after the correction surgery , m1 showed an exotropia of 20 during either eye viewing and m2 showed an exotropia of 30 ( lev ) and 20 ( rev ) .
thus , it appeared that both animals reverted to 60%80% of their original strabismus angle within 6 months .
alignment was also examined at 10 months , and the strabismus angle for m1 was still 20 but had changed slightly in m2 to 24 ( lev ) and 18 ( rev ) . longitudinal change in eye misalignment following strabismus treatment in m1 ( a d ) and m2 ( e h ) .
plots show eye positions of the viewing eye ( b , c , e , h ) and the nonviewing eye ( a , d , f , g ) during monocular viewing of a series of targets along the horizontal or vertical meridian . a , b ( m1 ) and e , f ( m2 ) show data collected when the animal viewed with their untreated eye ( treated eye under cover ) and c , d ( m1 ) and g , h ( m2 ) show data collected when the animals viewed with their treated eye .
each plot shows data collected at five time points : before surgery ( pre ; blue circle ) , 1 day after surgery ( p1d ; red triangle ) , 1 week after surgery ( p1w ; yellow square ) , 1 month after surgery ( p1 m ; gray diamond ) , and 6 months after surgery ( p6 ; green inverted triangle ) .
pairs of plots on each row show that the viewing eye is on target while the covered eye is abducted .
rightward and upward eye positions are positive and leftward and downward eye positions are negative .
we analyzed 4021 saccades at four time points ( pre [ 1449 saccades ] , p1w [ 648 saccades ] , p1 m [ 1103 saccades ] , and p6 m [ 821 saccades ] ) . because the numbers of saccadic trials acquired on any single day were relatively low , data from multiple days near the indicated time point were pooled for analysis .
average saccade gains ( ratio of saccade amplitude to target amplitude ) of the two animals are summarized in figure 2 . in general ,
saccade gain of the viewing eye , irrespective of whether the animal viewed with the treated or untreated eye , did not show significant longitudinal changes ( blue bars in 2a , 2c ; red bars in 2b , 2d ) , as might be expected if the goal of the viewing eye is to saccade onto the target .
longitudinal changes in the nonviewing eye were more striking , although slightly different in the two monkeys .
2a ) , the treated eye ( red bars ) showed a significant increase in saccade gain after surgery that decreased to presurgery values by p6 . on the other hand , when m2 viewed with the untreated eye ( fig .
2c ) , there was an immediate drop in saccade gain in the treated eye ( red bars ) following surgery that reverted to presurgical values by p1m p6 .
note that when viewing with the untreated eye , any changes in treated eye saccade gains can be attributed to adaptive muscle or neural changes .
2b ) , the untreated eye saccade gain ( blue bars ) decreased or remained the same at p1w and thereafter increased by p6 ( greater than pre values for leftward saccades ) . in m2 ( fig .
2d ) , the untreated eye saccade gain increased at p1w and thereafter decreased by p6 for leftward saccades only .
note that when viewing with the treated eye , any changes in untreated eye saccade gains are likely driven by a combination of hering 's law based neural mechanisms and adaptive untreated eye muscle or neural changes triggered by the surgical intervention of the treated muscle .
longitudinal change in horizontal saccade gains in m1 ( a , b ) and m2 ( c , d ) following strabismus treatment .
bars in each plot show means and sds of saccade gains of the untreated eye ( blue ) and treated eye ( red ) at four time points ( pre , p1w , p1 m , and p6 ) .
the asterisks represent statistically significant difference compared with presurgical values ( blue , untreated eye ; red , treated eye ) .
main sequence plots are shown in figure 3 along with the mean and 95% upper and lower confidence limits .
longitudinal changes in saccade peak velocity were relatively small and difficult to identify because of the large variability in saccade velocities .
there was a slight but significant increase in saccade velocity in both the treated and untreated eyes as animal m1 viewed with the treated eye ( figs .
3c , 3d ) as p6 velocities are higher than they were before surgery . a similar ,
albeit greater magnitude , increase in peak saccade velocity was observed in both the treated and untreated eyes as animal m2 viewed with the treated eye ( more so for rightward than leftward saccades ; figs .
estimated fit parameters for pvmax and a from equation 1 for each of the eyes under the different viewing conditions and at the different time points are provided in the table .
h ) showing horizontal saccade amplitude on the x - axis and horizontal saccade peak velocity on the y - axis .
negative saccade amplitudes indicate leftward saccades and positive amplitudes indicate rightward saccades . left column panels ( a , c , e , g )
show data from the untreated eye and right column panels ( b , d , f , g ) show data from the treated eye .
each data point represents a single saccade , and lines represent exponential rise - to - maximum fits to the main sequence data .
for these plots , viewing and nonviewing eyes ' data were collected when the animals viewed monocularly with either treated eye or untreated eye .
data points and curve fits are overlaid for saccade data collected at pre ( blue circle ) , p1w ( red triangle ) , p1 m ( gray diamond ) , and p6 ( green inverted triangle ) .
fit parameters for main sequence plots derived from equation 1 summary of leftward and rightward smooth - pursuit gains obtained from 15 to 30 cycles of smooth pursuit at each time point for each monkey are shown in figure 4 along with results of statistical comparison to presurgical smooth - pursuit gains .
longitudinal trends in smooth - pursuit gains reflected the trends observed for saccadic eye movement gains .
gains of viewing eye remained more or less constant following surgery ( blue bars in figs .
4a ) , there was a significant increase in gain in the treated eye ( red bars ) for both rightward and leftward pursuit that was mostly reversed by p6 . on the other hand , when m2 viewed with the untreated eye ( fig .
4c ) , there was a significant decrease in gain in the treated eye that mostly reversed by p6 .
smooth - pursuit gains calculated when the animals viewed with their treated eyes ( figs .
4b , 4d ) also followed trends observed during saccade analysis . longitudinal change in horizontal smooth - pursuit gains in m1 ( a , b ) and m2 ( c , d ) following strabismus treatment .
bars in each plot show mean smooth - pursuit gains and sds of the untreated eye ( blue ) and treated eye ( red ) at four time points ( pre , p1w , p1 m , and p6 ) .
leftward and rightward smooth - pursuit was analyzed separately and are represented by the directional arrows .
the asterisks represent statistically significant difference compared with presurgical values ( blue , untreated eye ; red , treated eye ) .
strabismic humans and monkeys often exhibit increased monocular viewing smooth - pursuit tracking gains for nasalward target motion compared with temporalward motion ( naso - temporal asymmetry ) .
both the monkeys in the current study displayed a naso - temporal ( n / t ) asymmetry prior to surgery ( except m2 during left eye viewing ; fig .
5b , blue bars ) , and we wondered whether surgical manipulation of eom resulted in any modification of this feature of strabismus .
a naso - temporal asymmetry index was calculated as the ratio of viewing eye temporalward smooth - pursuit gain to viewing eye nasalward smooth - pursuit gain for both treated and untreated eyes viewing conditions . in m1 , the naso - temporal asymmetry persisted mostly unchanged following surgery during either untreated or treated eye viewing . in m2 also , n / t asymmetry was unchanged during treated ( right ) eye viewing . during untreated (
left ) eye viewing , there was a slight improvement in the index ( reduced asymmetry ) that reversed by p1 m .
bars in each plot show a naso - temporal asymmetry index calculated as the ratio of the viewing eye temporalward and nasalward smooth - pursuit gain for m1 ( a ) and m2 ( b ) at four time points ( pre , p1w , p1 m , p6 ) .
n / t asymmetry index during untreated eye viewing is shown in blue and during treated eye viewing is shown in red .
fixation stability was assessed by calculating the bcea metric for each eye during monocular viewing ( fig .
when the untreated eye was viewing , fixation stability of the nonviewing treated eye ( red bars ) improved ( lower bcea ) after surgery but regressed by p6 in m2 only .
these data were not amenable for statistical testing because each bar represents a single data point for the fixation stability metric .
fixation stability of the viewing untreated eye ( blue bars ) did not show consistent longitudinal effects .
when the treated eye was viewing , fixation stability of nonviewing untreated eye ( blue bars ) showed postsurgical improvement that regressed by p6 in m1 but no consistent longitudinal effects in m2 .
fixation stability of the nonviewing eye was worse at all time points for both the monkeys , consistent with previous studies of fixation stability in strabismic monkeys
. longitudinal change in fixation stability ( m1 , a ; m2 , b ) following strabismus treatment .
bars in each plot show bcea values of the treated eye ( red ) and untreated eye ( blue ) during either eye viewing at the four time points ( pre , p1w , p1 m , p6 m ) .
prior to treatment , both monkeys had an exotropia whose magnitude depended on the eye of fixation , a likely indicator for dissociated horizontal deviation .
m1 had an exotropia of 27 under left eye viewing ( lev ) conditions and 30 under right eye viewing ( rev ) conditions .
m2 had an exotropia of 37 under lev conditions and 30 during rev . immediately after surgery ( p1d ) ,
exotropia in m1 reduced to 10 ( lev ) and 11 ( rev ) and exotropia in m2 reduced to 9 ( lev ) and 12 ( rev ) . the initial decrease in strabismus angle after the surgery was followed by a gradual reversal toward presurgical exotropia by the end of 6 months .
figure 1 is a hess plot showing alignment at different time points as the animals fixated a series of targets along the horizontal and vertical meridian . by 6 months after the correction surgery , m1 showed an exotropia of 20 during either eye viewing and m2 showed an exotropia of 30 ( lev ) and 20 ( rev ) .
thus , it appeared that both animals reverted to 60%80% of their original strabismus angle within 6 months .
alignment was also examined at 10 months , and the strabismus angle for m1 was still 20 but had changed slightly in m2 to 24 ( lev ) and 18 ( rev ) . longitudinal change in eye misalignment following strabismus treatment in m1 ( a d ) and m2 ( e h ) .
plots show eye positions of the viewing eye ( b , c , e , h ) and the nonviewing eye ( a , d , f , g ) during monocular viewing of a series of targets along the horizontal or vertical meridian . a , b ( m1 ) and e , f ( m2 ) show data collected when the animal viewed with their untreated eye ( treated eye under cover ) and c , d ( m1 ) and g , h ( m2 ) show data collected when the animals viewed with their treated eye .
each plot shows data collected at five time points : before surgery ( pre ; blue circle ) , 1 day after surgery ( p1d ; red triangle ) , 1 week after surgery ( p1w ; yellow square ) , 1 month after surgery ( p1 m ; gray diamond ) , and 6 months after surgery ( p6 ; green inverted triangle ) .
pairs of plots on each row show that the viewing eye is on target while the covered eye is abducted .
rightward and upward eye positions are positive and leftward and downward eye positions are negative .
we analyzed 4021 saccades at four time points ( pre [ 1449 saccades ] , p1w [ 648 saccades ] , p1 m [ 1103 saccades ] , and p6 m [ 821 saccades ] ) . because the numbers of saccadic trials acquired on any single day were relatively low , data from multiple days near the indicated time point were pooled for analysis .
average saccade gains ( ratio of saccade amplitude to target amplitude ) of the two animals are summarized in figure 2 . in general ,
saccade gain of the viewing eye , irrespective of whether the animal viewed with the treated or untreated eye , did not show significant longitudinal changes ( blue bars in 2a , 2c ; red bars in 2b , 2d ) , as might be expected if the goal of the viewing eye is to saccade onto the target .
longitudinal changes in the nonviewing eye were more striking , although slightly different in the two monkeys . when m1 viewed with the untreated eye ( fig .
2a ) , the treated eye ( red bars ) showed a significant increase in saccade gain after surgery that decreased to presurgery values by p6 . on the other hand , when m2 viewed with the untreated eye ( fig .
2c ) , there was an immediate drop in saccade gain in the treated eye ( red bars ) following surgery that reverted to presurgical values by p1m p6 .
note that when viewing with the untreated eye , any changes in treated eye saccade gains can be attributed to adaptive muscle or neural changes .
2b ) , the untreated eye saccade gain ( blue bars ) decreased or remained the same at p1w and thereafter increased by p6 ( greater than pre values for leftward saccades ) . in m2
2d ) , the untreated eye saccade gain increased at p1w and thereafter decreased by p6 for leftward saccades only .
note that when viewing with the treated eye , any changes in untreated eye saccade gains are likely driven by a combination of hering 's law based neural mechanisms and adaptive untreated eye muscle or neural changes triggered by the surgical intervention of the treated muscle .
longitudinal change in horizontal saccade gains in m1 ( a , b ) and m2 ( c , d ) following strabismus treatment .
bars in each plot show means and sds of saccade gains of the untreated eye ( blue ) and treated eye ( red ) at four time points ( pre , p1w , p1 m , and p6 ) .
the asterisks represent statistically significant difference compared with presurgical values ( blue , untreated eye ; red , treated eye ) .
main sequence plots are shown in figure 3 along with the mean and 95% upper and lower confidence limits .
longitudinal changes in saccade peak velocity were relatively small and difficult to identify because of the large variability in saccade velocities .
there was a slight but significant increase in saccade velocity in both the treated and untreated eyes as animal m1 viewed with the treated eye ( figs .
3c , 3d ) as p6 velocities are higher than they were before surgery . a similar
, albeit greater magnitude , increase in peak saccade velocity was observed in both the treated and untreated eyes as animal m2 viewed with the treated eye ( more so for rightward than leftward saccades ; figs .
a from equation 1 for each of the eyes under the different viewing conditions and at the different time points are provided in the table .
h ) showing horizontal saccade amplitude on the x - axis and horizontal saccade peak velocity on the y - axis .
negative saccade amplitudes indicate leftward saccades and positive amplitudes indicate rightward saccades . left column panels ( a , c , e , g )
show data from the untreated eye and right column panels ( b , d , f , g ) show data from the treated eye .
each data point represents a single saccade , and lines represent exponential rise - to - maximum fits to the main sequence data . for these plots , viewing and nonviewing eyes ' data were collected when the animals viewed monocularly with either treated eye or untreated eye .
data points and curve fits are overlaid for saccade data collected at pre ( blue circle ) , p1w ( red triangle ) , p1 m ( gray diamond ) , and p6 ( green inverted triangle ) .
summary of leftward and rightward smooth - pursuit gains obtained from 15 to 30 cycles of smooth pursuit at each time point for each monkey are shown in figure 4 along with results of statistical comparison to presurgical smooth - pursuit gains .
longitudinal trends in smooth - pursuit gains reflected the trends observed for saccadic eye movement gains .
gains of viewing eye remained more or less constant following surgery ( blue bars in figs .
4a ) , there was a significant increase in gain in the treated eye ( red bars ) for both rightward and leftward pursuit that was mostly reversed by p6 .
4c ) , there was a significant decrease in gain in the treated eye that mostly reversed by p6 .
smooth - pursuit gains calculated when the animals viewed with their treated eyes ( figs .
4b , 4d ) also followed trends observed during saccade analysis . longitudinal change in horizontal smooth - pursuit gains in m1 ( a , b ) and m2 ( c , d ) following strabismus treatment .
bars in each plot show mean smooth - pursuit gains and sds of the untreated eye ( blue ) and treated eye ( red ) at four time points ( pre , p1w , p1 m , and p6 ) .
leftward and rightward smooth - pursuit was analyzed separately and are represented by the directional arrows .
the asterisks represent statistically significant difference compared with presurgical values ( blue , untreated eye ; red , treated eye ) .
strabismic humans and monkeys often exhibit increased monocular viewing smooth - pursuit tracking gains for nasalward target motion compared with temporalward motion ( naso - temporal asymmetry ) .
both the monkeys in the current study displayed a naso - temporal ( n / t ) asymmetry prior to surgery ( except m2 during left eye viewing ; fig .
5b , blue bars ) , and we wondered whether surgical manipulation of eom resulted in any modification of this feature of strabismus .
a naso - temporal asymmetry index was calculated as the ratio of viewing eye temporalward smooth - pursuit gain to viewing eye nasalward smooth - pursuit gain for both treated and untreated eyes viewing conditions . in m1 , the naso - temporal asymmetry persisted mostly unchanged following surgery during either untreated or treated eye viewing . in m2 also , n / t asymmetry was unchanged during treated ( right ) eye viewing . during untreated ( left ) eye viewing , there was a slight improvement in the index ( reduced asymmetry ) that reversed by p1 m . longitudinal change in naso - temporal asymmetry following strabismus treatment .
bars in each plot show a naso - temporal asymmetry index calculated as the ratio of the viewing eye temporalward and nasalward smooth - pursuit gain for m1 ( a ) and m2 ( b ) at four time points ( pre , p1w , p1 m , p6 ) .
n / t asymmetry index during untreated eye viewing is shown in blue and during treated eye viewing is shown in red .
fixation stability was assessed by calculating the bcea metric for each eye during monocular viewing ( fig .
when the untreated eye was viewing , fixation stability of the nonviewing treated eye ( red bars ) improved ( lower bcea ) after surgery but regressed by p6 in m2 only .
these data were not amenable for statistical testing because each bar represents a single data point for the fixation stability metric .
fixation stability of the viewing untreated eye ( blue bars ) did not show consistent longitudinal effects .
when the treated eye was viewing , fixation stability of nonviewing untreated eye ( blue bars ) showed postsurgical improvement that regressed by p6 in m1 but no consistent longitudinal effects in m2 .
fixation stability of the nonviewing eye was worse at all time points for both the monkeys , consistent with previous studies of fixation stability in strabismic monkeys .
longitudinal change in fixation stability ( m1 , a ; m2 , b ) following strabismus treatment .
bars in each plot show bcea values of the treated eye ( red ) and untreated eye ( blue ) during either eye viewing at the four time points ( pre , p1w , p1 m , p6 m ) .
to our knowledge , this study is the first attempt at investigating longitudinal changes in eye alignment and eye movements following strabismus treatment surgery in either humans or animal models .
in addition to providing a detailed account of time course of change in alignment and movements , these data will provide a basis for examination of neural and muscle plasticity that is likely to occur as a consequence of correction surgery .
our main findings in this study were that 1 ) eye misalignment reduced as a consequence of resect recess surgery , but regressed to close to presurgical values by 6 months after surgery ; 2 ) patterns of longitudinal changes in saccadic and smooth - pursuit eye movements also showed immediate postsurgical changes that reversed by 6 months after treatment , although naso - temporal asymmetry of smooth - pursuit tracking was unchanged ; 3 ) there were only small changes in fixation stability ; and 4 ) the overall similarity in response to human strabismus surgical treatment validates our monkey model for strabismus . below
we discuss each of our findings in the context of longitudinal adaptive changes occurring in strabismus . compared with dynamic changes in eye movements that were generally small but significant ( discussed later ) , longitudinal changes in eye alignment were clear and consistent in the two monkeys in our study .
both the exotropic monkeys in the study responded to treatment in that exotropia was reduced significantly to 30% of presurgical misalignment immediately after surgery as might be expected following a resect
( day after surgery ) , the reduction in misalignment observed when viewing with the untreated eye is possibly only a consequence of the change in contractility of the treated eom as the brain may not have had sufficient time to adapt .
in other words , the neural signals to the eom of viewing ( untreated ) and nonviewing ( treated ) eyes are expected to be the same as in the presurgical condition . when the monkey is forced to view with the treated eye
, the brain must alter the neural signals to the treated muscles to compensate for their altered contractility to allow fixation of the target , for example , increase in neuronal drive of recessed lateral rectus from ipsilateral abducens nucleus . the anatomical connection between abducens nucleus and contralateral oculomotor nucleus ( underpinnings of hering 's law ) leads to increase in neuronal drive to the medial rectus muscle of the contralateral ( in this case untreated ) eye .
note that the change in neural drives to the treated and untreated eye eom when the monkey is forced to view with the treated eye is not a long - term adaptive response per se as the brain is only momentarily adjusting signals to enable target acquisition and fixation .
following the initial reduction in strabismus angle , the angle of misalignment reverted to 60%80% of presurgical value by 6 months after treatment , again similar to outcomes of strabismus correction surgery in a proportion of human subjects whose initial procedure resulted in undercorrection .
the lack of persistence of the initial improvement in strabismus angle may be because improvement in alignment in the two study animals was beyond the range at which central binocular factors would be expected to be able to maintain the initial improvement in postsurgical ocular alignment .
therefore , remodeling at the level of the eom along with central neural adaptation could act to fight the intent of surgery ( pullela m , et al .
additional studies directly examining neural drives and muscle contractility are needed to understand the relative plastic changes due to these two factors .
another point to note is that the patterns of alignment change following treatment , which are similar to human strabismus response to treatment , also help to validate the monkey model as suitable for investigating strabismus mechanisms .
there were significant small magnitude changes in saccadic and smooth - pursuit gains following treatment , although it was different in the two monkeys ( figs .
thus , saccade and smooth - pursuit gain for m1 showed an increase after surgery , whereas saccade and smooth - pursuit gains for m2 showed a decrease after surgery , although both animals regained presurgical gain values by p6 .
analysis of performance of saccades in human subjects after undergoing strabismus surgery showed an improvement after surgery that was proposed as due to improvement in binocular coordination because eye misalignment is corrected .
because full alignment was not achieved in our monkeys even on p1d , we suggest that the observed changes in saccade and smooth - pursuit gain in our monkeys are more likely to be driven by brain and muscle adaptation that is unrelated to binocular coordination .
it is unclear why eye movement gains increased after surgery in m1 but decreased after surgery in m2 .
we suggest that this likely represents variability that might be observed in humans as well and could represent differences in relative adaptation ( neural or muscle related ) of the recessed versus the resected muscle .
confirmation of this hypothesis would come from future studies that measure neuronal drive to the treated and untreated muscles .
the most likely explanation is that saccade velocities are inherently too variable to show significant changes following surgical treatment .
we also did not find any consistent changes in n / t asymmetry during monocular smooth - pursuit . because n / t asymmetry is fundamentally due to developmental loss of binocular inputs from sensory areas such as middle temporal / middle superior temporal ( mt / mst ) to brainstem areas such as the nucleus of the optic tract ( not ) , any longitudinal changes in n / t asymmetry would have been , in fact , surprising .
fixation stability or lack thereof in strabismic animals and humans is usually influenced by presence of visual problems such as amblyopia and oculomotor instabilities such as nystagmus and excessive drifts .
in addition , fixation stability may be influenced by several visual factors such as target size , shape , contrast , and luminance .
we measured fixation stability in these animals at the different time points and found a temporary improvement in fixation stability of the treated eye when the untreated eye was viewing but no consistent changes when the treated eye was viewing .
dell'osso et al . suggested that tenotomy surgery reduces nystagmus intensity in humans with infantile nystagmus syndrome due to manipulation of proprioceptive receptors in the eom .
it is possible that similar mechanisms are at play following the strabismus correction surgery that we performed , although another study that attempted tenotomy surgery in monkeys with infantile nystagmus showed inconsistent results .
our data suggest that surgical treatment of strabismus is followed by an adaptive response that evolves and reaches a steady state within the first 6 months after treatment . because adaptation can either oppose or facilitate the outcome of treatment strategies , the fundamental challenge to improving treatment methods is to identify and devise methods that will induce adaptation that promotes desired treatment effects while avoiding adaptation that may oppose or reverse desired treatment effects . as suggested earlier , both central neural adaption and peripheral muscle remodeling are likely driving the final state of alignment and ultimately determining the success or failure of the surgical treatment .
immediate ( p1d ) changes in alignment and eye movements are likely driven by changes in muscle contractility alone , but later changes ( p1 m and p6 m ) are likely due to a combination of neural plasticity and peripheral remodeling .
behavioral studies alone can not readily differentiate between these mechanisms , but they are critical to develop a framework to conduct and interpret neural recording studies or studies that evaluate muscle function .
such neuronal studies are underway in our laboratory in the same animals as in this study
. major portions of the strabismus treatment literature are accounts of outcomes following different types of surgical procedures .
the strength of these studies is the relatively large number and large variety ( e.g. , esotropes versus exotropes and patients with residual binocularity versus patients with no binocularity ) of patients that are evaluated .
due to several ( mostly practical ) reasons , monkey studies can not hope to replicate the large n of human studies .
however , the strength of our monkey investigation lies in the ability to perform careful and controlled longitudinal evaluation in the same animals that is not possible in human clinical investigation .
moreover , these behavioral studies provide a framework to perform a neurophysiologic investigation that is not possible in humans and is critical to extend our understanding of strabismus mechanisms including plasticity .
it is possible that outcomes in the current study might have been different ( i.e. , monkeys ' exotropia does not revert ) if we had chosen to treat both eyes and attempted to more closely align the eyes , given the general notion that surgical realignment in the vicinity of 510 pd helps facilitate binocularity .
however , on the other hand , both the animals in this study were reared with prisms from the first day of birth , likely preventing the development of even coarse stereopsis .
also , we purposely did not attempt a second procedure on the fellow eye because we wanted to be able to use the fellow eye as a control and thereby ascertain the nature and time course of plasticity that follows surgical treatment .
using the fellow eye as an untreated control is also quite critical when evaluating neural responses that are driving the extraocular muscles .
compared with dynamic changes in eye movements that were generally small but significant ( discussed later ) , longitudinal changes in eye alignment were clear and consistent in the two monkeys in our study .
both the exotropic monkeys in the study responded to treatment in that exotropia was reduced significantly to 30% of presurgical misalignment immediately after surgery as might be expected following a resect
( day after surgery ) , the reduction in misalignment observed when viewing with the untreated eye is possibly only a consequence of the change in contractility of the treated eom as the brain may not have had sufficient time to adapt .
in other words , the neural signals to the eom of viewing ( untreated ) and nonviewing ( treated ) eyes are expected to be the same as in the presurgical condition . when the monkey is forced to view with the treated eye
, the brain must alter the neural signals to the treated muscles to compensate for their altered contractility to allow fixation of the target , for example , increase in neuronal drive of recessed lateral rectus from ipsilateral abducens nucleus .
the anatomical connection between abducens nucleus and contralateral oculomotor nucleus ( underpinnings of hering 's law ) leads to increase in neuronal drive to the medial rectus muscle of the contralateral ( in this case untreated ) eye .
note that the change in neural drives to the treated and untreated eye eom when the monkey is forced to view with the treated eye is not a long - term adaptive response per se as the brain is only momentarily adjusting signals to enable target acquisition and fixation .
following the initial reduction in strabismus angle , the angle of misalignment reverted to 60%80% of presurgical value by 6 months after treatment , again similar to outcomes of strabismus correction surgery in a proportion of human subjects whose initial procedure resulted in undercorrection .
the lack of persistence of the initial improvement in strabismus angle may be because improvement in alignment in the two study animals was beyond the range at which central binocular factors would be expected to be able to maintain the initial improvement in postsurgical ocular alignment .
therefore , remodeling at the level of the eom along with central neural adaptation could act to fight the intent of surgery ( pullela m , et al .
additional studies directly examining neural drives and muscle contractility are needed to understand the relative plastic changes due to these two factors .
another point to note is that the patterns of alignment change following treatment , which are similar to human strabismus response to treatment , also help to validate the monkey model as suitable for investigating strabismus mechanisms .
there were significant small magnitude changes in saccadic and smooth - pursuit gains following treatment , although it was different in the two monkeys ( figs . 2 , 4 ) .
thus , saccade and smooth - pursuit gain for m1 showed an increase after surgery , whereas saccade and smooth - pursuit gains for m2 showed a decrease after surgery , although both animals regained presurgical gain values by p6 .
analysis of performance of saccades in human subjects after undergoing strabismus surgery showed an improvement after surgery that was proposed as due to improvement in binocular coordination because eye misalignment is corrected .
because full alignment was not achieved in our monkeys even on p1d , we suggest that the observed changes in saccade and smooth - pursuit gain in our monkeys are more likely to be driven by brain and muscle adaptation that is unrelated to binocular coordination .
it is unclear why eye movement gains increased after surgery in m1 but decreased after surgery in m2 .
we suggest that this likely represents variability that might be observed in humans as well and could represent differences in relative adaptation ( neural or muscle related ) of the recessed versus the resected muscle .
confirmation of this hypothesis would come from future studies that measure neuronal drive to the treated and untreated muscles .
the most likely explanation is that saccade velocities are inherently too variable to show significant changes following surgical treatment .
we also did not find any consistent changes in n / t asymmetry during monocular smooth - pursuit . because n / t asymmetry is fundamentally due to developmental loss of binocular inputs from sensory areas such as middle temporal / middle superior temporal ( mt / mst ) to brainstem areas such as the nucleus of the optic tract ( not ) , any longitudinal changes in n / t asymmetry would have been , in fact , surprising .
fixation stability or lack thereof in strabismic animals and humans is usually influenced by presence of visual problems such as amblyopia and oculomotor instabilities such as nystagmus and excessive drifts .
in addition , fixation stability may be influenced by several visual factors such as target size , shape , contrast , and luminance .
we measured fixation stability in these animals at the different time points and found a temporary improvement in fixation stability of the treated eye when the untreated eye was viewing but no consistent changes when the treated eye was viewing .
dell'osso et al . suggested that tenotomy surgery reduces nystagmus intensity in humans with infantile nystagmus syndrome due to manipulation of proprioceptive receptors in the eom .
it is possible that similar mechanisms are at play following the strabismus correction surgery that we performed , although another study that attempted tenotomy surgery in monkeys with infantile nystagmus showed inconsistent results .
our data suggest that surgical treatment of strabismus is followed by an adaptive response that evolves and reaches a steady state within the first 6 months after treatment . because adaptation can either oppose or facilitate the outcome of treatment strategies , the fundamental challenge to improving treatment methods is to identify and devise methods that will induce adaptation that promotes desired treatment effects while avoiding adaptation that may oppose or reverse desired treatment effects .
as suggested earlier , both central neural adaption and peripheral muscle remodeling are likely driving the final state of alignment and ultimately determining the success or failure of the surgical treatment .
immediate ( p1d ) changes in alignment and eye movements are likely driven by changes in muscle contractility alone , but later changes ( p1 m and p6 m ) are likely due to a combination of neural plasticity and peripheral remodeling .
behavioral studies alone can not readily differentiate between these mechanisms , but they are critical to develop a framework to conduct and interpret neural recording studies or studies that evaluate muscle function .
such neuronal studies are underway in our laboratory in the same animals as in this study .
major portions of the strabismus treatment literature are accounts of outcomes following different types of surgical procedures . the strength of these studies is the relatively large number and large variety ( e.g. , esotropes versus exotropes and patients with residual binocularity versus patients with no binocularity ) of patients that are evaluated . due to several ( mostly practical ) reasons , monkey studies can not hope to replicate the large n of human studies .
however , the strength of our monkey investigation lies in the ability to perform careful and controlled longitudinal evaluation in the same animals that is not possible in human clinical investigation .
moreover , these behavioral studies provide a framework to perform a neurophysiologic investigation that is not possible in humans and is critical to extend our understanding of strabismus mechanisms including plasticity .
it is possible that outcomes in the current study might have been different ( i.e. , monkeys ' exotropia does not revert ) if we had chosen to treat both eyes and attempted to more closely align the eyes , given the general notion that surgical realignment in the vicinity of 510 pd helps facilitate binocularity .
however , on the other hand , both the animals in this study were reared with prisms from the first day of birth , likely preventing the development of even coarse stereopsis .
also , we purposely did not attempt a second procedure on the fellow eye because we wanted to be able to use the fellow eye as a control and thereby ascertain the nature and time course of plasticity that follows surgical treatment .
using the fellow eye as an untreated control is also quite critical when evaluating neural responses that are driving the extraocular muscles .
Output:
| purposestrabismus correction surgery is well documented in both the literature and practice with varying levels of success and permanence .
our goal was to characterize longitudinal changes in eye alignment and eye movements following strabismus correction surgery in a monkey model for developmental strabismus.methodswe studied two juvenile rhesus monkeys with exotropia previously induced via an optical prism - rearing paradigm in infancy . eye misalignment was corrected via a resection recession surgery of the horizontal rectus muscles of one eye .
binocular search coils were used to collect eye movement data during smooth - pursuit , saccades , and fixation tasks before surgical treatment , immediately after surgery , and through 6 months after treatment.resultsboth animals showed an immediate 70% reduction in misalignment as a consequence of surgery that regressed to a 20%40% improvement by 6 months after treatment .
significant changes were observed in saccade and smooth - pursuit gain of the nonviewing eye after surgery , which also reverted to presurgical values by 6 months .
a temporary improvement in fixation stability of the nonviewing eye was observed after surgery ; naso - temporal ( n / t ) asymmetry of monocular smooth - pursuit remained unchanged.conclusionssurgical realignment is followed by plastic changes that often lead to reversal of surgery effects .
immediate improvement in misalignment and changes in eye movement gains are likely a result of contractility changes at the level of the extraocular muscle , whereas longer - term effects are likely a combination of neural and muscle adaptation . |
PubmedSumm8898 | ***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 of long duration results in irreversible functional and structural damage leading to several complications .
diabetes is often associated with severe periodontal disease and is considered a risk factor for periodontal disease progression .
analysis of the national health and nutrition examination survey ( nhanes ) iii data set showed that the prevalence of diabetes in patients with periodontal disease is twice of that seen in non - periodontal disease patients ( 12.5% versus 6.3% ) . in india , up to 70% of the adult population appears to have periodontal disease and in the diabetic , this is estimated to be 82.7% .
periodontal disease is caused by periodontal pathogens such as porphyromonas gingivalis , actinobacillus actinomycetemcomitans , campylobacter rectus etc .
pro - inflammatory cytokines and chemical mediators are significantly increased in gingival inflammation and in periodontal disease progression .
monocyte chemoattractant protein-1 , a chemokine , is implicated in the pathogenesis of numerous complications of diabetes .
the role of mcp-1 has been studied in the pathogenesis of interstitial lung disease , breast cancer cells , rheumatoid arthritis , cytomegalovirus encephalitis , and small cell vasculitis .
the over expression of mcp-1 is found to increase insulin resistance by initiating macrophage infiltration of the adipose tissue and thus predisposing to the onset of diabetes mellitus .
mcp-1 may play a role in the development of numerous complications of diabetes in angiopathy and cause infiltration and activation of monocytes in the glomerulus , which leads to the diabetic nephropathy .
the increased level of mcp-1 in microglia and macrophages leads to the development of diabetic retinopathy .
the role of serum mcp-1 as a biomarker of periodontitis is well documented ; however , its role in diabetic patients with periodontitis is unknown .
this study was conducted to determine the presence and concentration of serum mcp-1 in diabetic patients with and without periodontitis and to correlate it with glycemic status with periodontitis .
a prospective exploratory study was conducted in diabetic patients with and without periodontal disease , attending the out - patient clinic in a tertiary care hospital in sub - urban chennai .
the study protocol was approved by the institution ethics committee , and informed consent was obtained .
sample size was determined based on the number of patients to be enrolled to obtain a meaningful data and was done in consultation with a statistician using convenient sampling .
adult diabetic patients with ( 18 yrs ) with type ii dm who had not received any kind of dental treatment or prophylaxis in the past six months were included and the patients with hypertension , cardiovascular disorders , abnormal hepatic function , hemoglobinopathies , renal failure , retinopathy , pregnancy , patients on current antibiotic treatment or prophylaxis and other endocrine disorders such as hypothyroidism , hypo - parathyroidism , addison 's disease , cushing 's syndrome , and thyroid cancer , which would influence serum mcp-1 levels , were excluded from the study .
patients who were smokers , pan chewers , as well as habitual consumers of alcohol were also excluded .
subjects with hba1c < 7% were considered to have well controlled diabetes and poorly controlled / uncontrolled diabetes if hba1c 7% . fasting blood sugar ( fbs ) level , post - prandial blood sugar ( ppbs ) level , mpg , lipid profile , and routine urine analysis were also recorded . periodontal status of the study population was assessed by oral examination by a qualified dentist .
patients were enrolled for oral hygiene index ( ohi - s ) , evaluation of bleeding on probing ( bop ) , periodontal probing depths ( ppd ) , and clinical attachment loss ( cal ) .
presence of bop , ppd > 5 mm , and cal > 3 mm were considered diagnostic criteria for periodontal disease .
subsequently , the demographic details , general health conditions , oral hygiene behavior , and periodontal evaluation were analyzed .
group i : consists of diabetic patients with good glycemic control with no signs of periodontal disease group ii : consists of well - controlled diabetic patients with evidence of periodontal disease group iii : consists of diabetic patients with poor glycemic control and showed evidence of periodontal disease .
four milliliter of blood was collected in a sterile vacutainer ( bd diagnostics , franklin lakes , usa ) and immediately transferred to the laboratory .
the samples were centrifuged at 3500 rpm for 15 min and were aliquotted and stored at -70c until the time of assay .
serum mcp-1 levels were determined using a quantitative sandwich enzyme - linked immunosorbent assay ( human ccl2 ( mcp-1 ) elisa kit , bioscience , inc . ,
the sensitivity of the assay was 7 pg / ml-1000 pg / ml for mcp-1 .
the kit has been calibrated with national institute for biological standards and control ( nibsc ) ; the co - efficient of variation of this assay is 3.3% .
the absorbance ( od ) was measured at 450 nm by the elisa plate reader ( multiskan ex primary eia v.2.3 ) .
simple linear regression and correlation tests were performed using r statistical software ( version 2.11.0 ) , medcalc software ( version 12.6.1 ) to observe correlation between the serum mcp-1 and glycated hemoglobin level . the age and gender analysis were analyzed only after the completion of the study .
adult diabetic patients with ( 18 yrs ) with type ii dm who had not received any kind of dental treatment or prophylaxis in the past six months were included and the patients with hypertension , cardiovascular disorders , abnormal hepatic function , hemoglobinopathies , renal failure , retinopathy , pregnancy , patients on current antibiotic treatment or prophylaxis and other endocrine disorders such as hypothyroidism , hypo - parathyroidism , addison 's disease , cushing 's syndrome , and thyroid cancer , which would influence serum mcp-1 levels , were excluded from the study .
patients who were smokers , pan chewers , as well as habitual consumers of alcohol were also excluded .
subjects with hba1c < 7% were considered to have well controlled diabetes and poorly controlled / uncontrolled diabetes if hba1c 7% . fasting blood sugar ( fbs ) level , post - prandial blood sugar ( ppbs ) level , mpg , lipid profile , and routine urine analysis were also recorded .
periodontal status of the study population was assessed by oral examination by a qualified dentist .
patients were enrolled for oral hygiene index ( ohi - s ) , evaluation of bleeding on probing ( bop ) , periodontal probing depths ( ppd ) , and clinical attachment loss ( cal ) .
presence of bop , ppd > 5 mm , and cal > 3 mm were considered diagnostic criteria for periodontal disease .
subsequently , the demographic details , general health conditions , oral hygiene behavior , and periodontal evaluation were analyzed .
group i : consists of diabetic patients with good glycemic control with no signs of periodontal disease group ii : consists of well - controlled diabetic patients with evidence of periodontal disease group iii : consists of diabetic patients with poor glycemic control and showed evidence of periodontal disease .
four milliliter of blood was collected in a sterile vacutainer ( bd diagnostics , franklin lakes , usa ) and immediately transferred to the laboratory .
the samples were centrifuged at 3500 rpm for 15 min and were aliquotted and stored at -70c until the time of assay .
serum mcp-1 levels were determined using a quantitative sandwich enzyme - linked immunosorbent assay ( human ccl2 ( mcp-1 ) elisa kit , bioscience , inc . , catalogue number : 88 - 7399 ) .
the sensitivity of the assay was 7 pg / ml-1000 pg / ml for mcp-1 .
the kit has been calibrated with national institute for biological standards and control ( nibsc ) ; the co - efficient of variation of this assay is 3.3% .
the absorbance ( od ) was measured at 450 nm by the elisa plate reader ( multiskan ex primary eia v.2.3 ) .
simple linear regression and correlation tests were performed using r statistical software ( version 2.11.0 ) , medcalc software ( version 12.6.1 ) to observe correlation between the serum mcp-1 and glycated hemoglobin level .
the study group comprised of 37 adult diabetic patients ; majority ( 62% ) were females ( n = 21 ) and 18.9% were males ( n = 16 ) .
both group i and group ii consisted of well - controlled diabetic patients with a mean hba1c of 6.2% and a range of 5.2 - 6.9% . in diabetic patients with poor glycemic control ( group iii ) ,
[ table 1 ] group i patients were younger with a mean age of 26.86 years [ table 1 ] .
descriptive statistics of the study groups showing mean , median , standard deviation , and range for age , glycated hemoglobin ( hba1c ) , and serum mcp-1 levels all 37 diabetic patients serum samples tested positive for the presence of mcp-1 , with concentrations that ranged from 135.6 - 543.5 pg / ml . in diabetics with good glycemic control and no evidence of periodontal disease ( group i ) , the mean serum mcp-1 concentration was 149.3 pg / ml ( range : 135.6 - 160.4 pg / ml ) . in group
ii ( well - controlled diabetes with periodontal disease ) , the mean mcp-1 concentration was 398.8 pg / ml ( range : 330.4 - 435.1 pg / ml ) . in diabetics with poor glycemic control and periodontal disease ( group iii ) , the mean serum mcp-1 concentration was 482.3 pg / ml ( range : 460.9 - 543.5 pg / ml ) .
the mean serum mcp-1 concentration was highest ( 482.3 pg / ml ) in group iii and lowest ( 149.3 pg / ml ) in group i [ table 1 ] .
simple linear regression and correlation analysis performed to observe the relation between glycated hemoglobin ( hba1c ) levels and serum mcp-1 concentrations suggests a linear progression [ figures 1b and c ] in group ii and group iii .
the linear progression was more marked in group iii [ figure 1c ] , and the correlation was highly significant with a p < 0.001 , suggesting that serum mcp-1 levels are markedly elevated as the glycated hemoglobin levels increase in poorly - controlled diabetic patients ( hba1c 7% ) with periodontal disease . in group iii , in three patients with serum mcp-1 concentrations above 530 pg / ml , the corresponding hba1c values were found to be above 12.1% .
( a - c ) correlations of glycated hemoglobin levels ( hba1c ) with serum mcp-1 in groups i , ii , and iii respectively .
the values are not significant in group i and group ii , whereas in group iii , it is significant in group ii [ figure 1b ] , serum mcp-1 concentrations of 320 - 380 pg / ml clustered around hba1c of 6% ; serum mcp-1 was higher > 410 pg / ml when the hba1c levels were in the range of 6.5 - 6.9% .
two subjects with good glycemic control ( hba1c < 6% ) in group ii had elevated levels of serum mcp-1 ( > 410 pg / ml ) , which may be due to the severity of the periodontal disease .
the correlation between hba1c and serum mcp-1 was not significant in group i ( diabetic patients with good glycemic control and no periodontal disease ) [ figure 1a ] .
from the linear regression analysis performed on all study subjects [ figure 2 ] , it was found that a 1% rise of hba1c resulted in 37.278 pg / ml increase of serum mcp-1 concentration , which was statistically significant .
linear regression analysis between hba1c ( % ) and serum mcp-1 ( pg / ml ) in all the study subjects shows a significant intercept value of 37.278 when we analyzed the serum mcp-1 concentrations of each patient in the different groups , we found that the mcp-1 values tend to cluster based on hba1c levels [ figure 3 ] .
mcp-1 values in the range of 350 - 450 pg / ml clustered around group ii ( hba1c < 7% ) . in group iii , the values clustered around 460 - 550 pg / ml .
projection of serum mcp-1 levels in all the three study groups the serum mcp-1 concentrations in diabetic patients with periodontal disease were above 300 pg / ml irrespective of their glycemic status ( group ii and group iii ) .
however , the serum mcp-1 levels were above 460 pg / ml in diabetic patients with poor glycemic control and periodontal disease ( group iii ) , whereas it was only below 450 pg / ml in group ii ( well - controlled diabetic patients with periodontal disease ) .
simple linear regression and correlation analysis performed to observe the relation between glycated hemoglobin ( hba1c ) levels and serum mcp-1 concentrations suggests a linear progression [ figures 1b and c ] in group ii and group iii .
the linear progression was more marked in group iii [ figure 1c ] , and the correlation was highly significant with a p < 0.001 , suggesting that serum mcp-1 levels are markedly elevated as the glycated hemoglobin levels increase in poorly - controlled diabetic patients ( hba1c 7% ) with periodontal disease . in group iii , in three patients with serum mcp-1 concentrations above 530 pg
( a - c ) correlations of glycated hemoglobin levels ( hba1c ) with serum mcp-1 in groups i , ii , and iii respectively .
the values are not significant in group i and group ii , whereas in group iii , it is significant in group ii [ figure 1b ] , serum mcp-1 concentrations of 320 - 380 pg / ml clustered around hba1c of 6% ; serum mcp-1 was higher > 410 pg / ml when the hba1c levels were in the range of 6.5 - 6.9% .
two subjects with good glycemic control ( hba1c < 6% ) in group ii had elevated levels of serum mcp-1 ( > 410 pg / ml ) , which may be due to the severity of the periodontal disease .
the correlation between hba1c and serum mcp-1 was not significant in group i ( diabetic patients with good glycemic control and no periodontal disease ) [ figure 1a ] . from the linear regression analysis performed on all study subjects [ figure 2 ]
, it was found that a 1% rise of hba1c resulted in 37.278 pg / ml increase of serum mcp-1 concentration , which was statistically significant .
( p < 0.001 ) . linear regression analysis between hba1c ( % ) and serum mcp-1 ( pg / ml ) in all the study subjects shows a significant intercept value of 37.278
when we analyzed the serum mcp-1 concentrations of each patient in the different groups , we found that the mcp-1 values tend to cluster based on hba1c levels [ figure 3 ] .
for example , in group i , the serum mcp-1 values clustered below 200 pg / ml . mcp-1 values in the range of 350 - 450 pg / ml clustered around group ii ( hba1c < 7% ) . in group iii ,
projection of serum mcp-1 levels in all the three study groups the serum mcp-1 concentrations in diabetic patients with periodontal disease were above 300 pg / ml irrespective of their glycemic status ( group ii and group iii ) .
however , the serum mcp-1 levels were above 460 pg / ml in diabetic patients with poor glycemic control and periodontal disease ( group iii ) , whereas it was only below 450 pg / ml in group ii ( well - controlled diabetic patients with periodontal disease ) .
the process of tissue destruction ( connective tissue and alveolar bone ) in periodontitis results from the interaction of bacteria or bacterial substances with host cell as well the host response to bacterial invasion .
bacterial plaque is responsible for inducing host inflammatory processes followed by secondary colonization of periodontal pathogens such as porphyromonas gingivalis , actinobacillus actinomycetemcomitans , prevotella intermedia , and others .
the number of monocytes / macrophages are more in progressing periodontal lesions as compared to non - progressing periodontal lesions and may be closely related to the pathogenesis and progression of periodontitis .
mcp-1 is synthesized in inflamed gingiva by mononuclear phagocytes , endothelial cells , and osteoblasts . increased levels of mcp-1
have been reported in gingival biopsies of patients with periodontal disease and in the gingival crevicular fluid ( gcf ) of periodontal patients .
the recovery of periodontal pathogens has been studied in saliva and varying rates of detection tanerella forsythensis ( 56.9% ) , treponema denticola ( 38.2% ) , and porphyromonas gingivalis 35.4% reported .
periodontal disease is considered as potential risk factor for progression of various systemic diseases , also increased levels of serum mcp-1 due to periodontal disease may be a risk factor for systemic diseases .
the association between periodontal disease and cardiovascular diseases is well established ; the role of serum mcp-1 has also been assessed . however ,
the role of mcp-1 in periodontal disease and uncontrolled diabetes mellitus has not been studied . in our study ,
serum mcp-1 levels were raised in diabetic patients with good glycemic control having periodontal disease ( group ii ) when compared with well - controlled diabetic patients without periodontal disease ( group i ) , with even higher levels of serum mcp-1 in diabetic with poor glycemic control having periodontal disease ( group iii ) .
circulating levels of mcp-1 are known to be elevated in diabetic patients and may contribute to the development of complications in diabetics .
diabetic patients with good glycemic control and no periodontal disease ( group i ) were much younger ( mean age of 26.86 yrs ) when compared with group ii and group iii .
the patients were enrolled in to the different group based on their glycemic status , and it was incidental finding that patient with good glycemic controls were younger . aging does increase circulating levels of mcp-1 .
experimental studies on rat model have stated that aging induces expression of mcp-1/ccl-2 receptors leading to age - associated arterial remodeling .
however , age - related mcp changes are gradual and do not increase dramatically as seen in our study .
we believe that mcp-1 differences can not be dismissed because of age alone . when the glycated hemoglobin levels were in a range of 5.2 - 6.9% indicating good glycemic control , the serum mcp-1 concentrations were found to be within acceptable limits ( < 165 pg / ml in group i ) .
the concentration of mcp-1 in serum was increased by 37.278 pg / ml for every 1% rise in hba1c .
regression analysis performed for group iii was found to be significant , suggesting that poor glycemic control contributes to increase in serum mcp-1 levels . even in the absence of any complications such as renal failure , retinopathy , and cardiovascular diseases among the patients enrolled in the study ,
the serum mcp-1 levels clustered into specific ranges even without knowledge of hba1c and periodontal status . based on their glycemic status ,
the mcp-1 values were increased in group i ( 135 -160 pg / ml ) , group ii ( 330 - 435 pg / ml ) , and in group iii .
( 461 - 543 pg / ml ) thus , the determination of serum mcp-1 may be used to assess both the glycemic and periodontal status .
the clustering of serum mcp-1 values among the different groups of patients suggests that there may be threshold levels related to age , glycemic status , and periodontal disease .
if indeed threshold values are established , it will definitely alert the clinician to take measures to pre - empt the progression of diabetes to various complications . to our knowledge , this is the first study to determine serum mcp-1 levels in diabetic patients with periodontal disease and correlate with glycemic control .
this is a prospective exploratory study conducted in 37 diabetic patients , and mcp-1 levels were estimated as a onetime assessment .
prospective studies need to be undertaken with serial estimation of mcp-1 to determine the progression to complications in larger group of patients .
a significant positive correlation between serum mcp-1 and glycemic status ( hba1c ) has been documented .
it has been found that 1% rise of hba1c resulted in 37.278 pg / ml increase of serum mcp-1 concentration .
our findings suggest that glycemic status influences serum mcp-1 levels in diabetic patients with periodontal disease . elevated serum mcp-1 levels could contribute to onset and progression of several complications in diabetes .
thus , serum mcp-1 may serve as a biomarker of inflammatory activity and helps in early detection and intervention of diabetic complications .
Output:
| introduction : the role of serum monocyte chemoattractant protein-1 ( mcp-1 ) as a biomarker of periodontitis is well documented ; however , its role in diabetic patients with periodontitis is unknown.aim:this study was conducted to determine the presence and concentration of serum mcp-1 in diabetic patients with and without periodontitis and correlate it glycemic status with periodontitis.materials and methods : adult diabetic patients were enrolled and grouped into group i , ii , and iii based on their glycemic status and serum mcp-1 estimated by elisa .
linear regression and correlation tests were performed using r statistical software , medcalc software to observe correlation between the serum mcp-1 and glycated hemoglobin level among different groups.results:serum samples obtained from 37 patients tested positive for mcp-1 . mean serum mcp-1 concentration was highest ( 482.3 pg / ml ) in group iii , lowest ( 149.3 pg / ml ) in group i , and intermediate 398.8 pg / ml in group ii . correlation and regression analysis was done between hba1c and serum mcp-1 . a significant positive correlation ( p < 0.001 ) was observed .
serum mcp-1 increased by 37.278 pg / ml for every 1% rise in hba1c , and the levels were raised in group ii and group iii than in group i irrespective of their glycemic status . with an hba1c range of 6.5 - 6.9% ( group ii )
, the serum mcp-1 values cluster around 380 - 410 pg / ml .
elevated levels of serum mcp-1 ( > 500 pg / ml ) in three subjects corresponded to hba1c values more than 12.2% ( group iii).conclusion : to our knowledge , this is the first study to document serum mcp-1 levels in diabetic patients with periodontitis .
glycemic status influences serum mcp-1 , and lack of glycemic control contributes to increased serum mcp-1 levels .
serum mcp-1 may thus serve as a biomarker of inflammation and disease progression in diabetes with periodontitis . |
PubmedSumm8899 | ***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: genome - scale transcriptional regulatory network ( trn ) for any specific microbial organism is a critical component on the way to the next big milestone in system biology building an integrated metabolic and regulatory model that can accurately predict cellular growth phenotypes .
several approaches and associated web resources have been developed for genome - wide reconstruction of metabolic pathways for a number of microbial genomes .
biocyc maintains an encyclopedia of experimentally defined metabolic pathways in model organisms and uses it for reconstruction of metabolism in other sequenced genomes ( 1 ) .
model seed allows user to submit any complete genome to the annotation pipeline to generate a draft metabolic model ( 2 ) . at the same time , the large - scale trns so far are available only for a limited number of model organisms , such as escherichia coli ( 3 ) , bacillus subtilis ( 4 ) , corynebacterium glutamicum ( 5 ) and mycobacterium tuberculosis ( 6 ) .
a fundamental difference between the reconstruction of trns and metabolic pathways is that regulatory interactions are much less conserved across bacterial genomes than metabolic pathways ( 7 ) . to address the challenging problem of propagation of regulatory interactions between distant genomes
, we recently developed a strategy enabling the genomic reconstruction of large - scale trns in diverse microbial genomes ( 8) .
the bacterial species tree is subdivided into small taxonomic families , and a subset of 512 representative genomes is selected for each family ; then the comparative genomics techniques are used to reconstruct a collection of reference regulons in these genomes . at the next stage ,
these reference regulons are used for an automatic annotation of regulatory interactions in the remaining genomes from the same taxonomic group . in 200910 , with a goal of building collections of taxonomy - specific reference regulons , we developed two web resources for large - scale inference and analysis of regulatory interactions in prokaryotes : the regprecise database ( http://regprecise.lbl.gov ) to capture and visualize manually curated regulons ( 9 ) and the regpredict web server ( http://regpredict.lbl.gov ) for fast and accurate regulon reconstruction ( 8) . the community - based approach for regulon reconstruction implemented in the regpredict web server enabled fast accumulation of a large number of curated regulatory interactions ( 1013 ) .
the current release of regprecise 2.0 captures the detailed descriptions of 1000 regulogs controlled by protein transcription factors ( tfs ) in 13 taxonomic groups of bacteria ( 147 genomes total ) and 400 regulogs controlled of conserved ribonucleic acid ( rna ) regulatory motifs ( e.g. riboswitches ) in 22 taxonomic groups ( 255 genomes total ) .
the total number of effectors of analyzed regulators in regprecise exceeds 200 and includes the following major classes of metabolites : amino acids , carbohydrates , nucleotides , lipids and fatty acids , co - enzymes , peptides and antibiotics , secondary metabolites and inorganic chemicals . beside tf regulons ,
the last release of regprecise includes a large collection of curated regulons controlled by rna regulatory elements ( such as riboswitches ) annotated by the regpredict web server using rna models from the rfam database ( 14 ) .
we anticipate that the content of regprecise database will continue fast growing due to large - scale regulon annotation projects conducted by scientific community using regpredict .
regprecise serves as a core resource on transcriptional regulation for the microbial domain of the doe systems biology knowledgebase ( 15 ) , a community - driven cyber infrastructure for sharing and integrating data and analytical tools to accelerate predictive biology . in the context of this project
, we developed a comprehensive set of restful web services for programmatic access to the whole scope of transcriptional regulatory data provided by regprecise .
the hierarchical organization of the regprecise database has three major levels : i ) a regulon , ii ) a regulog and iii ) a collection of regulogs .
a regulon is the basic unit of regprecise that represents a set of genes in a particular genome that are co - regulated by the same tf or rna regulatory motif .
the major types of output in the regprecise web services application programming interface ( api ) are represented by six objects that provide the detailed information about reconstructed regulatory interactions ( figure 1 ) . the regulon object
, being a basic unit , provides the general description of regulon , including the name of genome , the common name of regulator , its protein family and predicted effector molecule and the metabolic pathway ( or biological process ) controlled by the regulator .
the regulationtype property of the regulon object identifies the type of mechanism of regulation , which is either by transcription factor ( tf ) or by rna regulatory element ( rna ) .
the regulator object represents the actual gene encoding tf and provides its gene name , locus tag and vimssid [ gene identifier in microbesonline ( 16 ) database ] . in rare cases
, comparative genomics does not allow unambiguous selection of true cognate regulator between several homologous tfs .
in this case , more than one regulator can be assigned to a particular regulon . in the case of regulation by rna elements
the gene object represents a regulated gene and provides general information , such as gene name , locus tag , gene vimssid and function .
the site object represents either tf - binding site or rna regulatory element and provides its sequence , score , position relative to the translational gene start and downstream gene identifiers .
the regulog object combines several regulons , controlled by orthologous regulators , that were reconstructed in a set of closely related genomes .
similar to the regulon object , the general information about regulator , effector and metabolic pathway is available for the regulog object . in addition
, the taxonname property describes the name of ncbi taxon representing all genomes analyzed in a given regulog .
finally , the regulogcollection object represents the highest level in the regprecise hierarchical data organization .
there are six types of collections available in regprecise : by taxonomy , orthologous tf , tf family , rna regulatory family , effector molecule of a regulator and regulated metabolic pathway .
the collectiontype property of the regulogcollection object encodes the type of collection and can possess one of the following values :
pathway. several types of collections , such as collection by effector and by metabolic pathway , have two - level hierarchical structure , and thus , the classname property representing the upper level is provided in addition to the collection name .
the developed web services api enables programmatic access to the whole content of the regprecise database .
the api is implemented as a set of restful web services providing data in either javascript object notation ( json ) or extensible markup language ( xml ) , two of the most popular formats . the base uniform resource locator ( url ) for all web services is http://regprecise.lbl.gov / services / rest/. the current version of regprecise web services api includes 14 resources that can be classified into four categories ( table 1 ) .
the core resources provide access to the regulators ( genes encoding either tfs or rna motifs ) , target regulated genes and sites ( either tf - binding sites or rna regulatory elements ) .
these three resources together provide complete information about the content of a particular regulon and can be queried by regulon identifier . at the same time , if a user is interested in all genes regulated by orthologs of a particular tf in a group of closely related genomes , the genes resource can be queried by an identifier of a corresponding regulog .
the regulog and regulon resources can be used to obtain summary information about the intrinsic attributes of a regulog / regulon , such as the associated metabolic pathway ( or biological process ) , effector molecules , the regulation mode ( activation or repression ) , the regulation type ( tf or rna ) and regulator family .
table 1.list of resources available in regprecise web services api 1.0resourcesdescriptioncore resources /regulatorsrepresents a list of analyzed regulators that belong to either a given regulon or regulog .
/genesrepresents a list of regulated genes that belong to either a given regulon or regulog .
/sitesrepresents a list of tf - binding sites or rna regulatory elements that belong to either a given regulon or regulog .
/regulonrepresents a regulon.navigation resources /regulogcollectionsrepresents various types of regulog classifications : by taxonomic group , orthologous tf , tf family , rna regulatory element , metabolic pathway or biological process , effector molecule or environmental signal .
/regulogsrepresents a list of regulogs in a collection of a given type and identifier .
/regulonsrepresents a list of regulons in either a particular regulog or a genome.statistics resources /regulogcollectionstatsrepresents general statistics on regulog collections of a particular type .
/genomestatsrepresents general statistics on genomes that have at least one reconstructed regulon.utility resources /searchregulonssearch regulons by the name or locus tag of either regulator or target regulated genes .
/releaserepresents the version and the release date of the current version of regprecise . list of resources available in regprecise web services api 1.0 the navigation resources allow traversing through the hierarchical organization of the regprecise data ( table 1 ) . the list of the available regulog collections can be retrieved for each of these types using the regulogcollections resource .
subsequently , the list of regulogs that belong to a particular collection can be obtained by the regulogs resource .
it is important that the collection identifiers are unique only within the space of regulog collections of a particular type .
thus in addition to these identifiers , it is necessary to provide the type of a collection as a parameter in a query .
finally , a list of regulons analyzed for a particular tf of rna motif in a set of closely related genomes can be accessed by the regulons resource given regulog identifier .
the alternative navigation route starts from a list of genomes that have at least one reconstructed regulon .
the same regulons resource can be used to get a list of all reconstructed regulons for a particular genome . to get an overview of the regprecise content
, we developed two resources providing the general statistics for regulog collections ( regulogcollectionstats resource ) and genomes ( genomestats resource ) .
the statistics includes the number of genomes , reconstructed regulogs , regulons , and regulatory sites for the tfs and rna elements .
finally , the utility resources allow for searching for regulons by locus tags of the target regulated genes or tfs ( searchregulons resource ) .
the searchextregulons resource takes ncbi taxonomy i d of a genome and comma - separated list of gene locus tags and returns the non - redundant list of regulons that contain at least one of the provided genes .
in particular , this resource can be used for automatic validation of gene clusters reconstructed by the analysis of expression data . the current version of the regprecise database underlying the web services api can be obtained by the release resource .
first , we provide a template program in perl that can be run to access several of the web services and parse the output data .
the program is organized in two perl scripts : ( i ) regpreciseadapter.pma perl module that provides access to the individual web services and ( ii ) regulons.plan example of workflow that can be implemented using a combination of several web services .
both scripts can be easily modified to access all the web services available . at the same time , each web service is accompanied with an example of accessing api using curl command - line tool .
in this study , we provide two examples of the possible scenarios of using regprecise web services api . scenario 1obtaining information on a trn available for a particular genome . to check the availability of regulatory interactions for a given genome
, the user can query the genomes resource . by analyzing the output for the presence of the ncbi taxonomy i d of the genome of interest
for instance , the ncbi taxonomy i d of shewanella baltica os155 is 325240 , which corresponds to the internal genome identifier genomeid = 7 .
the list of all reconstructed regulons in this genome can be retrieved by querying regulons?genomeid = 7 .
analysis of the regulationtype property of each regulon in the output will show that 63 regulons are regulated by tfs , whereas 14 regulons are controlled by rna regulatory elements . among tf - operated regulons , the tryptophane regulon trpr has regulonid = 6378 .
scenario 2obtaining all genes that are regulated by a particular rna motif in any genome .
analysis of the regulogcollections?collectiontype = rnafam query output identifies the corresponding regulog collection ( collectionid = 25 ) .
list of all reconstructed regulogs in this collection can be retrieved by querying regulogs?collectiontype = rnafam&collectionid = 25 . finally , by iterating through each regulog
, the complete list of genes regulated by fmn riboswitch can be retrieved by genes resource by providing regulog identifier as a parameter , e.g. genes?regulogid = 1450 .
we are currently working on the automatic conservative propagation of all regulons inferred in the reference set of genomes to all closely related genomes from the same taxonomic group .
we will develop new web services to enable programmatic access to the results of propagation .
this work was supported by the office of science , office of biological and environmental research , of the us department of energy ( doe ) under contract no .
[ de - ac02 - 05ch11231 ] , as part of the doe systems biology knowledgebase , and under contract no .
[ de - sc0004999 ] with sanford - burnham medical research institute and lawrence berkeley national laboratory , as part of genomic science program .
Output:
| web services application programming interface ( api ) was developed to provide a programmatic access to the regulatory interactions accumulated in the regprecise database ( http://regprecise.lbl.gov ) , a core resource on transcriptional regulation for the microbial domain of the department of energy ( doe ) systems biology knowledgebase .
regprecise captures and visualize regulogs , sets of genes controlled by orthologous regulators in several closely related bacterial genomes , that were reconstructed by comparative genomics .
the current release of regprecise 2.0 includes > 1400 regulogs controlled either by protein transcription factors or by conserved ribonucleic acid regulatory motifs in > 250 genomes from 24 taxonomic groups of bacteria .
the reference regulons accumulated in regprecise can serve as a basis for automatic annotation of regulatory interactions in newly sequenced genomes .
the developed api provides an efficient access to the regprecise data by a comprehensive set of 14 web service resources .
the regprecise web services api is freely accessible at http://regprecise.lbl.gov/regprecise/services.jsp with no login requirements . |
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